European Journal of Heart Failure (2016)

doi:10.1002/ejhf.679

In-hospital and 1-year mortality associated

with diabetes in patients with acute heart
failure: results from the ESC-HFA Heart
Failure Long-Term Registry
Giovanni Targher1, Marco Dauriz1, Cécile Laroche2, Pier Luigi Temporelli3,
Mahmoud Hassanein4, Petar M. Seferovic5, Jaroslaw Drozdz6, Roberto Ferrari7,
Stephan Anker8, Andrew Coats9, Gerasimos Filippatos10, Maria G. Crespo-Leiro11,
Alexandre Mebazaa12, Massimo F. Piepoli13, Aldo Pietro Maggioni2,14*, and
Luigi Tavazzi15, on behalf of the ESC-HFA HF Long-Term Registry investigators†
1 Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy;
2 EURObservational Research Programme, European Society of Cardiology, Sophia-Antipolis, France; 3 Cardiology Division, IRCCS Fondazione Salvatore Maugeri, Veruno, NO,
Italy; 4 Alexandria University, Alexandria, Egypt; 5 Department of Cardiology, Clinical Centre of Serbia, Belgrade, Serbia; 6 Department of Cardiology, Medical University, Lodz,
Poland; 7 Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Maria Cecilia Hospital, GVM Care & Research, E.S: Health Science Foundation,
Cotignola, Italy; 8 Innovative Clinical Trials, Department of Cardiology & Pneumology, University Medical Center Göttingen (UMG), Göttingen, Germany; 9 Monash University,
Australia and University of Warwick, Coventry, UK; 10 Cardiology Department, University Hospital 12 de Octubre, Madrid, Spain; 11 Unidad de Insuficiencia Cardiaca Avanzada y
Trasplante Cardiaco, Complexo Hospitalario, Universitario A Coruna, CHUAC, La Coruna, Spain; 12 Inserm 942, Hôpital Lariboisière, Université Paris Diderot, Paris, France;
13 Department of Cardiology, Polichirurgico Hospital G. da Saliceto, Piacenza, Italy; 14 ANMCO Research Center, Florence, Italy; and 15 Maria Cecilia Hospital, GVM Care &

Research, E.S. Health Science Foundation, Cotignola, Italy

Received 10 May 2016; revised 24 August 2016; accepted 20 September 2016

Aims The aim of this study was to evaluate the in-hospital and 1-year prognostic impact of diabetes and elevated blood
glucose levels at hospital admission in patients with acute heart failure (HF).
.....................................................................................................................................................................
Methods and We studied a multinational cohort of 6926 hospitalized patients with acute HF enrolled in the European Society
results of Cardiology (ESC) and Heart Failure Association (HFA) Long-Term Registry, of whom 49.4% (n = 3422) had
known or previously undiagnosed diabetes (defined as self-reported history, or medication use, or fasting glucose
levels ≥7.0 mmol/L or haemoglobin A1c ≥6.5%). Compared with those without diabetes, patients with known or
previously undiagnosed diabetes had higher cumulative rates of in-hospital mortality, 1-year mortality, and 1-year
HF re-hospitalization that occurred independently of multiple clinical risk factors: in-hospital mortality [6.8 vs.
4.4%; adjusted hazard ratio (HR) 1.774; 95% confidence interval (CI) 1.282–2.456, P < 0.001], 1-year all-cause
mortality (27.5 vs. 24%; adjusted HR 1.162; 95% CI 1.020–1.325, P = 0.024), and 1-year hospital re-admissions
for HF (23.2 vs. 18.5%; adjusted HR 1.320; 95% CI 1.139–1.530, P < 0.001). Moreover, elevated admission
blood glucose concentrations were powerfully prognostic for in-hospital mortality, but not for 1-year mortality or
re-hospitalizations, in both patients with and without diabetes.
.....................................................................................................................................................................
Conclusions Among patients hospitalized for acute HF, the presence of diabetes is independently associated with an increased
risk of in-hospital mortality, 1-year all-cause mortality, and 1-year re-hospitalizations for HF, underscoring the need
for more effective and personalized treatments of diabetes in this particularly high-risk patient population.
..........................................................................................................
Keywords Co-morbidities • Diabetes • Acute heart failure • Observational outcome study
.

*Corresponding author. European Society of Cardiology, EURObservational Research Programme. Tel: +39 033 5258338, Fax: +39 055 5101310, Email: amaggioni@escardio.org
† The list of members is given in Appendix 1

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
2 G. Targher et al.

Introduction EURObservational Research Programme (EORP) of the European

........................................................................................................................................................................
Society of Cardiology (ESC) and the ESC-Heart Failure Association
Diabetes mellitus and heart failure (HF) are two common diseases (HFA).17
that often co-exist. The prevalence of diabetes among patients with
HF is extremely high, and it has been estimated as between 30% and
50%.1 – 3 More than 40 years ago, the Framingham Heart study first Methods
reported that the risk for new-onset HF in patients with diabetes
was about two-fold higher in men and five-fold in women com- Study design
pared with individuals without diabetes.4 The pathogenesis of HF in The principles and procedures of the EORP of the ESC have been
diabetes is multifactorial, but can be largely attributed to ischaemic previously described.17,18 Briefly, the ESC-HF Long-Term Registry is
heart disease, hypertension, diabetic cardiomyopathy, and extracel- a prospective, multicentre, observational study of patients at 211
lular fluid volume expansion.1,2 Remarkably, diabetes per se is a sig- Cardiology Centres in 21 European and Mediterranean countries,
nificant risk factor for new-onset HF, independent of hypertension which are members of the ESC. The ESC-HFA endorsed the study,
which was conducted by an ad-hoc Executive Committee.
and ischaemic heart disease, suggesting that glycaemic control may
The national cardiology societies of each country agreed to partici-
influence the development of new-onset HF.5 Recently, in response
pate in the programme and were asked to select hospitals of different
to concerns about the cardiovascular safety of rosiglitazone, a num- levels of complexity from which patients could be recruited. The aim
ber of large randomized clinical trials have been designed to evalu- was to include a broad spectrum of cardiology and/or HF units follow-
ate the cardiovascular safety of the newer drugs for the treatment ing outpatients with HF and admitting patients with acute, worsening,
of type 2 diabetes. To date, no new sound adverse cardiovascular or de novo HF to develop a network of centres that would be reason-
safety signal (including the risk for HF) has arisen from the trials ably representative of the European reality. The number of participating
with incretin-based therapies (i.e. dipeptidyl peptidase 4 inhibitors centres for each country was decided according to the number of
and glucagon-like peptide 1 receptor agonists), and there is now inhabitants in that country, i.e. one centre per 2 million people, but
evidence of benefit from the EMPA-REG trial with empagliflozin, a no more than 25 and no less than 6 per country. To the extent that
sodium–glucose co-transporter 2 inhibitor.5,6 it was possible, the centres were also chosen to fulfil geographical cri-
teria within each country. In this way, the registry included a balanced
Despite the known high prevalence of diabetes among patients
proportion of centres with a range of cardiology facilities.
with HF, there are few contemporary, comparative data on the
The EORP Department at the ESC European Heart House was
in-hospital and post-discharge survival outcomes from multina- appointed to co-ordinate the project’s operations, to provide support
tional cohorts of patients with and without diabetes who have to the committees, national co-ordinators, and participating centres,
been acutely admitted to the hospital for HF, out of the context and to oversee the methodological aspects of the survey. The database
of randomized clinical trials. Additionally, while diabetes is associ- was established at the European Heart House, according to the
ated with increased mortality and morbidity in ambulatory patients requirements defined by the appointed Executive Committee with the
with chronic systolic HF,1,2 its influence as an independent pre- support of the EORP Department.
dictor of in-hospital and post-discharge adverse outcomes after
hospitalization for acute HF is not consistently apparent. In fact, the
published studies of patients hospitalized for HF that have explored
Patient population
the impact of diabetes per se on in-hospital and post-discharge clin- From May 2011 to April 2013, all outpatients seen at the clinics
ical outcomes in patients hospitalized for acute HF have reported and all patients acutely admitted to the hospital for acute, worsen-
conflicting results, suggesting the need for further studies. ing, or de novo HF were included in this registry during the enrolment
period (on 1 day per week for 12 consecutive months). Therefore,
Indeed, as will be discussed in detail below, some large registry
on the screening day, the following patients were entered in the reg-
databases and clinical trials have shown that diabetes was asso-
istry: (i) all outpatients with chronic HF diagnosed according to the
ciated with either poorer in-hospital and post-discharge survival clinical judgement of the responsible cardiologist at the participat-
outcomes or higher 1-year re-hospitalization rates in patients ing centres; and (ii) all inpatients admitted to the hospital’s cardi-
hospitalized for acute HF.7 – 10 In contrast, a number of other ology ward or intensive cardiac care unit for acute HF, for whom
recent studies did not find any significant and independent asso- an intravenous therapy (inotropes, vasodilators, or diuretics) was
ciation between diabetes status and mortality risk in this patient needed.
population.11 – 16 There were no specific exclusion criteria, except for age ≤18 years.
Thus, all these findings clearly suggest that the prognostic value The registry was approved by each local Institutional Review Board
of diabetes per se on in-hospital and post-discharge survival out- according to the rules of each participating country. No data were
comes in patients hospitalized for acute HF is still controversial. collected before detailed information was provided to the patient and
a signed informed consent was obtained.
Currently, there is continued debate on this topic and, therefore,
In the current analysis, we presented the 1-year data from the
it warrants in-depth investigation.
ESC-HF Long-Term registry concerning the rates of in-hospital
The major aim of this study was to explore the rates of mortality, 1-year all-cause and cardiac mortality, and 1-year HF
in-hospital mortality, 1-year all-cause mortality, and 1-year HF re-hospitalization of patients who were admitted to hospital for acute,
re-hospitalization among the patients with and without dia- worsening, or de novo HF. Data on mortality were available for the
betes, who were admitted to the hospital for acute HF, enrolled whole cohort (n = 6926), whereas data on 1-year HF re-hospitalization
in the General Long-term HF Registry that belongs to the were available in 6540 (94.4%) participants.

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
Acute heart failure and diabetes 3

Diagnosis of diabetes Results

........................................................................................................................................................................
Previously known diabetes was defined as self-reported
As shown in Table 1, the study cohort included 6926 (63.0% men,
physician-diagnosed diabetes, or use of medications for diabetes
mean age 69 years) hospitalized patients with acute HF, largely com-
(insulin or oral hypoglycaemic agents). In the absence of previously
posed of overweight or obese individuals of Caucasian ancestry
known diabetes, the diagnosis of new-onset diabetes was based on
a fasting plasma glucose level ≥7.0 mmol/L (≥126 mg/dL) and/or a (∼83%). The prevalence of diabetes in the study cohort was high
haemoglobin A1c (HbA1c ) level ≥6.5%, respectively. In accord with (n = 3422; 49.4%); 80.5% (n = 2755) of these patients had previously
the American Diabetes Association diagnostic criteria,19 only a known diabetes (i.e. self-reported history or use of hypoglycaemic
plasma glucose level ≥200 mg/dL (≥11.1 mmol/L), in the presence of drugs), whereas the remaining 667 (19.5%) patients had previously
classical hyperglycaemic symptoms, is sufficient for the diagnosis of undiagnosed diabetes (as defined in the Methods). Among those
new-onset diabetes without confirmation, whereas fasting glucose with previously undiagnosed diabetes, 116 patients had a fasting
levels between 126 and 199 mg/dL (or an HbA1c ≥6.5%) are consid- glucose level ≥200 mg/dL (i.e. a criterion sufficient for the diagno-
ered diagnostic for diabetes only if confirmed by at least two separate sis of diabetes without confirmation), whereas the remaining 549
testings.
patients had a fasting glucose level between 126 and 199 mg/dL,
about one-third of whom also had an HbA1c level ≥6.5%. So, simi-
larly to other large registry databases like this, since repeat glucose
Other clinical and laboratory data testings were not available, we could not distinguish in a subgroup
Body mass index (BMI) was calculated by dividing weight in kilo- of ∼400 patients the exact number of those with a ‘true’ new diag-
grams by height in metres squared. Patients were considered as hav- nosis of diabetes from those with (non-diabetic) transient stress
ing hypertension if their blood pressure was ≥140/90 mmHg or if hyperglycaemia during hospitalization. We were also unable to
they were taking antihypertensive drugs. Serum creatinine, glucose,
distinguish between type 1 and type 2 diabetes mellitus, although
HbA1c , and other biochemical blood measurements were determined
the vast majority of our diabetic cases were likely to be type 2.
using local standard laboratory procedures. Estimated glomerular fil-
Table 1 shows the baseline characteristics of patients strati-
tration rate (eGFR) was estimated using the four-variable Modification
of Diet in Renal Disease (MDRD) study equation.20 The presence fied by diabetes status at hospital admission. Mean plasma glu-
of chronic kidney disease (CKD) was defined as an eGFRMDRD cose levels were 168.8 ± 75 mg/dL in patients with diabetes and
<60 mL/min/1.73 m2 .20 Conventional trans-thoracic echocardiography 96.2 ± 14 mg/dL in those without diabetes, respectively. Mean
was used to measure the LV diameter, wall thickness, and EF according HbA1c levels (available only in 1001 participants; see footnote of
to international standard criteria. Table 1) were 7.4 ± 3.8% in patients with diabetes and 5.6 ± 0.5%
in those without. Patients with diabetes were more likely to be
female, older, non-smokers, obese, and hypertensive compared
Statistical analysis with those without diabetes. They also had a greater likelihood
The statistical analyses were performed at the ESC European Heart of ischaemic aetiology of HF, NYHA class III–V, CKD, prior
House. Categorical variables were reported and compared using a stroke or COPD, but a lower prevalence of AF, and LVEF >45%.
𝜒 2 test or a Fisher’s exact test if any expected cell count was <5. Moreover, patients with diabetes had lower levels of eGFRMDRD ,
For categorical variables with more than two possible values, exact haemoglobin, and sodium, and were more likely to be treated
P-values were estimated according to the Monte Carlo method. Con- with statins, renin–angiotensin system blockers, calcium channel
tinuous variables were reported either as means ± SD or as medi- blockers, nitrates, antiplatelets or anticoagulants, and less likely to
ans and interquartile range (IQR). Among-group comparisons were be treated with aldosterone antagonists, digitalis or amiodarone
made using a non-parametric test (the Kruskal–Wallis test). Two mul-
compared with those without diabetes. Most patients with dia-
tivariable regression models (model 1, adjusted for age, sex, systolic
betes were treated with insulin, oral hypoglycaemic drugs, or both.
blood pressure, eGFRMDRD , LVEF, HF aetiology, and HF clinical pre-
sentation; and model 2, the same covariates included in model 1 plus
There were no significant differences in terms of ethnic origin, de
BMI, smoking, hypertension, statin use, previous histories of stroke novo HF presentation, beta-blocker drug use, total cholesterol, and
and COPD, sodium levels, and haemoglobin levels) were applied to NT-proBNP levels (available only in a subgroup of 1499 patients)
estimate the risk associated with diabetes status at hospital admis- between the two groups.
sion in terms of in-hospital mortality (by logistic regression analysis), Collectively, over the follow-up period, there were 386 (5.6%)
1-year all-cause mortality, and 1-year re-hospitalization for HF (by cases of in-hospital mortality, 1781 (25.7%) cases of 1-year
Cox regression analysis). The covariates included in these multivari- all-cause mortality, 1001 (14.5%) cases of 1-year cardiac mortality
able regression models were chosen as potential confounding factors and 1361 (20.8%) cases of 1-year hospital re-admission due to HF.
based on their significance in univariable analyses or their biologi- As shown in Figure 1, the cumulative rates of in-hospital mortality
cal plausibility. We also examined the association between admission
and 1-year adverse clinical outcomes were markedly higher in
plasma glucose levels and the risk of adverse clinical outcomes after
patients with diabetes than in those without diabetes (P < 0.001
simultaneously stratifying the entire cohort of patients by quintiles of
plasma glucose concentrations (i.e. ∼1200 patients were included in for all between-group differences).
each quintile) and by diabetes status. A two-sided P-value <0.05 was Table 2 shows the association between quintiles of plasma
considered to be statistically significant. All analyses were performed glucose levels at hospital admission and adverse clinical outcomes
with SAS statistical software version 9.4 (SAS Institute, Inc., Cary, in the whole cohort of patients stratified by diabetes status. The
NC, USA). rates per 100 patient-years of all considered clinical outcomes

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
4 G. Targher et al.

Table 1 Baseline characteristics of the whole cohort of patients with acute heart failure stratified by diabetes status

Diabetic patients Non-diabetic patients P-value

(n = 3422) (n = 3504)
...........................................................................................................................................
Males 61.1% 64.8% 0.002
Age (years) 70.0 ± 11.4 68.0 ± 14.4 <0.001
Ethnic origin (Caucasian) 82.9% 82.2% 0.498
BMI (kg/m2 ) 29.3 ± 5.4 27.7 ± 5.3 <0.001
Systolic BP (mmHg) 134.9 ± 29.6 130.1 ± 27.3 <0.001
Diastolic BP (mmHg) 79.2 ± 16.1 78.1 ± 15.4 0.002
Total cholesterol (mg/dL) 164.6 ± 54.6 164.7 ± 50.8 0.400
Heart rate (b.p.m,) 82.0 ± 20.6 80.5 ± 20.7 <0.001
Plasma glucose (mg/dL) 168.8 ± 75.3 96.2 ± 14.2 <0.001
Haemoglobin A1c 7.4 ± 3.8 5.6 ± 0.5 <0.001
Hypertension 71.4% 57.6% <0.001
Smoking status 15.7% 18.1% 0.007
Diabetes medicationsa
Insulin 52.5% 0.0% NA
Oral hypoglycaemic drugs only 47.5% 0.0% NA
Diet only 0.0% 0.0% NA
Cardiovascular medications
Statins 47.3% 36.8% <0.001
ACE inhibitors or ARBs 73.4% 69.7% 0.002
Beta-blockers 62.8% 62.5% 0.809
Aldosterone antagonists 36.6% 41.4% <0.001
Diuretics 73.7% 71.5% 0.055
Digitalis 20.0% 23.1% 0.005
Calcium channel blockers 20.7% 14.0% <0.001
Antiplatelets or anticoagulants 78.8% 75.7% 0.004
Nitrates 30.6% 23.2% <0.001
Amiodarone 10.0% 11.7% 0.037
eGFRMDRD (mL/min/1.73 m2 ) 54.9 ± 25.2 62.6 ± 34.7 <0.001
eGFRMDRD <60 mL/min/1.73 m2 61.3% 50.0% <0.001
Haemoglobin (g/dL) 12.4 ± 2.2 12.7 ± 2.2 <0.001
Sodium (mEq/L) 137.6 ± 5.4 138.3 ± 5.1 <0.001
NT-proBNP (pg/dL) 3900.0 (1674–9300) 3791.0 (1619–8878) 0.321
LVEF (%) 39.2 ± 14.2 39.2 ± 14.5 0.971
LVEF >45% 28.3% 31.2% 0.025
NYHA class III–IV 86.8% 83.0% <0.001
HF aetiology (ischaemic) 63.7% 49.0% <0.001
HF (de novo) 28.5% 30.2% 0.118
Atrial fibrillation 42.2% 45.0% 0.020
COPD 21.8% 16.8% <0.001
Previous stroke 13.7% 10.6% <0.001

Data are expressed as means ± SD, medians (IQR), or percentages.

Plasma glucose measurements were available in 5727 patients (n = 2969 and 2758 patients, respectively), whereas HbA1c and NT-proBNP measurements were available in a
smaller group of patients (n = 1001 and 1499 patients, respectively).
BMI, body mass index; BP, blood pressure; eGFRMDRD , estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease study equation); HF,
heart failure; NA, not applicable.
a Data on diabetes treatment were available for 3321 (97.1%) patients with diabetes.

were almost always higher in patients with diabetes in each quintile associations were observed between admission blood glucose
....................

of plasma glucose levels (i.e. at the same range of plasma glucose levels and 1-year mortality or re-hospitalization rates in both
levels) than in those without diabetes. Elevated blood glucose levels groups of patients.
at admission were associated with a significantly higher risk of Table S1 in the Supplementary material online shows the same
in-hospital mortality in both diabetic and non-diabetic patients even associations between admission blood glucose levels and adverse
after adjusting for age, sex, systolic blood pressure, eGFRMDRD , clinical outcomes of those reported in Table 2. However, in this
LVEF, HF aetiology, and HF presentation. In contrast, no significant table, patients with diabetes were stratified by clinically chosen

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
Acute heart failure and diabetes 5

Figure 1 Cumulative incidence rates of in-hospital mortality, 1-year all-cause mortality, 1-year cardiac mortality and 1-year heart failure (HF)
re-hospitalization among patients admitted to the hospital for acute HF stratified by diabetes status.

cut-off levels (i.e. ≤125, 126–180, and >180 mg/dL), whereas presentation, lower BMI, lower systolic blood pressure (or a
................................................................................................

patients without diabetes were stratified by tertiles of plasma pre-existing non-hypertensive status), lower LVEF, and lower levels
glucose levels of the whole cohort of patients (i.e. ≤98, 98–132, of eGFRMDRD , haemoglobin, and sodium.
and >132 mg/dL) at hospital admission. It is important to remark Table 4 shows the effect of the adjustment for potential con-
that, as expected, for patients without diabetes, the maximum founding variables on the relationship between diabetes and 1-year
plasma glucose level was 125 mg/dL. Also in this case, the rates all-cause mortality. In regression model 2, the presence of diabetes
per 100 patient-years of all considered clinical outcomes were was associated with a 1.16-fold increased risk of 1-year all-cause
almost always higher in patients with diabetes than in those mortality. Other variables that were independently associated with
without diabetes in each cut-off of admission plasma glucose levels. 1-year all-cause mortality were older age, male sex, prior stroke,
Similarly, elevated admission blood glucose levels were significantly non-use of statins, lower systolic blood pressure (or a pre-existing
associated with a higher in-hospital mortality in patients with non-hypertensive status), lower levels of eGFRMDRD , haemoglobin,
diabetes (and only marginally in patients without diabetes) after and sodium, and lower LVEF. Similar findings were also observed
adjusting for age, sex, systolic blood pressure, eGFRMDRD , LVEF, for 1-year cardiac mortality (data not shown).
HF aetiology, and HF presentation. No significant associations Table 5 shows the effect of the adjustment for multiple poten-
were observed between admission blood glucose levels and 1-year tial confounding variables on the relationship between diabetes
follow-up outcomes in both groups of patients. and 1-year re-hospitalization for HF. Also in this case, the pres-
Table S2 in the Supplementary material online shows the age- and ence of diabetes was associated with a 1.32-fold increased risk of
sex-adjusted associations between diabetes treatment (insulin vs. 1-year hospital re-admission due to HF, independently of multiple
diet/oral drugs) at hospital admission and adverse clinical outcomes potential confounders (model 2). Other variables that were inde-
in the subgroup of patients with diabetes. As expected, diabetic pendently associated with HF hospital re-admissions were prior
patients treated with insulin showed a worse prognosis than those stroke, COPD, non-ischaemic HF aetiology, lower systolic blood
treated with oral hypoglycaemic drugs or diet alone. pressure, lower eGFRMDRD , lower haemoglobin, lower LVEF, and
Table 3 shows the effect of the adjustment for multiple potential worsening HF presentation.
confounding variables on the relationship between diabetes and Finally, we also performed some sensitivity analyses to assess the
in-hospital mortality. Presence of diabetes was associated with robustness of our observations. Supplementary material online,
an ∼1.6-fold increased risk of in-hospital mortality after adjusting Table S3 shows the age- and sex-adjusted associations between
for age, sex, systolic blood pressure, eGFRMDRD , LVEF, HF aeti- patients with reduced LVEF ≤45% or with LVEF >45% at hospital
ology, and HF presentation (model 1). Additional adjustment for admission and the risk of adverse clinical outcomes stratified
other potential confounding variables (model 2) did not weaken by diabetic status. Conversely, Supplementary material online,
the significant association between diabetes and in-hospital Table S4 shows the associations between patients with ischaemic
mortality. Notably, other variables that were independently or non-ischaemic HF aetiology and the risk of adverse clinical
associated with in-hospital mortality were older age, de novo HF outcomes stratified by diabetic status.

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
6 G. Targher et al.

Table 2 Association between plasma glucose quintiles at hospital admission and adverse outcomes in the whole
cohort of patients stratified by diabetes status

Group Outcome Plasma Events/ Rate per 100 Unadjusted Adjusted HR

glucose patients patient-years HR (95% CI)a
(mg/dL) (95% CI) (95% CI)
...........................................................................................................................................
Diabetic patients 1-year all-cause death ≤90 72/231 31.2 (25.3–37.6) Reference Reference
>90–103 59/207 28.5 (22.5–35.2) 0.92 (0.65–1.30) 0.90 (0.59–1.40)
>103–122 91/339 26.8 (22.2–31.9) 0.82 (0.61–1.12) 0.91 (0.63–1.32)
>122–165 264/1048 25.2 (22.6–27.9) 0.81 (0.63–1.06) 0.81 (0.59–1.12)
>165 335/1144 29.3 (26.7–32.0) 0.96 (0.75–1.24) 1.10 (0.81–1.49)
1-year cardiovascular death ≤90 43/231 18.6 (13.8–24.2) Reference Reference
>90–103 37/207 17.9 (12.9–23.8) 0.97 (0.62–1.50) 0.74 (0.42–1.32)
>103–122 49/339 14.5 (10.9–18.7) 0.75 (0.50–1.13) 0.76 (0.47–1.23)
>122–165 151/1048 14.4 (12.3–16.7) 0.78 (0.56–1.10) 0.69 (0.46–1.03)
>165 205/1144 17.9 (15.7–20.3) 0.99 (0.71–1.37) 0.99 (0.68–1.45)
In-hospital death ≤90 7/231 3.0 (1.2–6.1) Reference Reference
>90–103 15/207 7.2 (4.1–11.7) 2.50 (1.00–6.25) 2.93 (0.84–10.19)
>103–122 15/339 4.4 (2.5–7.2) 1.48 (0.59–3.69) 2.40 (0.74–7.75)
>122–165 78/1048 7.4 (5.9–9.2) 2.57 (1.17–5.65) 3.08 (1.07–8.84)
>165 94/1144 8.2 (6.7–10.0) 2.86 (1.31–6.25) 3.79 (1.33–10.78)
1-year HF re-hospitalization ≤90 67/224 29.9 (24.0–36.4) Reference Reference
>90–103 57/192 29.7 (23.3–36.7) 0.99 (0.69–1.42) 1.01 (0.70–1.45)
>103–122 77/324 23.8 (19.2–28.8) 0.73 (0.52–1.02) 0.73 (0.52–1.03)
>122–165 230/970 23.7 (21.1–26.5) 0.77 (0.58–1.02) 0.82 (0.62–1.08)
>165 242/1050 23.0 (20.5–25.7) 0.75 (0.57–0.98) 0.85 (0.64–1.12)
Non-diabetic patients 1-year all-cause death ≤90 218/981 22.2 (19.7–25.0) Reference Reference
>90–103 184/903 20.4 (17.8–23.2) 0.89 (0.73–1.08) 0.78 (0.62–0.98)
>103–122 205/796 25.8 (22.7–28.9) 1.18 (0.97–1.42) 1.04 (0.83–1.30)
>122–165b 25/78 32.1 (21.9–43.6) 1.65 (1.09–2.49) 1.38 (0.82–2.30)
>165 0/0 NA NA NA
1-year cardiovascular death ≤90 125/981 12.7 (10.7–15.0) Reference Reference
>90–103 103/903 11.4 (9.4–13.7) 0.86 (0.67–1.12) 0.81 (0.60–1.08)
>103–122 106/796 13.3 (11.0–15.9) 1.06 (0.82–1.37) 0.93 (0.69–1.25)
>122–165b 12/78 15.4 (8.2–25.3) 1.37 (0.76–2.47) 1.09 (0.53–2.24)
>165 0/0 NA NA NA
In-hospital death ≤90 31/981 3.2 (2.2–4.5) Reference Reference
>90–103 26/903 2.9 (1.9–4.2) 0.91 (0.54–1.54) 0.90 (0.52–1.55)
>103–122 38/796 4.8 (3.4–6.5) 1.54 (0.95–2.49) 1.41 (0.86–2.31)
>122–165* 7/78 9.0 (3.7–17.6) 3.02 (1.29–7.10) 2.82 (1.15–6.89)
>165 0/0 NA NA NA
1-year HF re-hospitalization ≤90 201/950 21.2 (18.6–23.9) Reference Reference
>90–103 174/877 19.8 (17.2–22.6) 0.91 (0.73–1.12) 0.80 (0.62–1.03)
>103–122 154/758 20.3 (17.5–23.4) 0.97 (0.78–1.21) 0.82 (0.63–1.07)
>122–165b 11/71 15.5 (8.0–26.0) 0.71 (0.36–1.38) 0.75 (0.33–1.71)
>165 0/0 NA NA NA

Cohort size for this analysis, n = 5727.

Cox regression analyses for 1-year all-cause death, 1-year cardiovascular death, and 1-year HF re-hospitalization, and logistic regression analyses for in-hospital death have
been performed.
CI, confidence interval, HF, heart failure; HR, hazard ratio, OR, odds ratio, NA, not applicable.
a Covariates considered for adjustment: age, sex, systolic blood pressure, estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease study

equation), LVEF, HF aetiology and HF presentation.

b Note that for non-diabetic patients the maximum of plasma glucose levels in the fourth quintile was 125 mg/dL.

As expected, patients with LVEF >45% at hospital admission outcomes stratified by diabetic status. Notably, in both of these
..............

had better clinical outcomes than those with reduced LVEF ≤45%, sensitivity analyses, the rates per 100 patient-years of adverse
irrespective of pre-existing diabetes. In contrast, there were no clinical outcomes were almost always higher in patients with
significant age- and sex-adjusted associations between patients diabetes than in those without diabetes, irrespective of either HF
with ischaemic or non-ischaemic HF aetiology and risk of adverse aetiology or the level of LVEF at hospital admission.

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
Acute heart failure and diabetes 7

Table 3 Multivariable logistic regression analysis for in-hospital mortality in the whole cohort of patients

Variables Regression model 1 Regression model 2

........................................ .........................................
OR (95% CI) P-value OR (95%CI) P-value
...........................................................................................................................................
Diabetes status, yes vs. no 1.580 (1.177–2.120) 0.002 1.774 (1.282–2.456) <0.001
Age, years 1.016 (1.003–1.028) 0.013 1.022 (1.008–1.036) 0.002
Sex, male vs. female 0.910 (0.670–1.236) 0.545 0.868 (0.623–1.211) 0.406
Systolic blood pressure, mmHg 0.974 (0.968–0.980) <0.001 0.980 (0.974–0.987) <0.001
eGFRMDRD , mL/min/1.73 m2 0.977 (0.971–0.984) <0.001 0.981 (0.973–0.988) <0.001
LVEF, % 0.987 (0.976–0.998) 0.018 0.988 (0.977–1.000) 0.048
HF aetiology, ischaemic vs. non-ischaemic 0.814 (0.605–1.095) 0.173 0.926 (0.667–1.287) 0.648
HF presentation, worsening vs. de novo 0.542 (0.401–0.733) <0.001 0.593 (0.422–0.833) 0.003
BMI, kg/m2 NC 0.951 (0.919–0.984) 0.004
Smoking status, yes vs. no NC 1.228 (0.796–1.895) 0.354
Hypertension status, yes vs. no NC 0.645 (0.454–0.915) 0.014
Statin use, yes vs. no NC 0.775 (0.556–1.082) 0.135
Previous stroke, yes vs. no NC 1.472 (0.970–2.232) 0.069
Previous COPD, yes vs. no NC 1.286 (0.894–1.850) 0.176
Haemoglobin, g/dL NC 0.902 (0.841–0.968) 0.004
Sodium, mEq/L NC 0.946 (0.925–0.967) <0.001

Model 1: adjusted for age, sex, systolic blood pressure, eGFRMDRD , LVEF, HF aetiology, and HF presentation.
Model 2: the same covariates included in model 1 plus BMI, smoking history, hypertension, statin use, previous stroke and COPD, haemoglobin, and sodium levels.
BMI, body mass index; CI, confidence interval; eGFRMDRD , estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease study equation); HF,
heart failure; NC, not considered; OR, odds ratio.

Table 4 Multivariable Cox regression analysis for 1-year all-cause mortality in the whole cohort of patients

Variables Regression model 1 Regression model 2

........................................ .........................................
HR (95% CI) P-value HR (95% CI) P-value
...........................................................................................................................................
Diabetes status, yes vs. no 1.133 (1.006–1.277) 0.040 1.162 (1.020–1.325) 0.024
Age, years 1.029 (1.023–1.035) <0.001 1.030 (1.024–1.036) <0.001
Sex, male vs. female 1.125 (0.988–1.280) 0.076 1.216 (1.058–1.399) 0.006
Systolic blood pressure, mmHg 0.991 (0.989–0.993) <0.001 0.995 (0.992–0.997) <0.001
eGFRMDRD , mL/min/1.73 m2 0.986 (0.984–0.989) <0.001 0.989 (0.986–0.992) <0.001
LVEF, % 0.985 (0.980–0.989) <0.001 0.984 (0.979–0.989) <0.001
HF aetiology, ischaemic vs. non-ischaemic 0.848 (0.750–0.958) <0.008 0.928 (0.812–1.060) 0.271
HF presentation, worsening vs. de novo 1.027 (0.898–1.176) 0.695 1.106 (0.952–1.286) 0.189
BMI, kg/m2 NC 0.987 (0.974–1.001) 0.061
Smoking status, yes vs. no NC 0.926 (0.763–1.123) 0.432
Hypertension status, yes vs. no NC 0.742 (0.636–0.866) <0.001
Statin use, yes vs. no NC 0.733 (0.640–0.840) <0.001
Previous stroke, yes vs. no NC 1.260 (1.059–1.498) 0.009
Previous COPD, yes vs. no NC 1.157 (0.994–1.348) 0.060
Haemoglobin, g/dL NC 0.897 (0.871–0.923) <0.001
Sodium, mEq/L NC 0.970 (0.961–0.980) <0.001

Model 1: adjusted for age, sex, systolic blood pressure, eGFRMDRD , LVEF, HF aetiology, and HF presentation.
Model 2: the same covariates included in model 1 plus BMI, smoking history, hypertension, statin use, previous stroke and COPD, haemoglobin, and sodium levels.
BMI, body mass index; CI, confidence interval; eGFRMDRD , estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease study equation); HF,
heart failure; HR, hazard ratio; NC, not considered.

Discussion and cardiac mortality, and 1-year hospital readmission due to HF

....................

in patients with diabetes (especially in those treated with insulin

In this prospective, observational registry of a large unselected that may reflect a greater disease severity) compared with those
European population of consecutive patients admitted to the without diabetes; (iii) a significant association between diabetes
hospital for acute HF, we observed: (i) a very high prevalence of and in-hospital mortality and 1-year follow-up outcomes even after
known and previously undiagnosed diabetes among these patients adjusting for multiple established risk factors and potential con-
(49.4%); (ii) higher rates of in-hospital mortality, 1-year all-cause founding variables (including also HF aetiology, HF presentation,

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
8 G. Targher et al.

Table 5 Multivariable Cox regression analysis for 1-year heart failure re-hospitalization in the whole cohort of patients

Variables Regression model 1 Regression model 2

........................................ .........................................
HR (95% CI) P-value HR (95% CI) P-value
...........................................................................................................................................
Diabetes status, yes vs. no 1.348 (1.175–1.548) <0.001 1.320 (1.139–1.530) <0.001
Age, years 1.002 (0.996–1.008) 0.519 1.000 (0.993–1.006) 0.904
Sex, male vs. female 1.082 (0.931–1.257) 0.306 1.067 (0.911–1.251) 0.422
Systolic blood pressure, mmHg 0.996 (0.993–0.998) 0.001 0.997 (0.994–0.999) 0.020
eGFRMDRD , mL/min/1.73 m2 0.991 (0.988–0.994) <0.001 0.991 (0.988–0.994) <0.001
LVEF, % 0.991 (0.985–0.996) <0.001 0.989 (0.983–0.994) <0.001
HF aetiology, ischaemic vs. non-ischaemic 0.828 (0.720–0.953) 0.008 0.803 (0.691–0.933) 0.004
HF presentation, worsening vs. de novo 2.070 (1.737–2.467) <0.001 1.854 (1.536–2.239) <0.001
BMI, kg/m2 NC 0.996 (0.982–1.010) 0.589
Smoking status, yes vs. no NC 0.940 (0.766–1.154) 0.554
Hypertension status, yes vs. no NC 0.885 (0.740–1.059) 0.182
Statin use, yes vs. no NC 1.163 (1.002–1.349) 0.046
Previous stroke, yes vs. no NC 1.343 (1.105–1.632) 0.003
Previous COPD, yes vs. no NC 1.333 (1.128–1.575) <0.001
Haemoglobin, g/dL NC 0.961 (0.931–0.993) 0.018
Sodium, mEq/L NC 1.001 (0.988–1.015) 0.853

Model 1: adjusted for age, sex, systolic blood pressure, eGFRMDRD , LVEF, HF aetiology, and HF presentation.
Model 2: the same covariates included in model 1 plus BMI, smoking history, hypertension, statin use, previous stroke and COPD, haemoglobin, and sodium levels.
BMI, body mass index; CI, confidence interval; eGFRMDRD , estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease study equation); HF,
heart failure; NC, not considered.

LVEF, haemoglobin, and eGFRMDRD ); and (iv) a significant and these data were not collected. The Organized Program to Initi-
.............................................................................................

independent association between high blood glucose levels at ate Lifesaving Treatment in Hospitalized Patients with Heart Failure
hospital admission and the risk of in-hospital mortality in both (OPTIMIZE-HF) registry showed that the presence of diabetes
patients with and without diabetes. did not independently predict in-hospital mortality, 60- to 90-day
Our findings provide a contemporary picture on short- and post-discharge mortality, or re-hospitalizations.15 Moreover, Kosi-
mid-term adverse clinical outcomes of a large European cohort of borod et al. did not find any association between diabetes and
acute HF patients with and without diabetes, outside the context 30-day and 1-year all-cause mortality in elderly patients hospi-
of randomized clinical trials. In addition, our findings also shed light talized with acute HF.12 Finally, the presence of diabetes was
on the previously reported discrepant results (as discussed below) strongly associated with higher rates of in-hospital mortality but
regarding the prognostic impact of diabetes per se on adverse it did not significantly predict 1-year post-discharge mortality or
clinical outcomes among inpatients with acute HF. In fact, to re-hospitalization rates in the cohort of 1176 inpatients from the
date, despite the high prevalence of diabetes among patients with Italian Network on HF (IN-HF) Outcome registry.16
acute HF (ranging from 30% to 50%),1 – 3 the association between To date, studies of patients with acute HF that have also specif-
diabetes and HF often remains under-recognized by clinicians, and ically examined the association between admission blood glucose
there are conflicting data regarding the prognostic impact of dia- levels and the rates of mortality and hospital readmission are
betes per se on the risk of mortality and re-hospitalizations, both in limited and discrepant. Some studies did not find any association
the short and mid term, among patients hospitalized for acute HF. between elevated admission blood glucose levels and mortality,
Our findings expand previous observations supporting that both in the short and long term.12,14,21 Our results are consistent
patients with acute HF and diabetes have poor in-hospital mor- with other observations suggesting that elevated admission blood
tality and/or post-discharge adverse outcomes compared with glucose levels are a prognostic marker for in-hospital mortality
those without diabetes.7,9,10 However, our findings also contrast in both patients with and without diabetes.10,22,23 For example,
with those from other previously published studies. For instance, Sud et al.22 demonstrated that mildly elevated hyperglycaemia was
in a large retrospective cohort study of Scottish patients dis- significantly associated with increased rates of 30-day all-cause
charged from hospital with a diagnosis of acute HF between 1986 mortality and re-hospitalizations in patients with acute HF. How-
and 2003, the presence of diabetes was associated with a lower ever, similarly to our findings, the association between admission
mortality at 30 days, but it was an independent predictor of blood glucose levels and mortality was no longer significant at
higher mortality at 1 year.8 Similarly, the presence of diabetes did 1 year among these patients, regardless of pre-existing diabetes.22
not independently predict in-hospital mortality in the cohort of Although additional studies are certainly needed, our findings
patients from the Acute Decompensated Heart Failure National further suggest that in-hospital hyperglycaemia is a reliable marker
Registry (ADHERE).11 However, the ADHERE registry did not of poor short-term outcomes and mortality in patients with and
address the impact of diabetes on post-discharge outcomes as without diabetes.24,25

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
Acute heart failure and diabetes 9

Unfortunately, as specified in the Results, we cannot exactly do not represent those acutely admitted to other hospital facili-

........................................................................................................................................................................
distinguish in a certain number of our patients between those ties. Accordingly, our patient cohort does not represent the whole
with newly diagnosed diabetes and those with non-diabetic stress gamut of patients with acute HF. Fourthly, as discussed above, this
hyperglycaemia, as repeat glucose testings or extensive HbA1c study cannot exactly distinguish between a new diagnosis of dia-
measurements were not performed. However, it is known that a betes and transient stress hyperglycaemia in a subgroup of patients.
significant association between transient stress hyperglycaemia and However, we would like to note that this is an intrinsic limitation
adverse clinical outcomes does exist in the short term (e.g. a longer of most epidemiological studies or registry databases, like this, in
length of hospital stay, a higher admission rate to an intensive care which the confirmation of diabetes diagnosis, on at least two sep-
unit, and a higher rate of in-hospital mortality), but not in the longer arate occasions, in patients with previously undiagnosed diabetes
term.24,25 Thus, it is important to underline that some misclassifi- has never been made. Finally, we lacked detailed information about
cation of new-onset diabetes based on a single blood glucose mea- the use of different classes of oral hypoglycaemic agents, the hypo-
surement was likely in our clinical setting (i.e. some of our newly glycaemic events, and the extra-cardiac causes of mortality and
diagnosed diabetic inpatients might have transient stress hypergly- re-hospitalization, and also follow-up data on plasma glucose and
caemia). If so, this misclassification could have partly affected the HbA1c levels were not available.
assessment of the ‘true’ prevalence of diabetes and its prognostic In conclusion, our contemporary results from the ESC-HF
effect on in-hospital mortality; in contrast, given that in the liter- Long-Term Registry show that the presence of diabetes is asso-
ature, transient stress hyperglycaemia has not been reported to ciated with substantially increased rates of in-hospital mortality,
be significantly associated with adverse clinical outcomes in the 1-year all-cause mortality, and 1-year HF re-hospitalization in
longer term,24,25 our results are most likely to be a conservative patients hospitalized for acute HF. Notably, these associations
estimate of the impact of diabetes on 1-year clinical outcomes. remain statistically significant after adjusting for multiple clinical
The major strengths of our study are intrinsic to the design risk factors and potential confounding variables (including also HF
of the ESC-HF Long-Term Registry, which is one of the largest, aetiology, HF presentation, LVEF, and kidney function parameters).
multinational, and nationally representative systematic collections Furthermore, elevated admission blood glucose concentrations are
of contemporary European patients with HF. The sample size of powerfully prognostic for in-hospital mortality in patients both with
our registry provides an adequate statistical power to keep the and without established diabetes. In an era where there is increas-
possible occurrence of both type I and type II errors to a minimum. ing emphasis on chronic disease management as a strategy to
Thus, we believe that the added value of our registry to the existing contain healthcare costs, these findings further highlight the prog-
literature is that it provides solid and updated data regarding nostic value of diabetes and the need for therapies that improve
in-hospital and 1-year survival rates in a large unselected cohort survival outcomes in this particularly high-risk patient population.26
of acute HF patients followed by cardiologists, thus providing a
picture of European patients, who were not included in controlled
trials but were currently being treated in general cardiology clinical
Supplementary Information
practice. In addition, our registry also provides clear evidence Additional Supporting Information may be found in the online
of the impact of diabetes per se on the risk of both in-hospital version of this article:
mortality and 1-year follow-up outcomes as well as the possible Table S1. Associations between plasma glucose levels at hospital
impact of elevated blood glucose levels at hospital admission admission and adverse clinical outcomes stratified by diabetes
on the risk of in-hospital mortality, regardless of pre-existing status.
diabetes. Finally, in our registry, thorough sensitivity analyses that Table S2. Associations between diabetes treatment (insulin vs.
accounted for a reasonably large number of established risk factors diet/oral drugs) at hospital admission and adverse clinical outcomes
were also possible because of the availability of systematically in the subgroup of diabetic patients.
collected clinical data, laboratory measures, and instrumental data Table S3. Associations between patients with either reduced LVEF
(including echocardiographic functional measures, i.e. LVEF) for a ≤45% or with LVEF >45% at hospital admission and adverse clinical
large number of patients. outcomes stratified by diabetes status.
Some important limitations of this registry should also be men- Table S4. Associations between patients with ischaemic or
tioned. First, although we sought to balance the methodolog- non-ischaemic HF aetiology at hospital admission and adverse clin-
ical need for consecutiveness of enrolment with the practical ical outcomes stratified by diabetes status.
feasibility, thereby decreasing the workload for centres by limit-
ing recruitment to 1 day per week for 12 months, we cannot Acknowledgements
prove definitely the consecutiveness of patient enrolment. How- The Executive Committee of the study had full access to the data
ever, local audits were performed to verify the quality of data and and takes complete responsibility for the integrity and the accuracy
the consecutiveness of enrolment. Secondly, representativeness is of the data analysis.
often recognized as a limitation in all observational studies. To
lessen this problem, the centres were selected in proportion to
the population size of participating countries, taking into account Funding
the different technological levels of the invited centres. Thirdly, all Since the start of EORP, the following companies have sup-
patients were enrolled in cardiology wards and clinics, and they ported the programme: Abbott Vascular Int. (2011–2014),

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology
10 G. Targher et al.

Amgen Cardiovascular (2012–2018), AstraZeneca (2014–2017), 12. Kosiborod M, Inzucchi SE, Spertus JA, Wang Y, Masoudi FA, Havranek EP,

........................................................................................................................................................................
Krumholz HM. Elevated admission glucose and mortality in elderly patients
Bayer (2013–2018), Boehringer Ingelheim (2013–2016), Boston
hospitalized with heart failure. Circulation 2009;119:1899–1907.
Scientific (2010–2012), The Bristol Myers Squibb and Pfizer 13. Parissis JT, Ikonomidis I, Rafouli-Stergiou P, Mebazaa A, Delgado J, Farmakis D,
Alliance (2014–2016), The Alliance Daiichi Sankyo Europe Vilas-Boas F, Paraskevaidis I, Anastasiou-Nana M, Follath F. Clinical characteristics
GmbH and Eli Lilly and Company (2014–2017), Edwards and predictors of in-hospital mortality in acute heart failure with preserved left
ventricular ejection fraction. Am J Cardiol 2011;107:79–84.
(2016–2019), Gedeon Richter Plc. (2014–2017), Menarini
14. Cleland JG, Chiswell K, Teerlink JR, Stevens S, Fiuzat M, Givertz MM, Davison BA,
Int. Op. (2010–2012), MSD-Merck & Co. (2011–2014), Novar- Mansoor GA, Ponikowski P, Voors AA, Cotter G, Metra M, Massie BM, O’Connor
tis Pharma AG (2014–2017), ResMed (2014–2016), Sanofi CM. Predictors of post-discharge outcomes from information acquired shortly
(2010–2011), SERVIER (2012–2015). after admission for acute heart failure: a report from the placebo-controlled
randomized study of the selective A1 adenosine receptor antagonist rolofylline
Conflicts of interest: R.F. reported that he received a honorar-
for patients hospitalized with acute decompensated heart failure and volume
ium from Servier for steering committee membership consulting overload to assess treatment effect on congestion and renal function (PROTECT)
and speaking, and support for travel to study meetings from Servier. study. Circ Heart Fail 2014;7:76–87.
In addition, he received personal fees from Boehringer-Ingelheim, 15. Greenberg BH, Abraham WT, Albert NM, Chiswell K, Clare R, Stough WG,
Gheorghiade M, O’Connor CM, Sun JL, Yancy CW, Young JB, Fonarow GC.
Novartis, Merck Serono, and Irbtech. Finally, he is a stockholder
Influence of diabetes on characteristics and outcomes in patients hospitalized
in Medical Trials Analyis. L.T. reports personal fees from Servier, with heart failure: a report from the Organized Program to Initiate Lifesaving
St Jude Medical, CVIE Therapeutics, Cardiorentis, Medtronic, and Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF). Am Heart
from Boston Scientific, outside the submitted work. A.P.M. reports J 2007;154:277.e1–e8.
16. Targher G, Dauriz M, Tavazzi L, Temporelli PL, Lucci D, Urso R, Lecchi G, Bellanti
grants from Novartis, Bayer, and Cardiorentis, outside the submit-
G, Merlo M, Rossi A, Maggioni AP; IN-HF Outcome Investigators. Prognostic
ted work. All other authors have no conflicts to declare. impact of in-hospital hyperglycemia in hospitalized patients with acute heart
failure: results of the IN-HF (Italian Network on Heart Failure) Outcome registry.
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European Journal of Heart Failure © 2016 European Society of Cardiology
Acute heart failure and diabetes 11

Appendix 1 N. Nyolczas, A. Csaba Nagy; Pecs (Baranya): R. Halmosi; ISRAEL

........................................................................................................................................................................
Hadera: J. Elber, I. Alony, A. Shotan, A. Vazan Fuhrmann; Haifa:
Committees and Investigators O. Amir; ITALY Atri: S. Romano, S. Marcon, M. Penco, M. Di
Mauro, E. Lemme; Brescia: V. Carubelli, R. Rovetta, M. Metra, M.
Executive Committee: M.G. Crespo-Leiro, S.D. Anker, A.J. Coats, R. Bulgari, F. Quinzani, C. Lombardi; Cotignola: S. Bosi, G. Schiavina,
Ferrari, G. Filippatos, A.P. Maggioni, A. Mebazaa, M.F. Piepoli A. Squeri, A. Barbieri; Cremona: G. Di Tano, S. Pirelli; Ferrara:
Steering Committee (National Co-ordinators): O. Amir, O. Chioncel, R. Ferrari, A. Fucili; Foggia: T. Passero, S. Musio, M. Di Biase, M.
U. Dahlström, J.F. Delgado Jimenez, J. Drozdz, A. Erglis, E. Correale, G. Salvemini; Lumezzane: S. Brognoli, E. Zanelli, A.
Fazlibegovic, C. Fonseca, F. Fruhwald, P. Gatzov, E. Goncalvesova, Giordano; Milano: P. Agostoni, G. Italiano, E. Salvioni; Modena:
M. Hassanein, J. Hradec, A. Kavoliuniene, M. Lainscak, D. Logeart, S. Copelli, M.G. Modena, L. Reggianini, C. Valenti, A. Olaru; Mon-
B. Merkely, M. Metra, M. Otljanska, P.M. Seferovic, E. Srbinovska serrato: S. Bandino, M. Deidda, G. Mercuro, C. Cadeddu Dessalvi;
Kostovska, A. Temizhan, D. Tousoulis Novara: P.N. Marino, M.V. Di Ruocco, C. Sartori, C. Piccinino;
EORP Team: M. Andarala, T. Ferreira, E. Fiorucci, G. Gracia, C. Palermo: G. Parrinello, G. Licata, D. Torres, S. Giambanco, S.
Laroche, C. Pommier, C.Taylor Busalacchi, S. Arrotti, S. Novo, R.M. Inciardi, P. Pieri, P.R. Chirco,
Local monitors: A. Cuculici (Republic of Moldova, Romania), C. M. Ausilia Galifi, G. Teresi, D. Buccheri, A. Minacapelli; Passirana
Gaulhofer (Austria), E. Perez Casado (Portugal, Spain), E. Szymczyk di rho (Milano): M. Veniani, A. Frisinghelli; Pavia: S.G. Priori, S.
(Poland), F. Ramani (Italy), G. Mulak (France, Switzerland), IL. Cattaneo, C. Opasich, A. Gualco; Roma: M. Pagliaro, M. Mancone,
Schou (Denmark), J. Semenka (Bulgaria, Czech Republic, Hungary, F. Fedele, A. Cinque, M. Vellini, I. Scarfo, F. Romeo, F. Ferraiuolo,
Poland, Slovakia), J. Stojkovic (Bosnia Herzegovina, Croatia, Serbia, D. Sergi; San Bonifacio (Verona): M. Anselmi; Sassuolo: F.
Slovenia), R. Mehanna (Egypt), V. Mizarienne (Latvia). Melandri, E. Leci, E. Iori; Torino: V. Bovolo, S. Pidello, S. Frea, S.
Bergerone, M. Botta, F.G. Canavosio, F. Gaita; Trieste: M. Merlo,
M. Cinquetti, G. Sinagra, F. Ramani, E. Fabris, D. Stolfo; Udine: J.
Investigators from the participating Artico, D. Miani, C. Fresco, C. Daneluzzi, A. Proclemer; Verona:
centres M. Cicoira, L. Zanolla, G. Marchese, F. Torelli, C. Vassanelli;
AUSTRIA Braunau: J. Auer; Graz: K. Ablasser, F. Fruhwald, T. LATVIA Jelgava: N. Voronina; Riga: A. Erglis; LITHUANIA Kau-
Dolze, K. Brandner; Innsbruck: S. Gstrein, G. Poelzl; Sankt Poel- nas: V. Tamakauskas, V. Smalinskas, R. Karaliute, I. Petraskiene,
ten: D. Moertl; Vienna: S. Reiter, A. Podczeck-Schweighofer; E. Kazakauskaite, E. Rumbinaite, A. Kavoliuniene; Marijam-
BOSNIA HERZEGOVINA Mostar: A. Muslibegovic, M. Vasilj, E. pole: V. Vysniauskas, R. Brazyte-Ramanauskiene, D. Petraskiene;
Fazlibegovic, M. Cesko, D. Zelenika, B. Palic, D. Pravdic, D. POLAND Biala: S. Stankala, P. Switala, Z. Juszczyk; Bydgoszcz:
Cuk; BULGARIA Sofia: K. Vitlianova, T. Katova, T. Velikov, T. W. Sinkiewicz, W. Gilewski, J. Pietrzak; Chelmza: T. Orzel, P.
Kurteva, P. Gatzov, Vidin: D. Kamenova; Varna: M. Antova, V. Kasztelowicz; Czestochowa: P. Kardaszewicz, M. Lazorko-Piega,
Sirakova; CZECH REPUBLIC Brno: J. Krejci, M. Mikolaskova, J. J. Gabryel; Gdansk: K. Mosakowska, J. Bellwon, A. Rynkiewicz, G.
Spinar; Prague: J. Krupicka, F. Malek, M. Hegarova; Olomouc: Raczak, E. Lewicka, A. Dabrowska-Kugacka; Kielce: R. Bartkowiak,
M. Lazarova; Znojmo: Z. Monhart; EGYPT Alexandria: M. Has- B. Sosnowska-Pasiarska, B. Wozakowska-Kaplon; Kluczbork: A.
sanein, M. Sobhy, F. El Messiry, A.H. El Shazly, Y. Elrakshy; Assiut: Krzeminski; Krakow: M. Zabojszcz, E. Mirek-Bryniarska, A.
A. Youssef; Benha: A.A. Moneim; Cairo: M. Noamany, A. Reda, Grzegorzko, K. Bury, J. Nessler, J. Zalewski, A. Furman; Lodz:
T.K. Abdel Dayem, N. Farag, S. Ibrahim Halawa, M. Abdel Hamid, K. M. Broncel, A. Poliwczak, A. Bala, P. Zycinski, M. Rudzinska, L.
Said, A. Saleh; Damanhour, El Beheira: H. Ebeid; Giza Cairo: Jankowski, J.D. Kasprzak, L. Michalak, K. Wojtczak Soska, J. Drozdz,
R. Hanna, R. Aziz, O. Louis, M.A. Enen, B.S. Ibrahim; Ismailya: I. Huziuk, A. Retwinski; Lublin: P. Flis, J. Weglarz, A. Bodys; Poz-
G. Nasr; Port Said: A. Elbahry; Tanta: H. Sobhy, M. Ashmawy; nan: S. Grajek, M. Kaluzna-Oleksy, E. Straburzynska-Migaj, R.
Zagazig: M. Gouda, W. Aboleineen; FRANCE Besançon: Y. Dankowski, K. Szymanowska, J. Grabia, A. Szyszka, A. Now-
Bernard, P. Luporsi, N. Meneveau, M. Pillot, M. Morel, M-F. icka; Pruszkow: M. Samcik, L. Wolniewicz, K. Baczynska, K.
Seronde, F. Schiele, F. Briand; Bron – Lyon: F. Delahaye; Créteil: Komorowska, I. Poprawa, E. Komorowska, D. Sajnaga, A. Zolbach,
T. Damy; Dijon: J-C. Eicher; Lille: P. de Groote, M. Fertin, N. A. Dudzik-Plocica, A-F. Abdulkarim, A. Lauko-Rachocka; Prze-
Lamblin; Paris: R. Isnard, C. Lefol, S. Thevenin, A. Hagege, G. worsk: L. Kaminski, A. Kostka, A. Cichy; Sieradz: P. Ruszkowski,
Jondeau, D. Logeart; Poitiers: V. Le Marcis, J-F. Ly, D. Coisne, B. M. Splawski; Starachowice: G. Fitas, A. Szymczyk, A. Ser-
Lequeux; Rennes: V. Le Moal, S. Mascle, P. Lotton, N. Behar, E. wicka, A. Fiega; Strzegom: D. Zysko; Szczecin: W. Krysiak,
Donal, C. Thebault, C. Ridard, A. Reynaud, A. Basquin; Rouen: S. Szabowski, E. Skorek; Warszawa: P. Pruszczyk, P. Bienias, M.
F. Bauer; Senlis: R. Codjia; Toulouse: M. Galinier; GREECE Ciurzynski, M. Welnicki, A. Mamcarz, A. Folga, T. Zielinski, T.
Athens: P. Tourikis, M. Stavroula, D. Tousoulis, C. Stefanadis, Rywik, P. Leszek, M. Sobieszczanska-Malek, M. Piotrowska, K.
C. Chrysohoou, I. Kotrogiannis, V. Matzaraki, T. Dimitroula, A. Kozar-Kaminska, K. Komuda, J. Wisniewska, A. Tarnowska, P.
Karavidas, G. Tsitsinakis, C. Kapelios, J. Nanas, H. Kampouri, E. Balsam, M. Marchel, G. Opolski, A. Kaplon-Cieslicka, R.J. Gil,
Nana, E. Kaldara, A. Eugenidou; Heraklion, Crete: P. Vardas, I. O. Mozenska, K. Byczkowska, K. Gil, A. Pawlak, A. Michalek, P.
Saloustros, A. Patrianakos; Volos: T. Tsaknakis, S. Evangelou, N. Krzesinski, K. Piotrowicz, B. Uzieblo-Zyczkowska, A. Stanczyk, A.
Nikoloulis, H. Tziourganou, A. Tsaroucha, A. Papadopoulou, A. Skrobowski; Wroclaw: P. Ponikowski, E. Jankowska; Zabrze: P.
Douras; HUNGARY Budapest: L. Polgar, B. Merkely, A. Kosztin, Rozentryt, L. Polonski, E. Gadula-Gacek, E. Nowalany-Kozielska,

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European Journal of Heart Failure © 2016 European Society of Cardiology
12 G. Targher et al.

A. Kuczaj, Z. Kalarus, M. Szulik, K. Przybylska, J. Klys; Zamosc: G. A.B. Genis, S. Mirabet, A. Mendez, L. Garcia-Cosio, E. Roig, V.

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Prokop-Lewicka, A. Kleinrok; PORTUGAL Carnaxide: C. Tavares Leon, J. Gonzalez-Costello, G. Muntane, A. Garay; Granada:
Aguiar, A. Ventosa; Faro: S. Pereira, R. Faria, J. Chin, I. De Jesus; V. Alcade-Martinez, S. Lopez Fernandez, R. Rivera-Lopez, M.
Guilhufe-Penafiel: R. Santos, P. Silva, N. Moreno, C. Queirós, C. Puga-Martinez, M. Fernandez-Alvarez, J.L. Serrano-Martinez; La
Lourenço, A. Pereira, A. Castro, A. Andrade; Lisboa: T. Oliveira Coruna: M.G. Crespo-Leiro, Z. Grille-Cancela, R. Marzoa-Rivas,
Guimaraes, S. Martins, R. Placido, G. Lima, D. Brito, A.R. Francisco, P. Blanco-Canosa, M.J. Paniagua-Martin, E. Barge-Caballero; La
R. Cardiga, M. Proenca, I. Araujo, F. Marques, C. Fonseca; Porto: Laguna – Santa Cruz de Tenerife (Canary Islands): I.
B. Moura, S. Leite, M. Campelo, J. Silva-Cardoso, J. Rodrigues, Laynez Cerdena, I. Famara Hernandez Baldomero, A. Lara Padron;
I. Rangel, E. Martins, A. Sofia Correia; Santarem: M. Peres, L. Madrid: S. Ofelia Rosillo, R. Dalmau Gonzalez-Gallarza, O. Sal-
Marta, G. Ferreira da Silva, D. Severino, D. Durao; Vila Real: vador Montanes, A.M. Iniesta Manjavacas, A. Castro Conde,
S. Leao, P. Magalhaes, I. Moreira, A. Filipa Cordeiro, C. Ferreira, A. Araujo, T. Soria, P. Garcia-Pavia, M. Gomez-Bueno, M.
C. Araujo, A. Ferreira, A. Baptista; ROMANIA Brasov: M. Radoi; Cobo-Marcos, L. Alonso-Pulpon, J. Segovia Cubero, I. Sayago,
Bucharest: G. Bicescu, D. Vinereanu, C-J. Sinescu, C. Macarie, A. Gonzalez-Segovia, A. Briceno, P. Escribano Subias, M. Vicente
R. Popescu, I. Daha, G-A. Dan, C. Stanescu, A. Dan; Constanta: Hernandez, M.J. Ruiz Cano, M.A. Gomez Sanchez, J.F. Delgado
E. Craiu; Galati: E. Nechita; Iasi: V. Aursulesei; Timisoara: Jimenez, E. Barrios Garrido-Lestache; Malaga: J.M. Garcia Pinilla;
R. Christodorescu; SERBIA Belgrade: P. Otasevic, P.M. Sefer- Manacor (Mallorca): B. Garcia de la Villa, A. Sahuquillo; Mar-
ovic, D. Simeunovic, A.D. Ristic, V. Celic, M. Pavlovic-Kleut, J. bella (Malaga): R. Bravo Marques, F. Torres Calvo; Murcia:
Suzic Lazic, B. Stojcevski, B. Pencic, A. Stevanovic, A. Andric; M.T. Perez-Martinez, M.R. Gracia-Rodenas, I. P. Garrido-Bravo,
Kragujevac: V. Iric-Cupic, M. Jovic, G. Davidovic, S. Milanov; F. Pastor-Perez, D.A. Pascual-Figal; Oviedo: B. Diaz Molina;
Nis: V. Mitic, V. Atanaskovic, S. Antic, M. Pavlovic, D. Stanojevic; Sabadell (Barcelona): J. Orus, F. Epelde Gonzalo; San Juan
Niska Banja: V. Stoickov, S. Ilic, M. Deljanin Ilic, D. Petrovic; de Alicante: V. Bertomeu, R. Valero, R. Martinez-Abellan, J.
Sremska Kamenica (Vojvodina): S. Stojsic, S. Kecojevic, S. Quiles, J.A. Rodrigez-Ortega, I. Mateo, A. ElAmrani; Sevilla:
Dodic, N. Cemerlic Adic, M. Cankovic, J. Stojiljkovic, B. Miha- C. Fernandez-Vivancos; Tortosa: D. Bierge Valero; Valen-
jlovic, A. Radin; Zemun, Belgrade: S. Radovanovic, M. Krotin; cia: L. Almenar-Bonet, I.J. Sanchez-Lazaro, E. Marques-Sule,
SLOVAKIA Banovce nad Bebravou: A. Klabnik; Bratislava: E. L. Facila-Rubio, J. Perez-Silvestre, P. Garcia-Gonzalez, F.
Goncalvesova, M. Pernicky, J. Murin; Martin: F. Kovar; Presov: J. Ridocci-Soriano, D. Garcia-Escriva, A. Pellicer-Cabo; Valladolid:
Kmec, H. Semjanova; SLOVENIA Brezice: M. Strasek, M. Savnik L. de la Fuente Galan, J. Lopez Diaz, A. Recio Platero; Vigo: J.C.
Iskra; Izola: T. Ravnikar, N. Cernic Suligoj, J. Komel; Ljubljana: Arias; Zaragoza: T. Blasco-Peiro, M. Sanz Julve, E. Sanchez-Insa,
Z. Fras, B. Jug; Maribor: T. Glavic, R. Losic, M. Bombek, I. C. Aured-Guallar, A. Portoles-Ocampo; SWEDEN Stockholm:
Krajnc, B. Krunic; Murska Sobota: S. Horvat, D. Kovac, D. Rajt- M. Melin, E. Hägglund; Lindesberg: A. Stenberg, I-M. Lindahl;
man; Ptuj: V. Cencic, M. Letonja; Sempeter pri Novi Gorici: Varberg: B. Asserlund, L. Olsson; Linköping: U. Dahlström,
R. Winkler, M. Valentincic, C. Melihen-Bartolic, A. Bartolic; M. Afzelius; Jönköping: P. Karlström, L. Tengvall; Kristianstad:
Slovenj Gradec: M. Pusnik Vrckovnik, M. Kladnik, C. Slemenik P-A.Wiklund, B. Olsson; TURKEY Ankara: S. Kalayci, A. Temizhan;
Pusnik, A. Marolt; Trbovlje: J. Klen, B. Drnovsek, B. Leskovar; Eskisehir: Y. Cavusoglu; Kilis: E. Gencer; Sivas: M.B. Yilmaz, H.
SPAIN Albacete: M.J. Fernandez Anguita, J.C. Gallego Page, F.M. Gunes
Salmeron Martinez; Barakaldo (Vizcaya): J. Andres; Barcelona:

© 2016 The Authors

European Journal of Heart Failure © 2016 European Society of Cardiology