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Predictors of two-year mortality in Asian patients with heart failure and preserved ejection fraction
Predictors of Two-year Mortality in Asian Patients with Heart Failure and Preserved Ejection Fraction Jonathan Yap, David Sim, Choon Pin Lim, Shaw Yang Chia, Yun Yun Go, Fazlur Rehman Jaufeerally, Ling Ling Sim, Reginald Liew, Chi-Keong Ching PII: DOI: Reference:
S0167-5273(15)00090-X doi: 10.1016/j.ijcard.2015.01.063 IJCA 19624
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
3 October 2014 9 December 2014 25 January 2015
Please cite this article as: Yap Jonathan, Sim David, Lim Choon Pin, Chia Shaw Yang, Go Yun Yun, Jaufeerally Fazlur Rehman, Sim Ling Ling, Liew Reginald, Ching Chi-Keong, Predictors of Two-year Mortality in Asian Patients with Heart Failure and Preserved Ejection Fraction, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.01.063
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ACCEPTED MANUSCRIPT Predictors of Two-year Mortality in Asian Patients with Heart Failure and Preserved Ejection Fraction
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Jonathan Yap MBBS, MRCP1, David Sim MBBS, MRCP 1, Choon Pin Lim MBBS, MRCP 1, Shaw Yang Chia1, Yun Yun Go MBBS, MRCP 1, Fazlur Rehman Jaufeerally
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MBBS, MRCP 2, Ling Ling Sim1, Reginald Liew MBBS, MRCP 3, Chi-Keong Ching
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MBBS, MRCP 1,3
Department of Cardiology, National Heart Centre Singapore
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Department of Internal Medicine, Singapore General Hospital
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Duke-NUS Graduate Medical School, Singapore
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Dr Chi-Keong Ching
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Corresponding author:
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National Heart Centre Singapore
Mistri Wing, 17 Third Hospital Avenue Singapore 168752
Tel. +65 67048963
Fax. +65 68449069
Email: [email protected]
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ACCEPTED MANUSCRIPT ABSTRACT
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Introduction
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Mortality in patients with heart failure and preserved ejection fraction (HFpEF) remains high. Data from Asia is lacking. We aim to study the impact of ethnicity and other
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predictors of mortality in patients admitted for HFpEF in a multi-ethnic Asian country.
Material and methods
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Consecutive patients admitted to two local institutions with heart failure and ejection fraction ≥50% on transthoracic echocardiogram from Jan 2008 to Dec 2009 were
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included. All patients were followed-up for 2 years. Overall mortality was obtained from
Results
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the national registry of deaths in our country.
A total of 1960 patients with heart failure were included. 751 (38.3%) patients had HFpEF. Overall mortality at two years was 26.6% (n=200) compared to 37.1% (n=449) in patients with reduced ejection fraction (HR 0.618 (95% CI 0.508-0.753), p<0.001). Ethnicity did not predict mortality. On multivariable Cox regression analysis, significant predictors of two-year mortality in HFpEF patients were older age (HR 1.027 (1.0111.044)), prior myocardial infarction (HR 1.577 (1.104-2.253)), prior stroke (HR 1.475 (1.055-2.061)), smoking (HR 1.467 (1.085-1.985)), higher creatinine levels (HR 1.002 (1.001-1.003)) and use of mineralocorticoid receptor antagonists (HR 1.884 (1.226-
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ACCEPTED MANUSCRIPT 2.896)). Use of warfarin (HR 0.506 (0.304-0.842)) and statins (HR 0.585 (0.435-0.785))
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were associated with significantly lower mortality.
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Conclusions
In our Asian population presenting with HFpEF, two-year mortality was 26.6%. Ethnicity
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did not predict mortality. Older age, prior myocardial infarction, prior stroke, smoking,
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and higher creatinine levels were found to be significant predictors of mortality.
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Keywords: Heart failure; Preserved ejection fraction; Mortality; Ethnicity
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HF-Heart failure
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Abbreviations
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HFpEF- Heart failure with preserved ejection fraction HFrEF- Heart failure with reduced ejection fraction SCDB- Singapore Cardiac DataBank DRG- Diagnosis-related group
NRDO- National Registry of Diseases Office MI- Myocardial infarction ACE-I- Angiotensin converting enzyme inhibitors ARB- Angiotensin receptor blockers
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ACCEPTED MANUSCRIPT INTRODUCTION Heart failure (HF) occurs in patients with preserved ejection fraction (EF) (1). This
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entity, commonly known as heart failure with preserved ejection fraction (HFpEF), has
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been increasing in prevalence and accounts for about half of all heart failure presentations (2). HFpEF is associated with mortality rates higher than the general population (3).
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Registries such as the Acute Decompensated Heart Failure National Registry (ADHERE)
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(4) and the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) (5) showed similar 60-90 day mortality among
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HFpEF patients compared to those with heart failure and reduced EF (HFrEF) (5). Previous studies looking at longer-term mortality also yielded mixed results. Several
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registry/population-based studies showed similar longer-term mortality rates between both groups (6-8), while others (2,9), including a recent meta-analysis (9), showed better
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outcomes amongst those with HFpEF (2,9).
Ethnicity has been shown to play an important role in mortality outcomes in heart failure (10-12). Previous studies in Asian patients with heart failure showed increased adverse outcomes in Malays and Indians compared to Chinese, but these did not focus on patients with HFpEF (11-12). Furthermore, the ADHERE registry showed patients from Asia were younger and had more severe clinical symptoms when compared to western cohorts (13,14). The impact of ethnicity as well as other predictors of mortality has hitherto not been well studied in Asian patients with HFpEF. We report the clinical demographics and 2-year mortality of patients admitted with HFpEF compared to those with HFrEF in a
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ACCEPTED MANUSCRIPT multi-ethnic Asian country, and investigate the impact of ethnicity and other predictors
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on mortality.
MATERIAL AND METHODS
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Singapore is a multi-ethnic city-state in Asia comprising 5.31 million people (74%
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Chinese, 13% Malay, 9% Indian) (15). Tertiary care in Singapore is served by an efficient healthcare network of public hospitals accounting for 77% of all hospital
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admissions (16). The Singapore Cardiac Databank (SCDB) collects a national registry of various cardiovascular diseases as described previously (17, 18). The SCDB Heart
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Failure (SCDB-HF) registry prospectively collects data on all heart failure admissions to all public hospitals in Singapore starting from 1 January 2008. The registry collects
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information on demographics, comorbidities, medical history, clinical characteristics, initial evaluations, laboratory and imaging results, treatment and discharge outcomes. All consecutive patients ≥21 years and admitted with the diagnosis-related group (DRG) code 252 (Heart Failure) will be included in the registry. Data were collected by trained coordinators using a standardized case report form, entered into an electronic database and subsequently internally and externally validated. Ejection fraction was obtained from transthoracic echocardiogram within 1 month of the admission. In this registry, the optimal echocardiographic method of assessing EF for each case was determined by the cardiologist reporting the echocardiogram and not limited to one particular method. Registry participation did not alter any treatment or medical care and was not linked to
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ACCEPTED MANUSCRIPT specific therapy/medication. The study was approved by the institutional review board of
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the respective institutions. The study complies with the Declaration of Helsinki.
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Study Population
We identified 2176 consecutive patients who were admitted with DRG code 252 (Heart
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Failure) from two institutions in the SCDB-HF registry from 1 Jan 2008 to 31 Dec 2009.
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HFpEF was defined as heart failure patients with EF≥50% and ≥grade 1 diastolic dysfunction on the echocardiogram or NT-proBNP level > 220pg/ml. 55 patients were
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excluded due to incomplete follow-up; 93 patients with no recent documented EF and 68
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patients with EF≥50% that did not fulfill the criteria were excluded.
Outcomes
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All mortality data in Singapore are kept by the National Registry of Diseases Office (NRDO). All patients were followed-up for 2 years. Mortality data and cause of death was obtained from NRDO. Primary outcome measure was 2-year all-cause mortality and secondary outcome measures were 2-year cardiovascular mortality, in-hospital mortality and length of stay.
Statistical Analysis Data was analyzed using the Statistical Package for the Social Sciences (SPSS®, version 16.0). The demographic and risk factor profile of the study population was characterized using descriptive statistics. All parameters analysed were taken at admission with the exception of medications which were taken on discharge. The 2 test was used to
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ACCEPTED MANUSCRIPT compare categorical variables and the t-test used to investigate the relationship between continuous variables between the 2 groups. Cox proportional hazard modeling was
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applied to all-cause and cardiovascular mortality. Variables significant on univariate
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analysis (p<0.05) were selected for the multivariate models. Multivariate Cox proportional hazard models were run separately for each group to calculate the hazard
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ratios and associated confidence intervals for mortality for the respective variable. A
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separate multivariate analysis using variables with p<0.1 was performed as well. A p
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value of <0.05 was taken to be statistically significant.
RESULTS
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Study population
A total of 1960 patients were analysed in the study (Table 1). 38.3% (n=751) of these
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patients had HFpEF. The HFpEF group had a significantly higher proportion of patients of Chinese ethnicity and a lower proportion of Malay ethnicity compared to patients with HFrEF. HFpEF patients were also significantly older and had a significantly higher proportion of females. HFpEF patients had a lower proportion of coronary artery disease, previous myocardial infarction, diabetes, hyperlipidemia and peripheral vascular disease, and a higher proportion of atrial fibrillation, hypertension and stroke.
Patients with HFpEF presented with a higher systolic blood pressure, lower diastolic blood pressure, lower heart rate and narrower QRS duration on ECG. They also had a lower creatinine, hemoglobin and NT-proBNP level.
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Outcomes
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The all-cause mortality rate of patients with HFpEF at 2 years was 26.6% (n=200)
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compared to 37.1% (n=449) of patients with HFrEF (HR 0.668 (95% CI 0.566-0.790), p<0.001). This was significant even on multivariate analysis (HR 0.618 (95% CI 0.508-
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0.753), p<0.001). See Fig 1.
The cardiovascular mortality at 2 years in patients with HFpEF was 13.3% (n=100)
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compared to 24.7% (n=299) in patients with HFrEF (HR 0.503 (95% CI 0.401-0.631), p<0.001). This was significant even on multivariate analysis (HR 0.535 (95% CI 0.411-
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0.696), p<0.001). Noncardiovascular mortality accounted for 50.0% (100/200) of overall
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mortality in HFpEF patients compared to 33.4% (150/449) in HFrEF patients (p=0.012).
There was no significant difference in in-hospital mortality rate of patients with HFpEF compared to those with HFrEF (1.2% (n=9) vs 1.1% (n=13), p=0.801). The average length of stay of patients with HFpEF was 5.7 days (SD 5.3) compared to 5.1 days (SD 4.0) in patients with HFrEF (p=0.022). Between the HFpEF and HFrEF cohort, there were no significant differences in intensive care unit admissions (1.2% (n=9) vs 1.9% (n=23), p=0.232), need for inotropes (1.1% (n=8) vs 2.1% (n=25), p=0.094), mechanical ventilation (0.5% (n=4) vs 1.4% (n=17), p=0.068) or dialysis (0.3% (n=2) vs 0.4% (n=5), p=0.595). On discharge, 96.7% (726/751) of HFpEF patients and 96.9% (1172/1209) of HFrEF reported improvements in symptoms (p=0.741). There was a mild overall increase
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ACCEPTED MANUSCRIPT in creatinine levels on discharge in both the HFpEF (9.4%) and HFrEF group (7.2%) but
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this was not significant between both groups (p=0.341).
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Predictors of 2-year mortality
Table 2 highlights the differences in characteristics of patients with HFpEF who died as
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compared to survivors, while Table 3 highlights the significant multivariate predictors of
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overall and cardiovascular mortality in all patients and patients with HFpEF and HFrEF.
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In the overall cohort, older age, prior MI, stroke, peripheral vascular disease, higher creatinine levels, reduced ejection fraction and use of mineralocorticoid receptor
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antagonists were associated with significantly increased mortality. Higher systolic blood pressure, higher sodium levels and use of angiotensin converting enzyme inhibitors
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(ACE-I) /angiotensin receptor blockers (ARB), beta-blockers, diuretics, aspirin and statins were associated with decreased mortality. Ethnicity was not a significant predictor of overall mortality (Malay vs Chinese: HR 0.993 (0.801-1.231), p=0.949; Indian vs Chinese: HR 0.810 (0.626-1.048), p=0.109) or cardiovascular mortality.
In patients with HFpEF, older age (HR 1.027 (1.011-1.044), p<0.001), prior MI (HR 1.577 (1.104-2.253), p=0.012), prior stroke (HR 1.475 (1.055-2.061), p=0.023), history of cigarette smoking (HR 1.467 (1.085-1.985), p=0.013), higher creatinine levels (HR 1.002 (1.001-1.003) p<0.001) and use of mineralocorticoid receptor antagonists (HR 1.884 (1.226-2.896), p=0.004) were associated with significantly increased mortality. Use of warfarin (HR 0.506 (0.304-0.842), p=0.009) and statins (HR 0.585 (0.435-0.785),
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ACCEPTED MANUSCRIPT p<0.001) were associated with decreased mortality. The 2-year overall mortality in Chinese, Malay and Indian patients was 28.7% (n=160), 22.0% (n=20) and 16.7% (n=15)
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respectively. Ethnicity was not predictive of either overall (Malay vs Chinese: HR 0.818
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(0.548-1.220), p=0.324; Indian vs Chinese: HR 0.779 (0.517-1.175), p=0.234) or
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cardiovascular mortality.
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In patients with HFrEF, older age, prior myocardial infarction (MI), diabetes mellitus, stroke and peripheral vascular disease, higher creatinine levels were associated with
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significantly increased mortality. On the other hand, patients with higher systolic blood pressure, higher sodium levels and prescribed with ACE-I/ARB, beta-blockers and
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diuretics were associated with decreased mortality. Ethnicity also did not predict allcause (Malay vs Chinese: HR 1.045 (0.818-1.335), p=0.724; Indian vs Chinese: HR
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0.965 (0.718-1.298), p=0.815) or cardiovascular mortality.
Inclusion of addition variables with p<0.1 into the multivariate model did not change the predictors of overall and cardiovascular mortality for the entire cohort and patients with HFrEF. For patients with HFpEF, higher systolic blood pressure and use of betablockers and antiplatelets were found to be additional predictors of lower overall mortality and higher systolic blood pressure was found to be an additional predictor of lower cardiovascular mortality.
A sub-group analysis was performed in patients with EF 40-49% and <40%. In patients with heart failure and EF 40-49%, significant predictors of overall mortality were
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ACCEPTED MANUSCRIPT presence of coronary artery disease and stroke while significant predictors of cardiovascular mortality were stroke and lower diastolic blood pressure. In patients with
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EF <40%, older age, prior MI, diabetes mellitus, peripheral vascular disease and higher
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creatinine levels were associated with higher overall and cardiovascular mortality while higher systolic blood pressure, higher sodium levels and the use of ACE-I/ARB,
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betablockers and diuretics were associated with lower overall and cardiovascular
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mortality.
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DISCUSSION
To our knowledge, we report for the first time, the clinical demographics, treatment and
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impact of ethnicity and other predictors on long-term mortality of patients admitted for
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HFpEF in a multi-ethnic Asian country.
HFpEF is a common entity, comprising of 40% of all heart failure admissions in our multi-ethnic population. The reported prevalence of HFpEF varies from 26% (7) to more than 50% (4,8,19). The study from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) showed a prevalence of 26% in the Japanese (7). The OPTIMIZE-HF and ADHERE (4,5) studies, both of which reported a prevalence of about 50%, defined HFpEF as EF≥40%. These differences in prevalence are largely due to the differences in the cohort characteristics, the setting of the study as well as the definition of HFpEF.
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ACCEPTED MANUSCRIPT In our study, there was a greater proportion of Chinese and a lower proportion of Malays amongst patients with HFpEF compared to HFrEF. Possible postulates include the
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differences in pathogenesis between HFpEF and HFrEF, and the differences in lifestyle,
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risk factors and genetic variations amongst the different ethnicities (20). The rest of the characteristics of patients with HFpEF in our multi-ethnic Asian cohort were largely
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similar to those shown in other studies. Patients with HFpEF were older and more likely
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to be female, as well as having a higher incidence of hypertension and lower incidence of coronary artery disease in our study. This is typically seen in most cohorts of HFpEF
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patients (2,4,5,7). Our HFpEF patients also had lower NT-proBNP levels. Lower NTproBNP levels has also been well described in HFpEF patients (21, 22, 23), reflecting
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less ventricular volume overload and lower diastolic wall stress as a result of concentric LV remodelling (23,24). Lower NT-proBNP in the HFpEF group might also be explained
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by a more frequent misdiagnosis in these patients, with more patients without heart failure in the HFpEF group (25,26).
Our study demonstrated that HFpEF is not a benign entity, with a 2-year mortality rate of 26.6%, albeit lower than in patients with HFrEF. The ADHERE registry showed reduced in-hospital mortality among patients with HFpEF (2.8% vs 3.9%) compared to REF patients. The OPTIMIZE-HF registry also showed lower inpatient mortality for HFpEF patients but similar 60-90 day mortality of about 10%. Results from studies on longerterm mortality showed differing outcomes. The JCARE-CARD registry report a similar mortality of about 19% after a mean follow-up of 2.4 years (7). However, the Metaanalysis Global Group in Chronic Heart Failure (MAGGIC) meta-analysis showed higher
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ACCEPTED MANUSCRIPT long-term mortality rates in patients with HFrEF. It is difficult to compare mortality rates amongst different studies for the reasons earlier mentioned (eg. different cohorts and
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definitions). However, despite the differences in studies, the mortality rate for HFpEF
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remains high.
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In our study, cardiovascular deaths accounted for 51.4% of all mortality in HFpEF
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patients. This is similar to the proportion of 51-60% found in other epidemiological studies. (8,27,28). The proportion of non-cardiovascular deaths in our HFpEF patients
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was significantly higher than that of our HFrEF patients (49% vs 33%). Once again, this was similar to that found in other studies (~ 50% vs ~ 30%) (27-29). This difference has
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HFpEF patients (27).
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been shown to be mainly as a result of fewer coronary artery disease related deaths in
Our study is the first to describe the effect of ethnicity on long-term outcomes in patients with HFpEF in a multi-ethinic Asian population. Ethnicity has been previously shown to be an important factor in influencing mortality in heart failure (10-11). Data from the Studies of Left Ventricular Dysfunction (SOLVD) trials show higher mortality among the black compared to white patients (10). The Multi-Ethnic Study of Atherosclerosis (MESA) study showed the risk of incident HF to be different amongst the races (20). In several local studies (11,12,25), Malays and Indians had proportionally higher admission rates for heart failure than Chinese (11,12,25). One study found that Malay race was a significant predictor of mortality compared to Chinese race (11) but another did not show any significant ethnic differences in mortality (12). A local study in patients with HFrEF
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ACCEPTED MANUSCRIPT also did not show any ethnic differences in mortality (30). As mentioned, these studies did not specifically look at patients with HFpEF but accounted for all heart failure
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patients. The majority of HFpEF studies involve Western cohorts with little
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representation from Asia. In our study, ethnicity was not a significant predictor of longterm mortality in patients with HFpEF. The pathogenesis of HFpEF and HFrEF are
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are not extendable to patients with HFpEF (31).
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markedly different and results from previous heart failure studies including all-comers
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Interestingly, our study found that a longer QRS duration was associated with increased cardiovascular mortality (but not overall mortality) in HFpEF patients. Many previous
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studies have shown the association between longer QRS duration and mortality in heart failure patients (32,33) but these did not specifically look at patients with HFpEF. This
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observation may reflect the deleterious effect of electrical dysynchrony and this raises an interesting hypothesis for further research. In our study, other clinical predictors of mortality in HFpEF patients included advanced age, prior MI, prior stroke, smoking and higher creatinine levels. These are similar to that found in other studies (see Table 4).
Due to the observational nature of the registry, it is difficult to draw any firm conclusions regarding the effects of medication on outcomes. To date, there is little evidence of benefit for majority of the heart failure medications used in the treatment of HFpEF (3438). There was some initial promise seen for aldosterone antagonists. However, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial showed improved left ventricular diastolic function but no improvements in symptoms or exercise
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ACCEPTED MANUSCRIPT capacity with the use of spironoalctone (39). The recently concluded Treatment of Preserved Cardiac function heart failure with an Aldosterone antagonist (TOPCAT) trial
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using spironolactone showed a reduction in hospitalisations for heart failure but did not
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show any reduction in cardiovascular mortality in patients with HFpEF (40). No treatment has been shown to reduce mortality in HFpEF and guidelines suggest diuretics
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for symptom relief and to treat underlying hypertension, myocardial ischemia and rapid
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AF (41).
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The results of our study shed important insights in the management of this group of patients admitted for HFpEF, allowing the clinician to pay particular attention to those at
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higher risk of adverse outcomes. The strengths of our study are the large study population as well as being the first study to provide valuable knowledge on HFpEF patients in the
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setting of a multi-ethnic Asian country. Less than 5% of the study cohort did not have their EF assessed. Furthermore, our national registry provided robust mortality data.
Limitations
Our study has several limitations inherent to most registry studies. Firstly, the definition of HFpEF was based on an EF ≥50% and evidence of diastolic dysfunction or raised NTproBNP levels. In light of the registry nature of the study, there are limitations to having a more precise definition. In fact, most other major HFpEF studies relied primarily on a EF cut-off (2,4,5,7). We have sought to be more precise with our inclusion criteria with the inclusion of diastolic function assessment or raised NT-proBNP levels in line with guidelines (1) and several randomized controlled trials (39,40). Secondly, missing data on
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ACCEPTED MANUSCRIPT clinical variables may have introduced bias, however, with the exception of NT-proBNP results, there was <3% missing data for the rest of the variables. About 20% of the NT-
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proBNP results were not available and this variable was not included in the multivariate
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models. Thirdly, our cohort was limited to hospitalized patients; HF presentations in the ambulatory/community setting may have different characteristics. Once again, this was
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similar to other major studies on HFpEF patients (2,4,5,7). Fourthly, socio-economic data
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was not collected as part of the registry and this may confound comparisons. Lastly, restriction to patients with DRG code of 252 may result in the possibility of
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misclassification.
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CONCLUSIONS
In our Asian population presenting with heart failure and preserved ejection fraction,
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two-year mortality was 26.6%. Ethnicity did not predict mortality. Older age, prior myocardial infarction, prior stroke, smoking and higher creatinine levels were significant predictors of mortality.
CONFLICT OF INTEREST
The authors of the study have no conflicts of interest to declare
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20. Bahrami H, Kronmal R, Bluemke DA, Olson J, Shea S, Liu K, Burke GL, Lima JA. Differences in the incidence of congestive heart failure by ethnicity: the multiethnic study of atherosclerosis. Arch Intern Med. 2008;168:2138-45. 21. Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P, Omland T, Storrow AB, Krishnaswamy P, Abraham WT, Clopton P,Steg G, Aumont MC, Westheim A, Knudsen CW, Perez A, Kamin R, Kazanegra R, Herrmann HC, McCullough PA. Bedside B-type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly multinational study. J Am Coll Cardiol 2003;41:2010 – 2017. 22. Iwanaga Y, Nishi I, Furuichi S, Noguchi T, Sase K, Kihara Y, Goto Y, Nonogi H. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with
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23. van Veldhuisen DJ, Linssen GC, Jaarsma T, van Gilst WH, Hoes AW, Tijssen JG,
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Paulus WJ, Voors AA, Hillege HL. B-type natriuretic peptide and prognosis in heart failure patients with preserved and reduced ejection fraction. J Am Coll
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Cardiol. 2013;61:1498-506.
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24. Cheung BM, Kumana CR. Natriuretic peptides--relevance in cardiovascular
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25. Carlsen CM, Bay M, Kirk V, Gøtze JP, Køber L, Nielsen OW. Prevalence and prognosis of heart failure with preserved ejection fraction and elevated N-terminal
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pro brain natriuretic peptide: a 10-year analysis from the Copenhagen Hospital Heart Failure Study. Eur J Heart Fail. 2012;14:240-7.
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26. Paulus WJ, Van Ballegoij JJ. Treatment of heart failure with normal ejection fraction: an inconvenient truth. J Am Coll Cardiol. 2010;55:526–37. 27. Chan MM, Lam CS. How do patients with heart failure with preserved ejection fraction die? Eur J Heart Fail. 2013;15:604-13. 28. Henkel DM, Redfield MM, Weston SA, Gerber Y, Roger VL. Death in heart failure: a community perspective. Circ Heart Fail. 2008;1:91–97. 29. Hamaguchi S, Kinugawa S, Sobirin MA, Goto D, Tsuchihashi-Makaya M, Yamada S, Yokoshiki H, Tsutsui H. Mode of death in patients with heart failure and reduced vs. preserved ejection fraction: report from the registry of hospitalized heart failure patients. Circ J. 2012;76:1662–1669 .
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ACCEPTED MANUSCRIPT 30. Seow SC, Chai P, Lee YP, Chan YH, Kwok BW, Yeo TC, Chia BL. Heart failure mortality in Southeast Asian patients with left ventricular systolic dysfunction. J
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Card Fail. 2007;13:476-81.
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31. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J. 2011;32:670.
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32. Wang NC, Maggioni AP, Konstam MA, Zannad F, Krasa HB, Burnett JC Jr,
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Grinfeld L, Swedberg K, Udelson JE, Cook T, Traver B, Zimmer C, Orlandi C, Gheorghiade M; Efficacy of Vasopressin Antagonism in Heart Failure Outcome
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Study With Tolvaptan (EVEREST) Investigators. Clinical implications of QRS duration in patients hospitalized with worsening heart failure and reduced left
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ventricular ejection fraction. JAMA. 2008;299:2656-66.
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ACCEPTED MANUSCRIPT 33. Iuliano S, Fisher SG, Karasik PE, Fletcher RD, Singh SN; Department of Veterans Affairs Survival Trial of Antiarrhythmic Therapy in Congestive Heart
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Failure. QRS duration and mortality in patients with congestive heart failure. Am
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Heart J. 2002;143:1085-91.
34. Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J; PEP-
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CHF Investigators. The perindopril in elderly people with chronic heart failure
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(PEP-CHF) study. Eur Heart J. 2006;27:2338-45.
35. Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR,
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Anderson S, Donovan M, Iverson E, Staiger C, Ptaszynska A; I-PRESERVE Investigators Irbesartan in patients with heart failure and preserved ejection
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fraction. N Engl J Med. 2008;359:2456-67. 36. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ,
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Michelson EL, Olofsson B, Ostergren J; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:77781.
37. van Veldhuisen DJ, Cohen-Solal A, Böhm M, Anker SD, Babalis D, Roughton M, Coats AJ, Poole-Wilson PA, Flather MD; SENIORS Investigators. Betablockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol. 2009;53:2150-8.
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ACCEPTED MANUSCRIPT 38. Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, Love TE, Aronow WS, Adams KF Jr, Gheorghiade M. Effects of digoxin on morbidity and
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mortality in diastolic heart failure: the ancillary digitalis investigation group trial.
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Circulation. 2006;114:397-403.
39. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke
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W, Duvinage A, Stahrenberg R, Durstewitz K, Löffler M, Düngen HD, Tschöpe
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C, Herrmann-Lingen C, Halle M, Hasenfuss G, Gelbrich G, Pieske B; Aldo-DHF Investigators. Effect of spironolactone on diastolic function and exercise capacity
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Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis
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EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. 41. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, PooleWilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur J Heart Fail. 2008;10:933-89.
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ACCEPTED MANUSCRIPT Table 1. Demographics and clinical characteristics of study population HFpEF
HFrEF
(n=1960)
(n=751)
(n=1209)
69.1 (12.2)
73.1 (10.6)
PT
Overall
Mean age (SD)
53.1
Race 70.7
Malay Indian
66.6 (12.5)
<0.001
64.1
<0.001 0.011
74.2
68.6
15.5
12.1
17.6
11.9
12.0
11.9
1.8
1.7
1.9
45.7
41.0
48.6
0.001
28.9
16.2
36.7
<0.001
Atrial fibrillation
25.8
34.0
20.7
<0.001
Diabetes mellitus
52.0
47.1
55.1
0.001
Hypertension
73.5
80.3
69.3
<0.001
Hyperlipidemia
62.0
57.9
64.6
0.003
Stroke
16.2
18.4
14.8
0.037
Peripheral vascular disease
6.8
5.3
7.7
0.043
Chronic obstructive pulmonary disease
12.6
14.2
11.5
0.074
Ever smoker
38.1
26.5
45.2
<0.001
Systolic blood pressure (SD) (mmHg)
139 (30)
143 (30)
136 (30)
<0.001
Diastolic blood pressure (SD (mmHg))
76 (18)
73 (17)
78 (19)
<0.001
Heart rate (SD)
88 (23)
84 (24)
90 (22)
<0.001
QRS (SD) (ms)
101 (25)
94 (20)
106 (27)
<0.001
MA
NU
Chinese
35.3
SC
Male
RI
Demographics
P value*
D
Others
Prior coronary artery disease
AC CE P
Prior myocardial infarction
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Clinical Characteristics
25
ACCEPTED MANUSCRIPT 9720 (14030)
5814 (10147)
12323 (15619)
<0.001
137 (104)
129 (100)
142 (106)
0.005
Sodium (SD) (mmol/L)
136 (7)
136 (5)
136 (8)
0.246
Potassium (SD) (mmol/L)
4.2 (1.2)
4.2 (0.8)
4.3 (1.3)
0.252
Hemoglobin (SD) (g/dL)
12.2 (3.6)
11.7(2.0)
12.6(4.2)
<0.001
41.9
55.7
<0.001
Discharge Medications
SC
RI
Creatinine (SD) (umol/L)
PT
NT-proBNP (SD) (pg/mL)**
50.4
ARB
20.1
20.2
20.0
0.905
ACE inhibitor/ARB
68.9
59.9
74.4
<0.001
59.2
50.1
64.9
<0.001
16.7
8.3
21.9
<0.001
47.5
39.9
52.2
<0.001
83.3
77.9
86.7
<0.001
23.1
17.2
26.7
<0.001
51.3
40.3
58.1
<0.001
14.1
10.9
16.1
0.001
13.7
16.8
11.7
0.002
67.6
60.9
71.8
<0.001
MA
NU
ACE inhibitor
Betablocker Mineralocorticoid-receptor antagonist
D
Nitrate
TE
Diuretic
Aspirin Plavix Warfarin Statin
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Digoxin
*Comparing HFpEF vs HFrEF
**375 patients with missing data (159 with HFpEF) Mean and SD are reported for continuous data and frequency and percentages for categorical data.
26
ACCEPTED MANUSCRIPT Table 2. Baseline characteristics of patients with HFpEF who died as compared to survivors at 2 years Dead (n=200)
72.1 (10.5)
75.8 (10.1)
<0.001
34.3
38.0
0.494
SC
Male
RI
Demographics Mean age (SD)
Race 72.1
Malay
12.9
10.0
Indian
13.6
7.5
0.064
80.0
MA
NU
Chinese
1.5
2.5
39.9
44.0
0.317
13.6
23.5
0.001
Atrial fibrillation
34.1
33.5
0.736
Diabetes mellitus
48.6
43.0
0.189
Hypertension
80.9
78.5
0.378
Hyperlipidemia
59.2
54.5
0.181
Stroke
16.2
24.5
0.011
Peripheral vascular disease
4.5
7.5
0.118
Chronic obstructive pulmonary disease
13.8
15.5
0.619
Ever smoker
23.4
35.0
0.004
Systolic blood pressure (SD) (mmHg)
144 (29)
139 (31)
0.057
Diastolic blood pressure (SD) (mmHg)
73 (17)
70 (17)
0.033
Heart rate (SD)
84 (24)
85 (22)
0.668
QRS (SD) (ms)
93 (19)
96 (24)
0.051
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Others
P value
PT
Alive (n= 551)
Prior coronary artery disease
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Prior myocardial infarction
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Clinical characteristics
27
ACCEPTED MANUSCRIPT 10991 (14824)
<0.001
Creatinine (SD) (umol/L)
118 (81)
160 (131)
<0.001
Sodium (SD) (mmol/L)
137 (5)
136 (6)
0.052
Potassium (SD) (mmol/L)
4.2 (0.8)
4.3 (0.8)
0.058
Hemoglobin (SD) (g/dL)
11.9 (2.0)
11.3 (2.2)
<0.001
ARB ACE inhibitor/ARB Betablocker Mineralocorticoid-receptor antagonist
Statin
TE AC CE P
Digoxin
Warfarin
20.7
19.0
0.916
62.1
54.0
0.025
53.9
39.5
<0.001
6.5
13.0
0.004
39.2
42.0
0.586
78.9
75.0
0.188
17.6
16.0
0.530
42.5
34.5
0.038
11.6
9.0
0.330
19.6
9.0
0.001
64.6
50.5
<0.001
D
Nitrate
Plavix
0.122
NU
43.4
Aspirin
38.0
MA
ACE inhibitor
SC
Discharge Medications
Diuretic
PT
4204 (7316)
RI
NT-proBNP (SD) (pg/mL)*
*159 patients with missing data Mean and SD are reported for continuous data and frequency and percentages for categorical data.
28
ACCEPTED MANUSCRIPT
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Table 3. Multivariate predictors of 2-year overall and cardiovascular mortality in study population
Hazard Ratio
P value
Predictors
(95% CI) Overall cohort
NU
Overall cohort
SC
Predictors
Cardiovascular mortality
RI
Overall mortality
1.022 (1.014-1.030)
<0.001
Age
Prior myocardial
1.519 (1.274-1.812)
<0.001
Prior myocardial
P value
(95% CI)
1.013 (1.003-1.023)
0.009
1.455 (1.167-1.816)
0.001
Stroke
1.319 (1.024-1.700)
0.032
Systolic blood pressure
0.990 (0.985-0.995)
<0.001
QRS
1.005 (1.001-1.009)
0.014
<0.001
Creatinine
1.002 (1.002-1.003)
<0.001
0.023
Sodium
0.990 (0.982-0.999)
0.030
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Age
Hazard Ratio
infarction
PT ED
infarction 1.346 (1.106-1.639)
0.003
Peripheral vascular
1.343 (1.032-1.747)
0.028
Systolic blood pressure
0.992 (0.988-0.996)
<0.001
Creatinine
1.002 (1.001-1.002)
Sodium
0.991 (0.984-0.999)
ACE inhibitor/ARB
0.754 (0.636-0.895)
0.001
ACE inhibitor/ARB
0.722 (0.581-0.898)
0.003
Betablocker
0.791 (0.663-0.919)
0.003
Betablocker
0.781 (0.637-0.958)
0.018
Mineralocorticoid-
1.255 (1.016-1.550)
0.035
Ejection fraction (reduced
1.869 (1.437-2.433)
<0.001
receptor antagonist
AC
disease
CE
Stroke
compared to preserved)
29
Aspirin
0.799 (0.675-0.946)
0.009
Statin
0.799 (0.666-0.959)
0.016
Ejection fraction (reduced
1.618 (1.328-1.969)
<0.001
RI
0.035
SC
0.796 (0.643-0.984)
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Diuretic
PT
ACCEPTED MANUSCRIPT
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compared to preserved)
HFrEF
Age
1.018 (1.008-1.027)
<0.001
Prior myocardial
1.336 (1.091-1.636)
0.005
Age
1.011 (1.001-1.022)
0.043
Prior myocardial
1.330 (1.035-1.710)
0.026
infarction
Diabetes mellitus
1.280 (1.035-1.582)
0.023
Systolic blood pressure
0.990 (0.984-0.996)
0.002
Stroke
1.403 (1.100-1.789)
0.006
Diastolic blood pressure
0.989 (0.978-1.000)
0.047
Peripheral vascular
1.369 (1.007-1.860)
AC
CE
infarction
PT ED
HFrEF
0.045
Creatinine
1.002 (1.001-1.003)
<0.001
Systolic blood pressure
0.990 (0.985-0.996)
0.001
Sodium
0.989 (0.980-0.998)
0.012
Creatinine
1.002 (1.001-1.003)
<0.001
ACE inhibitor/ARB
0.732 (0.563-0.951)
0.019
Sodium
0.990 (0.982-0.997)
0.007
disease
30
0.001
Betablocker
0.783 (0.642-0.955)
0.016
Diuretic
0.709 (0.541-0.930)
0.013
RI
0.698 (0.565-0.864)
HFpEF
HFpEF 1.027 (1.011-1.044)
0.001
Stroke
2.058 (1.306-3.243)
0.002
Prior myocardial
1.577 (1.104-2.253)
0.012
QRS
1.013 (1.005-1.021)
0.002
Stroke
1.475 (1.055-2.061)
0.023
Creatinine
1.002 (1.001-1.003)
<0.001
Eversmoke
1.467 (1.085-1.985)
0.013
Hemoglobin
0.857 (0.770-0.955)
0.005
Creatinine
1.002 (1.001-1.003)
<0.001
Warfarin
0.364 (0.174-0.762)
0.007
Warfarin
0.506 (0.304-0.842)
0.009
Statin
0.575 (0.373-0.886)
0.012
Mineralocorticoid-
1.884 (1.226-2.896)
AC
PT ED
CE
infarction
MA
Age
NU
SC
ACE inhibitor/ARB
PT
ACCEPTED MANUSCRIPT
0.004
receptor antagonist Statin
0.585 (0.435-0.785)
<0.001
31
ACCEPTED MANUSCRIPT Table 4. Summary of predictors of all-cause mortality in HFPEF studies ADHERE (13)
Bhatia et al (4)
Ather et al (19)
Owan et al (2)
Tribouilloy
Outcome
In-hospital
PT
et al (8) 1-year mortality
2-year mortality
5-year mortality
Lower SBP
PVD
Tachycardia
Malignancy
Dysponea at rest
Dementia
High urea levels
Dialysis
levels
AC CE P
Hyponatremia
Low SBP
Older age
Older age
COPD
Female
Stroke
Malignancy
DM
DM
Dementia
Low BP
COPD
Renal insufficiency
High creatinine
Malignancy
levels Liver disease
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High creatinine
Stroke
NU
Older age
MA
Older age
D
Predictors
SC
RI
mortality
5-year mortality
Tachypnoea
Rheumatological
Anaemia
Low GFR
Hyponatremia
disorder
Absence of
High creatinine
betablocker
levels
Anaemia
Hyponatremia Anaemia
FIGURE LEGENDS Figure 1. Cox proportional hazards model for overall survival for preserved vs reduced EF
32
AC CE P
Figure 1
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
33
S0167-5273(15)00090-X doi: 10.1016/j.ijcard.2015.01.063 IJCA 19624
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
3 October 2014 9 December 2014 25 January 2015
Please cite this article as: Yap Jonathan, Sim David, Lim Choon Pin, Chia Shaw Yang, Go Yun Yun, Jaufeerally Fazlur Rehman, Sim Ling Ling, Liew Reginald, Ching Chi-Keong, Predictors of Two-year Mortality in Asian Patients with Heart Failure and Preserved Ejection Fraction, International Journal of Cardiology (2015), doi: 10.1016/j.ijcard.2015.01.063
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Predictors of Two-year Mortality in Asian Patients with Heart Failure and Preserved Ejection Fraction
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Jonathan Yap MBBS, MRCP1, David Sim MBBS, MRCP 1, Choon Pin Lim MBBS, MRCP 1, Shaw Yang Chia1, Yun Yun Go MBBS, MRCP 1, Fazlur Rehman Jaufeerally
RI
MBBS, MRCP 2, Ling Ling Sim1, Reginald Liew MBBS, MRCP 3, Chi-Keong Ching
SC
MBBS, MRCP 1,3
Department of Cardiology, National Heart Centre Singapore
2
Department of Internal Medicine, Singapore General Hospital
3
Duke-NUS Graduate Medical School, Singapore
MA
NU
1
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Dr Chi-Keong Ching
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Corresponding author:
AC CE P
National Heart Centre Singapore
Mistri Wing, 17 Third Hospital Avenue Singapore 168752
Tel. +65 67048963
Fax. +65 68449069
Email: [email protected]
1
ACCEPTED MANUSCRIPT ABSTRACT
PT
Introduction
RI
Mortality in patients with heart failure and preserved ejection fraction (HFpEF) remains high. Data from Asia is lacking. We aim to study the impact of ethnicity and other
NU
SC
predictors of mortality in patients admitted for HFpEF in a multi-ethnic Asian country.
Material and methods
MA
Consecutive patients admitted to two local institutions with heart failure and ejection fraction ≥50% on transthoracic echocardiogram from Jan 2008 to Dec 2009 were
TE
D
included. All patients were followed-up for 2 years. Overall mortality was obtained from
Results
AC CE P
the national registry of deaths in our country.
A total of 1960 patients with heart failure were included. 751 (38.3%) patients had HFpEF. Overall mortality at two years was 26.6% (n=200) compared to 37.1% (n=449) in patients with reduced ejection fraction (HR 0.618 (95% CI 0.508-0.753), p<0.001). Ethnicity did not predict mortality. On multivariable Cox regression analysis, significant predictors of two-year mortality in HFpEF patients were older age (HR 1.027 (1.0111.044)), prior myocardial infarction (HR 1.577 (1.104-2.253)), prior stroke (HR 1.475 (1.055-2.061)), smoking (HR 1.467 (1.085-1.985)), higher creatinine levels (HR 1.002 (1.001-1.003)) and use of mineralocorticoid receptor antagonists (HR 1.884 (1.226-
2
ACCEPTED MANUSCRIPT 2.896)). Use of warfarin (HR 0.506 (0.304-0.842)) and statins (HR 0.585 (0.435-0.785))
PT
were associated with significantly lower mortality.
RI
Conclusions
In our Asian population presenting with HFpEF, two-year mortality was 26.6%. Ethnicity
SC
did not predict mortality. Older age, prior myocardial infarction, prior stroke, smoking,
NU
and higher creatinine levels were found to be significant predictors of mortality.
MA
Keywords: Heart failure; Preserved ejection fraction; Mortality; Ethnicity
TE
HF-Heart failure
D
Abbreviations
AC CE P
HFpEF- Heart failure with preserved ejection fraction HFrEF- Heart failure with reduced ejection fraction SCDB- Singapore Cardiac DataBank DRG- Diagnosis-related group
NRDO- National Registry of Diseases Office MI- Myocardial infarction ACE-I- Angiotensin converting enzyme inhibitors ARB- Angiotensin receptor blockers
3
ACCEPTED MANUSCRIPT INTRODUCTION Heart failure (HF) occurs in patients with preserved ejection fraction (EF) (1). This
PT
entity, commonly known as heart failure with preserved ejection fraction (HFpEF), has
RI
been increasing in prevalence and accounts for about half of all heart failure presentations (2). HFpEF is associated with mortality rates higher than the general population (3).
SC
Registries such as the Acute Decompensated Heart Failure National Registry (ADHERE)
NU
(4) and the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) (5) showed similar 60-90 day mortality among
MA
HFpEF patients compared to those with heart failure and reduced EF (HFrEF) (5). Previous studies looking at longer-term mortality also yielded mixed results. Several
TE
D
registry/population-based studies showed similar longer-term mortality rates between both groups (6-8), while others (2,9), including a recent meta-analysis (9), showed better
AC CE P
outcomes amongst those with HFpEF (2,9).
Ethnicity has been shown to play an important role in mortality outcomes in heart failure (10-12). Previous studies in Asian patients with heart failure showed increased adverse outcomes in Malays and Indians compared to Chinese, but these did not focus on patients with HFpEF (11-12). Furthermore, the ADHERE registry showed patients from Asia were younger and had more severe clinical symptoms when compared to western cohorts (13,14). The impact of ethnicity as well as other predictors of mortality has hitherto not been well studied in Asian patients with HFpEF. We report the clinical demographics and 2-year mortality of patients admitted with HFpEF compared to those with HFrEF in a
4
ACCEPTED MANUSCRIPT multi-ethnic Asian country, and investigate the impact of ethnicity and other predictors
RI
PT
on mortality.
MATERIAL AND METHODS
SC
Singapore is a multi-ethnic city-state in Asia comprising 5.31 million people (74%
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Chinese, 13% Malay, 9% Indian) (15). Tertiary care in Singapore is served by an efficient healthcare network of public hospitals accounting for 77% of all hospital
MA
admissions (16). The Singapore Cardiac Databank (SCDB) collects a national registry of various cardiovascular diseases as described previously (17, 18). The SCDB Heart
TE
D
Failure (SCDB-HF) registry prospectively collects data on all heart failure admissions to all public hospitals in Singapore starting from 1 January 2008. The registry collects
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information on demographics, comorbidities, medical history, clinical characteristics, initial evaluations, laboratory and imaging results, treatment and discharge outcomes. All consecutive patients ≥21 years and admitted with the diagnosis-related group (DRG) code 252 (Heart Failure) will be included in the registry. Data were collected by trained coordinators using a standardized case report form, entered into an electronic database and subsequently internally and externally validated. Ejection fraction was obtained from transthoracic echocardiogram within 1 month of the admission. In this registry, the optimal echocardiographic method of assessing EF for each case was determined by the cardiologist reporting the echocardiogram and not limited to one particular method. Registry participation did not alter any treatment or medical care and was not linked to
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ACCEPTED MANUSCRIPT specific therapy/medication. The study was approved by the institutional review board of
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the respective institutions. The study complies with the Declaration of Helsinki.
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Study Population
We identified 2176 consecutive patients who were admitted with DRG code 252 (Heart
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Failure) from two institutions in the SCDB-HF registry from 1 Jan 2008 to 31 Dec 2009.
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HFpEF was defined as heart failure patients with EF≥50% and ≥grade 1 diastolic dysfunction on the echocardiogram or NT-proBNP level > 220pg/ml. 55 patients were
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excluded due to incomplete follow-up; 93 patients with no recent documented EF and 68
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patients with EF≥50% that did not fulfill the criteria were excluded.
Outcomes
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All mortality data in Singapore are kept by the National Registry of Diseases Office (NRDO). All patients were followed-up for 2 years. Mortality data and cause of death was obtained from NRDO. Primary outcome measure was 2-year all-cause mortality and secondary outcome measures were 2-year cardiovascular mortality, in-hospital mortality and length of stay.
Statistical Analysis Data was analyzed using the Statistical Package for the Social Sciences (SPSS®, version 16.0). The demographic and risk factor profile of the study population was characterized using descriptive statistics. All parameters analysed were taken at admission with the exception of medications which were taken on discharge. The 2 test was used to
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ACCEPTED MANUSCRIPT compare categorical variables and the t-test used to investigate the relationship between continuous variables between the 2 groups. Cox proportional hazard modeling was
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applied to all-cause and cardiovascular mortality. Variables significant on univariate
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analysis (p<0.05) were selected for the multivariate models. Multivariate Cox proportional hazard models were run separately for each group to calculate the hazard
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ratios and associated confidence intervals for mortality for the respective variable. A
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separate multivariate analysis using variables with p<0.1 was performed as well. A p
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value of <0.05 was taken to be statistically significant.
RESULTS
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Study population
A total of 1960 patients were analysed in the study (Table 1). 38.3% (n=751) of these
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patients had HFpEF. The HFpEF group had a significantly higher proportion of patients of Chinese ethnicity and a lower proportion of Malay ethnicity compared to patients with HFrEF. HFpEF patients were also significantly older and had a significantly higher proportion of females. HFpEF patients had a lower proportion of coronary artery disease, previous myocardial infarction, diabetes, hyperlipidemia and peripheral vascular disease, and a higher proportion of atrial fibrillation, hypertension and stroke.
Patients with HFpEF presented with a higher systolic blood pressure, lower diastolic blood pressure, lower heart rate and narrower QRS duration on ECG. They also had a lower creatinine, hemoglobin and NT-proBNP level.
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Outcomes
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The all-cause mortality rate of patients with HFpEF at 2 years was 26.6% (n=200)
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compared to 37.1% (n=449) of patients with HFrEF (HR 0.668 (95% CI 0.566-0.790), p<0.001). This was significant even on multivariate analysis (HR 0.618 (95% CI 0.508-
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0.753), p<0.001). See Fig 1.
The cardiovascular mortality at 2 years in patients with HFpEF was 13.3% (n=100)
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compared to 24.7% (n=299) in patients with HFrEF (HR 0.503 (95% CI 0.401-0.631), p<0.001). This was significant even on multivariate analysis (HR 0.535 (95% CI 0.411-
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0.696), p<0.001). Noncardiovascular mortality accounted for 50.0% (100/200) of overall
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mortality in HFpEF patients compared to 33.4% (150/449) in HFrEF patients (p=0.012).
There was no significant difference in in-hospital mortality rate of patients with HFpEF compared to those with HFrEF (1.2% (n=9) vs 1.1% (n=13), p=0.801). The average length of stay of patients with HFpEF was 5.7 days (SD 5.3) compared to 5.1 days (SD 4.0) in patients with HFrEF (p=0.022). Between the HFpEF and HFrEF cohort, there were no significant differences in intensive care unit admissions (1.2% (n=9) vs 1.9% (n=23), p=0.232), need for inotropes (1.1% (n=8) vs 2.1% (n=25), p=0.094), mechanical ventilation (0.5% (n=4) vs 1.4% (n=17), p=0.068) or dialysis (0.3% (n=2) vs 0.4% (n=5), p=0.595). On discharge, 96.7% (726/751) of HFpEF patients and 96.9% (1172/1209) of HFrEF reported improvements in symptoms (p=0.741). There was a mild overall increase
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ACCEPTED MANUSCRIPT in creatinine levels on discharge in both the HFpEF (9.4%) and HFrEF group (7.2%) but
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this was not significant between both groups (p=0.341).
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Predictors of 2-year mortality
Table 2 highlights the differences in characteristics of patients with HFpEF who died as
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compared to survivors, while Table 3 highlights the significant multivariate predictors of
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overall and cardiovascular mortality in all patients and patients with HFpEF and HFrEF.
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In the overall cohort, older age, prior MI, stroke, peripheral vascular disease, higher creatinine levels, reduced ejection fraction and use of mineralocorticoid receptor
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antagonists were associated with significantly increased mortality. Higher systolic blood pressure, higher sodium levels and use of angiotensin converting enzyme inhibitors
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(ACE-I) /angiotensin receptor blockers (ARB), beta-blockers, diuretics, aspirin and statins were associated with decreased mortality. Ethnicity was not a significant predictor of overall mortality (Malay vs Chinese: HR 0.993 (0.801-1.231), p=0.949; Indian vs Chinese: HR 0.810 (0.626-1.048), p=0.109) or cardiovascular mortality.
In patients with HFpEF, older age (HR 1.027 (1.011-1.044), p<0.001), prior MI (HR 1.577 (1.104-2.253), p=0.012), prior stroke (HR 1.475 (1.055-2.061), p=0.023), history of cigarette smoking (HR 1.467 (1.085-1.985), p=0.013), higher creatinine levels (HR 1.002 (1.001-1.003) p<0.001) and use of mineralocorticoid receptor antagonists (HR 1.884 (1.226-2.896), p=0.004) were associated with significantly increased mortality. Use of warfarin (HR 0.506 (0.304-0.842), p=0.009) and statins (HR 0.585 (0.435-0.785),
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ACCEPTED MANUSCRIPT p<0.001) were associated with decreased mortality. The 2-year overall mortality in Chinese, Malay and Indian patients was 28.7% (n=160), 22.0% (n=20) and 16.7% (n=15)
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respectively. Ethnicity was not predictive of either overall (Malay vs Chinese: HR 0.818
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(0.548-1.220), p=0.324; Indian vs Chinese: HR 0.779 (0.517-1.175), p=0.234) or
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cardiovascular mortality.
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In patients with HFrEF, older age, prior myocardial infarction (MI), diabetes mellitus, stroke and peripheral vascular disease, higher creatinine levels were associated with
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significantly increased mortality. On the other hand, patients with higher systolic blood pressure, higher sodium levels and prescribed with ACE-I/ARB, beta-blockers and
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diuretics were associated with decreased mortality. Ethnicity also did not predict allcause (Malay vs Chinese: HR 1.045 (0.818-1.335), p=0.724; Indian vs Chinese: HR
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0.965 (0.718-1.298), p=0.815) or cardiovascular mortality.
Inclusion of addition variables with p<0.1 into the multivariate model did not change the predictors of overall and cardiovascular mortality for the entire cohort and patients with HFrEF. For patients with HFpEF, higher systolic blood pressure and use of betablockers and antiplatelets were found to be additional predictors of lower overall mortality and higher systolic blood pressure was found to be an additional predictor of lower cardiovascular mortality.
A sub-group analysis was performed in patients with EF 40-49% and <40%. In patients with heart failure and EF 40-49%, significant predictors of overall mortality were
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ACCEPTED MANUSCRIPT presence of coronary artery disease and stroke while significant predictors of cardiovascular mortality were stroke and lower diastolic blood pressure. In patients with
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EF <40%, older age, prior MI, diabetes mellitus, peripheral vascular disease and higher
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creatinine levels were associated with higher overall and cardiovascular mortality while higher systolic blood pressure, higher sodium levels and the use of ACE-I/ARB,
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betablockers and diuretics were associated with lower overall and cardiovascular
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mortality.
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DISCUSSION
To our knowledge, we report for the first time, the clinical demographics, treatment and
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impact of ethnicity and other predictors on long-term mortality of patients admitted for
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HFpEF in a multi-ethnic Asian country.
HFpEF is a common entity, comprising of 40% of all heart failure admissions in our multi-ethnic population. The reported prevalence of HFpEF varies from 26% (7) to more than 50% (4,8,19). The study from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD) showed a prevalence of 26% in the Japanese (7). The OPTIMIZE-HF and ADHERE (4,5) studies, both of which reported a prevalence of about 50%, defined HFpEF as EF≥40%. These differences in prevalence are largely due to the differences in the cohort characteristics, the setting of the study as well as the definition of HFpEF.
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ACCEPTED MANUSCRIPT In our study, there was a greater proportion of Chinese and a lower proportion of Malays amongst patients with HFpEF compared to HFrEF. Possible postulates include the
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differences in pathogenesis between HFpEF and HFrEF, and the differences in lifestyle,
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risk factors and genetic variations amongst the different ethnicities (20). The rest of the characteristics of patients with HFpEF in our multi-ethnic Asian cohort were largely
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similar to those shown in other studies. Patients with HFpEF were older and more likely
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to be female, as well as having a higher incidence of hypertension and lower incidence of coronary artery disease in our study. This is typically seen in most cohorts of HFpEF
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patients (2,4,5,7). Our HFpEF patients also had lower NT-proBNP levels. Lower NTproBNP levels has also been well described in HFpEF patients (21, 22, 23), reflecting
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less ventricular volume overload and lower diastolic wall stress as a result of concentric LV remodelling (23,24). Lower NT-proBNP in the HFpEF group might also be explained
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by a more frequent misdiagnosis in these patients, with more patients without heart failure in the HFpEF group (25,26).
Our study demonstrated that HFpEF is not a benign entity, with a 2-year mortality rate of 26.6%, albeit lower than in patients with HFrEF. The ADHERE registry showed reduced in-hospital mortality among patients with HFpEF (2.8% vs 3.9%) compared to REF patients. The OPTIMIZE-HF registry also showed lower inpatient mortality for HFpEF patients but similar 60-90 day mortality of about 10%. Results from studies on longerterm mortality showed differing outcomes. The JCARE-CARD registry report a similar mortality of about 19% after a mean follow-up of 2.4 years (7). However, the Metaanalysis Global Group in Chronic Heart Failure (MAGGIC) meta-analysis showed higher
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ACCEPTED MANUSCRIPT long-term mortality rates in patients with HFrEF. It is difficult to compare mortality rates amongst different studies for the reasons earlier mentioned (eg. different cohorts and
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definitions). However, despite the differences in studies, the mortality rate for HFpEF
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remains high.
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In our study, cardiovascular deaths accounted for 51.4% of all mortality in HFpEF
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patients. This is similar to the proportion of 51-60% found in other epidemiological studies. (8,27,28). The proportion of non-cardiovascular deaths in our HFpEF patients
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was significantly higher than that of our HFrEF patients (49% vs 33%). Once again, this was similar to that found in other studies (~ 50% vs ~ 30%) (27-29). This difference has
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HFpEF patients (27).
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been shown to be mainly as a result of fewer coronary artery disease related deaths in
Our study is the first to describe the effect of ethnicity on long-term outcomes in patients with HFpEF in a multi-ethinic Asian population. Ethnicity has been previously shown to be an important factor in influencing mortality in heart failure (10-11). Data from the Studies of Left Ventricular Dysfunction (SOLVD) trials show higher mortality among the black compared to white patients (10). The Multi-Ethnic Study of Atherosclerosis (MESA) study showed the risk of incident HF to be different amongst the races (20). In several local studies (11,12,25), Malays and Indians had proportionally higher admission rates for heart failure than Chinese (11,12,25). One study found that Malay race was a significant predictor of mortality compared to Chinese race (11) but another did not show any significant ethnic differences in mortality (12). A local study in patients with HFrEF
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ACCEPTED MANUSCRIPT also did not show any ethnic differences in mortality (30). As mentioned, these studies did not specifically look at patients with HFpEF but accounted for all heart failure
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patients. The majority of HFpEF studies involve Western cohorts with little
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representation from Asia. In our study, ethnicity was not a significant predictor of longterm mortality in patients with HFpEF. The pathogenesis of HFpEF and HFrEF are
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are not extendable to patients with HFpEF (31).
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markedly different and results from previous heart failure studies including all-comers
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Interestingly, our study found that a longer QRS duration was associated with increased cardiovascular mortality (but not overall mortality) in HFpEF patients. Many previous
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studies have shown the association between longer QRS duration and mortality in heart failure patients (32,33) but these did not specifically look at patients with HFpEF. This
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observation may reflect the deleterious effect of electrical dysynchrony and this raises an interesting hypothesis for further research. In our study, other clinical predictors of mortality in HFpEF patients included advanced age, prior MI, prior stroke, smoking and higher creatinine levels. These are similar to that found in other studies (see Table 4).
Due to the observational nature of the registry, it is difficult to draw any firm conclusions regarding the effects of medication on outcomes. To date, there is little evidence of benefit for majority of the heart failure medications used in the treatment of HFpEF (3438). There was some initial promise seen for aldosterone antagonists. However, the Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF) trial showed improved left ventricular diastolic function but no improvements in symptoms or exercise
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ACCEPTED MANUSCRIPT capacity with the use of spironoalctone (39). The recently concluded Treatment of Preserved Cardiac function heart failure with an Aldosterone antagonist (TOPCAT) trial
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using spironolactone showed a reduction in hospitalisations for heart failure but did not
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show any reduction in cardiovascular mortality in patients with HFpEF (40). No treatment has been shown to reduce mortality in HFpEF and guidelines suggest diuretics
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for symptom relief and to treat underlying hypertension, myocardial ischemia and rapid
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AF (41).
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The results of our study shed important insights in the management of this group of patients admitted for HFpEF, allowing the clinician to pay particular attention to those at
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higher risk of adverse outcomes. The strengths of our study are the large study population as well as being the first study to provide valuable knowledge on HFpEF patients in the
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setting of a multi-ethnic Asian country. Less than 5% of the study cohort did not have their EF assessed. Furthermore, our national registry provided robust mortality data.
Limitations
Our study has several limitations inherent to most registry studies. Firstly, the definition of HFpEF was based on an EF ≥50% and evidence of diastolic dysfunction or raised NTproBNP levels. In light of the registry nature of the study, there are limitations to having a more precise definition. In fact, most other major HFpEF studies relied primarily on a EF cut-off (2,4,5,7). We have sought to be more precise with our inclusion criteria with the inclusion of diastolic function assessment or raised NT-proBNP levels in line with guidelines (1) and several randomized controlled trials (39,40). Secondly, missing data on
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ACCEPTED MANUSCRIPT clinical variables may have introduced bias, however, with the exception of NT-proBNP results, there was <3% missing data for the rest of the variables. About 20% of the NT-
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proBNP results were not available and this variable was not included in the multivariate
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models. Thirdly, our cohort was limited to hospitalized patients; HF presentations in the ambulatory/community setting may have different characteristics. Once again, this was
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similar to other major studies on HFpEF patients (2,4,5,7). Fourthly, socio-economic data
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was not collected as part of the registry and this may confound comparisons. Lastly, restriction to patients with DRG code of 252 may result in the possibility of
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misclassification.
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CONCLUSIONS
In our Asian population presenting with heart failure and preserved ejection fraction,
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two-year mortality was 26.6%. Ethnicity did not predict mortality. Older age, prior myocardial infarction, prior stroke, smoking and higher creatinine levels were significant predictors of mortality.
CONFLICT OF INTEREST
The authors of the study have no conflicts of interest to declare
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Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis
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EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370:1383-92. 41. Dickstein K, Cohen-Solal A, Filippatos G, McMurray JJ, Ponikowski P, PooleWilson PA, Strömberg A, van Veldhuisen DJ, Atar D, Hoes AW, Keren A, Mebazaa A, Nieminen M, Priori SG, Swedberg K; ESC Committee for Practice Guidelines (CPG). ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the diagnosis and treatment of acute and chronic heart failure 2008 of the European Society of Cardiology. Eur J Heart Fail. 2008;10:933-89.
24
ACCEPTED MANUSCRIPT Table 1. Demographics and clinical characteristics of study population HFpEF
HFrEF
(n=1960)
(n=751)
(n=1209)
69.1 (12.2)
73.1 (10.6)
PT
Overall
Mean age (SD)
53.1
Race 70.7
Malay Indian
66.6 (12.5)
<0.001
64.1
<0.001 0.011
74.2
68.6
15.5
12.1
17.6
11.9
12.0
11.9
1.8
1.7
1.9
45.7
41.0
48.6
0.001
28.9
16.2
36.7
<0.001
Atrial fibrillation
25.8
34.0
20.7
<0.001
Diabetes mellitus
52.0
47.1
55.1
0.001
Hypertension
73.5
80.3
69.3
<0.001
Hyperlipidemia
62.0
57.9
64.6
0.003
Stroke
16.2
18.4
14.8
0.037
Peripheral vascular disease
6.8
5.3
7.7
0.043
Chronic obstructive pulmonary disease
12.6
14.2
11.5
0.074
Ever smoker
38.1
26.5
45.2
<0.001
Systolic blood pressure (SD) (mmHg)
139 (30)
143 (30)
136 (30)
<0.001
Diastolic blood pressure (SD (mmHg))
76 (18)
73 (17)
78 (19)
<0.001
Heart rate (SD)
88 (23)
84 (24)
90 (22)
<0.001
QRS (SD) (ms)
101 (25)
94 (20)
106 (27)
<0.001
MA
NU
Chinese
35.3
SC
Male
RI
Demographics
P value*
D
Others
Prior coronary artery disease
AC CE P
Prior myocardial infarction
TE
Clinical Characteristics
25
ACCEPTED MANUSCRIPT 9720 (14030)
5814 (10147)
12323 (15619)
<0.001
137 (104)
129 (100)
142 (106)
0.005
Sodium (SD) (mmol/L)
136 (7)
136 (5)
136 (8)
0.246
Potassium (SD) (mmol/L)
4.2 (1.2)
4.2 (0.8)
4.3 (1.3)
0.252
Hemoglobin (SD) (g/dL)
12.2 (3.6)
11.7(2.0)
12.6(4.2)
<0.001
41.9
55.7
<0.001
Discharge Medications
SC
RI
Creatinine (SD) (umol/L)
PT
NT-proBNP (SD) (pg/mL)**
50.4
ARB
20.1
20.2
20.0
0.905
ACE inhibitor/ARB
68.9
59.9
74.4
<0.001
59.2
50.1
64.9
<0.001
16.7
8.3
21.9
<0.001
47.5
39.9
52.2
<0.001
83.3
77.9
86.7
<0.001
23.1
17.2
26.7
<0.001
51.3
40.3
58.1
<0.001
14.1
10.9
16.1
0.001
13.7
16.8
11.7
0.002
67.6
60.9
71.8
<0.001
MA
NU
ACE inhibitor
Betablocker Mineralocorticoid-receptor antagonist
D
Nitrate
TE
Diuretic
Aspirin Plavix Warfarin Statin
AC CE P
Digoxin
*Comparing HFpEF vs HFrEF
**375 patients with missing data (159 with HFpEF) Mean and SD are reported for continuous data and frequency and percentages for categorical data.
26
ACCEPTED MANUSCRIPT Table 2. Baseline characteristics of patients with HFpEF who died as compared to survivors at 2 years Dead (n=200)
72.1 (10.5)
75.8 (10.1)
<0.001
34.3
38.0
0.494
SC
Male
RI
Demographics Mean age (SD)
Race 72.1
Malay
12.9
10.0
Indian
13.6
7.5
0.064
80.0
MA
NU
Chinese
1.5
2.5
39.9
44.0
0.317
13.6
23.5
0.001
Atrial fibrillation
34.1
33.5
0.736
Diabetes mellitus
48.6
43.0
0.189
Hypertension
80.9
78.5
0.378
Hyperlipidemia
59.2
54.5
0.181
Stroke
16.2
24.5
0.011
Peripheral vascular disease
4.5
7.5
0.118
Chronic obstructive pulmonary disease
13.8
15.5
0.619
Ever smoker
23.4
35.0
0.004
Systolic blood pressure (SD) (mmHg)
144 (29)
139 (31)
0.057
Diastolic blood pressure (SD) (mmHg)
73 (17)
70 (17)
0.033
Heart rate (SD)
84 (24)
85 (22)
0.668
QRS (SD) (ms)
93 (19)
96 (24)
0.051
D
Others
P value
PT
Alive (n= 551)
Prior coronary artery disease
AC CE P
Prior myocardial infarction
TE
Clinical characteristics
27
ACCEPTED MANUSCRIPT 10991 (14824)
<0.001
Creatinine (SD) (umol/L)
118 (81)
160 (131)
<0.001
Sodium (SD) (mmol/L)
137 (5)
136 (6)
0.052
Potassium (SD) (mmol/L)
4.2 (0.8)
4.3 (0.8)
0.058
Hemoglobin (SD) (g/dL)
11.9 (2.0)
11.3 (2.2)
<0.001
ARB ACE inhibitor/ARB Betablocker Mineralocorticoid-receptor antagonist
Statin
TE AC CE P
Digoxin
Warfarin
20.7
19.0
0.916
62.1
54.0
0.025
53.9
39.5
<0.001
6.5
13.0
0.004
39.2
42.0
0.586
78.9
75.0
0.188
17.6
16.0
0.530
42.5
34.5
0.038
11.6
9.0
0.330
19.6
9.0
0.001
64.6
50.5
<0.001
D
Nitrate
Plavix
0.122
NU
43.4
Aspirin
38.0
MA
ACE inhibitor
SC
Discharge Medications
Diuretic
PT
4204 (7316)
RI
NT-proBNP (SD) (pg/mL)*
*159 patients with missing data Mean and SD are reported for continuous data and frequency and percentages for categorical data.
28
ACCEPTED MANUSCRIPT
PT
Table 3. Multivariate predictors of 2-year overall and cardiovascular mortality in study population
Hazard Ratio
P value
Predictors
(95% CI) Overall cohort
NU
Overall cohort
SC
Predictors
Cardiovascular mortality
RI
Overall mortality
1.022 (1.014-1.030)
<0.001
Age
Prior myocardial
1.519 (1.274-1.812)
<0.001
Prior myocardial
P value
(95% CI)
1.013 (1.003-1.023)
0.009
1.455 (1.167-1.816)
0.001
Stroke
1.319 (1.024-1.700)
0.032
Systolic blood pressure
0.990 (0.985-0.995)
<0.001
QRS
1.005 (1.001-1.009)
0.014
<0.001
Creatinine
1.002 (1.002-1.003)
<0.001
0.023
Sodium
0.990 (0.982-0.999)
0.030
MA
Age
Hazard Ratio
infarction
PT ED
infarction 1.346 (1.106-1.639)
0.003
Peripheral vascular
1.343 (1.032-1.747)
0.028
Systolic blood pressure
0.992 (0.988-0.996)
<0.001
Creatinine
1.002 (1.001-1.002)
Sodium
0.991 (0.984-0.999)
ACE inhibitor/ARB
0.754 (0.636-0.895)
0.001
ACE inhibitor/ARB
0.722 (0.581-0.898)
0.003
Betablocker
0.791 (0.663-0.919)
0.003
Betablocker
0.781 (0.637-0.958)
0.018
Mineralocorticoid-
1.255 (1.016-1.550)
0.035
Ejection fraction (reduced
1.869 (1.437-2.433)
<0.001
receptor antagonist
AC
disease
CE
Stroke
compared to preserved)
29
Aspirin
0.799 (0.675-0.946)
0.009
Statin
0.799 (0.666-0.959)
0.016
Ejection fraction (reduced
1.618 (1.328-1.969)
<0.001
RI
0.035
SC
0.796 (0.643-0.984)
NU
Diuretic
PT
ACCEPTED MANUSCRIPT
MA
compared to preserved)
HFrEF
Age
1.018 (1.008-1.027)
<0.001
Prior myocardial
1.336 (1.091-1.636)
0.005
Age
1.011 (1.001-1.022)
0.043
Prior myocardial
1.330 (1.035-1.710)
0.026
infarction
Diabetes mellitus
1.280 (1.035-1.582)
0.023
Systolic blood pressure
0.990 (0.984-0.996)
0.002
Stroke
1.403 (1.100-1.789)
0.006
Diastolic blood pressure
0.989 (0.978-1.000)
0.047
Peripheral vascular
1.369 (1.007-1.860)
AC
CE
infarction
PT ED
HFrEF
0.045
Creatinine
1.002 (1.001-1.003)
<0.001
Systolic blood pressure
0.990 (0.985-0.996)
0.001
Sodium
0.989 (0.980-0.998)
0.012
Creatinine
1.002 (1.001-1.003)
<0.001
ACE inhibitor/ARB
0.732 (0.563-0.951)
0.019
Sodium
0.990 (0.982-0.997)
0.007
disease
30
0.001
Betablocker
0.783 (0.642-0.955)
0.016
Diuretic
0.709 (0.541-0.930)
0.013
RI
0.698 (0.565-0.864)
HFpEF
HFpEF 1.027 (1.011-1.044)
0.001
Stroke
2.058 (1.306-3.243)
0.002
Prior myocardial
1.577 (1.104-2.253)
0.012
QRS
1.013 (1.005-1.021)
0.002
Stroke
1.475 (1.055-2.061)
0.023
Creatinine
1.002 (1.001-1.003)
<0.001
Eversmoke
1.467 (1.085-1.985)
0.013
Hemoglobin
0.857 (0.770-0.955)
0.005
Creatinine
1.002 (1.001-1.003)
<0.001
Warfarin
0.364 (0.174-0.762)
0.007
Warfarin
0.506 (0.304-0.842)
0.009
Statin
0.575 (0.373-0.886)
0.012
Mineralocorticoid-
1.884 (1.226-2.896)
AC
PT ED
CE
infarction
MA
Age
NU
SC
ACE inhibitor/ARB
PT
ACCEPTED MANUSCRIPT
0.004
receptor antagonist Statin
0.585 (0.435-0.785)
<0.001
31
ACCEPTED MANUSCRIPT Table 4. Summary of predictors of all-cause mortality in HFPEF studies ADHERE (13)
Bhatia et al (4)
Ather et al (19)
Owan et al (2)
Tribouilloy
Outcome
In-hospital
PT
et al (8) 1-year mortality
2-year mortality
5-year mortality
Lower SBP
PVD
Tachycardia
Malignancy
Dysponea at rest
Dementia
High urea levels
Dialysis
levels
AC CE P
Hyponatremia
Low SBP
Older age
Older age
COPD
Female
Stroke
Malignancy
DM
DM
Dementia
Low BP
COPD
Renal insufficiency
High creatinine
Malignancy
levels Liver disease
TE
High creatinine
Stroke
NU
Older age
MA
Older age
D
Predictors
SC
RI
mortality
5-year mortality
Tachypnoea
Rheumatological
Anaemia
Low GFR
Hyponatremia
disorder
Absence of
High creatinine
betablocker
levels
Anaemia
Hyponatremia Anaemia
FIGURE LEGENDS Figure 1. Cox proportional hazards model for overall survival for preserved vs reduced EF
32
AC CE P
Figure 1
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
33