Heart failure admissions in adults with congenital heart disease; risk factors and prognosis

International Journal of Cardiology 168 (2013) 2487–2493

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Heart failure admissions in adults with congenital heart disease; risk factors and prognosis A.C. Zomer a, b, c, I. Vaartjes b, E.T. van der Velde d, H.M.Y. de Jong a, T.C. Konings e, L.J. Wagenaar f, W.F. Heesen g, F. Eerens h, L.H.B. Baur i, j, D.E. Grobbee b, B.J.M. Mulder a, c,⁎ a

Department of Cardiology, Academic Medical Center, Amsterdam, The Netherlands Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands d Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands e Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands f Department of Cardiology, Medical Spectrum Twente, Enschede, The Netherlands g Department of Cardiology, Vie Curi Medical Center, Venlo, The Netherlands h Department of Cardiology, University Maastricht, Maastricht, The Netherlands i Department of Cardiology, Atrium Medical Center Parkstad, Heerlen, The Netherlands j Faculty of Health, Medicine and Life Sciences, University Maastricht, Maastricht, The Netherlands b c

a r t i c l e

i n f o

Article history: Received 4 November 2012 Received in revised form 17 January 2013 Accepted 9 March 2013 Available online 18 April 2013 Keywords: Adults Congenital heart disease Heart failure Admission Mortality

a b s t r a c t Background: Heart failure (HF) is a serious complication and often the cause of death in adults with congenital heart disease (CHD). Therefore, our aims were to determine the frequency of HF-admissions, and to assess risk factors of first HF-admission and of mortality after first HF-admission in adults with CHD. Methods: The Dutch CONCOR registry was linked to the Hospital Discharge Registry and National Mortality Registry to obtain data on HF-admissions and mortality. Risk factors for both HF-admission and mortality were assessed using Cox regression models. Results: Of 10,808 adult patients (49% male), 274 (2.5%) were admitted for HF during a median follow-up period of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient-years, but the incidence of HF itself will be higher. Main defect, multiple defects, and surgical interventions in childhood were identified as independent risk factors of HF-admission. Patients admitted for HF had a five-fold higher risk of mortality than patients not admitted (hazard ratio (HR) = 5.3; 95% confidence interval 4.2–6.9). One- and three-year mortality after first HF-admission were 24% and 35% respectively. Independent risk factors for three-year mortality after first HF-admission were male gender, pacemaker implantation, admission duration, non-cardiac medication use and high serum creatinine. Conclusions: The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years. Mortality risk is substantially increased after HF-admission, which emphasises the importance to identify patients at high risk of HF-admission. These patients might benefit from closer follow-up and earlier medical interventions. The presented risk factors may facilitate surveillance. © 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction An increasing number of patients with congenital heart disease (CHD) reach adulthood due to improved developments in paediatric cardiology, cardiac surgery and thorough follow-up. With these improvements survival has increased tremendously. However, adults with CHD are often faced with symptoms, sequelae, and complications from residual defects and interventions, including arrhythmias, endocarditis, and congestive heart failure [1–4]. ⁎ Corresponding author at: Department of Cardiology, Room B2-240, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: + 31 20 5662193; fax: + 31 20 5666809. E-mail address: [email protected] (B.J.M. Mulder). URL: http://www.concor.net (B.J.M. Mulder). 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.03.003

Several studies have investigated the occurrence and risk factors of arrhythmias and endocarditis in adults with CHD [5–8]. Yet, only a few studies have focused on the occurrence of heart failure (HF) in adults with CHD [9–11], and it is unknown how often patients need to be admitted. Moreover, the prognosis of HF in this patient group is poorly described, while HF is one of the main causes of death in these patients [12–14]. Numerous studies have confirmed the poor prognosis in patients who develop (symptomatic) HF secondary to acquired heart disease. Both morbidity and mortality (after hospitalization) are high [15,16]. Whether the prognosis of HF in patients with CHD is as poor as in patients with acquired heart disease is still unclear. Risk factors of mortality after HF have been identified from clinical trials and population-based studies for patients with acquired heart disease [16,17]. However, risk factors of mortality in adult CHD patients

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with HF may be different. Knowledge of mortality risk factors can be used to generate predictive models that can aid clinicians' decision making, in particular by identifying patients who are at high or low risk of death. Patients at high risk of death might benefit from early interventions and increased medical surveillance. Therefore, the aims of the present study were 1) to assess the frequency of HF-admissions in adults with CHD, 2) to identify risk factors of first HF-admission using simple clinical parameters and 3) to identify risk factors of mortality in adult CHD patients first hospitalized for HF using information routinely available to clinicians at hospital presentation.

2. Material and methods 2.1. CONCOR registration The CONgenital CORvitia (CONCOR) Dutch national registry database has been described in detail [18]. Briefly, CONCOR aims to facilitate research into the aetiology of CHD and on its outcome. From November 2001, patients with CHD aged 18 years or older have been recruited and included by three independent, permanently employed research nurses. Clinical data such as diagnosis, clinical events, and procedures — classified using the European Pediatric Cardiac Code Short List coding scheme [19] — as well as patient and family history were obtained from medical records. In case of multiple diagnoses in one patient, a pre-specified hierarchical scheme founded on consensus-based classification of defect severity [20] was used, by means of which the diagnosis with the worst prognosis was established as main diagnosis. After entry, data on major events during follow-up were systematically recorded from the patients' medical letters written by their cardiologist. Currently, 107 Dutch hospitals are participating, including all eight tertiary referral

centres from which 65% of patients originate. Currently, an estimated 35–50% (over 14,000 patients) of the total adult CHD population in the Netherlands is registered in CONCOR. 2.2. Patient selection and data collection To identify patients admitted for HF in adulthood, the CONCOR registry (n = 11,666 on date of linkage, 4 May 2010) was merged to the national Hospital Discharge Registry. Using a combination of zip code, gender and date of birth, the status of 93% of patients was assessed; 858 patients (7%) could not be linked owing to missing or erroneously registered zip codes. All patients with one or more hospital admissions for HF (primary or secondary discharge diagnosis; ICD-9 CM code 428) between January 1st 1995 and December 31st 2007 were selected. Afterwards, medical records of these patients were extensively explored to 1) confirm the admission(s) for HF, 2) to determine when the patient had his/her first HF-admission in adulthood, and 3) to collect clinical parameters from the first HF-admission as candidate risk factors of mortality after HF-admission. HF-admission was confirmed when patients had a clinical presentation of HF (e.g. pulmonary rales, jugular venous distension, orthopnea, dyspnea on ordinary exertion, ankle oedema, and pulmonary congestion/oedema on X-ray) and/or responded to (diuretic) treatment with clinical improvement, and were admitted to the hospital for at least 1 day. Mortality was assessed by merging the CONCOR registry to the National Mortality Registry until December 31st 2009. 2.3. Risk factors and outcome Candidate risk factors of first HF-admission in adulthood were collected from the CONCOR database. Patient characteristics (gender, main defect; left-sided or right-sided, and the presence of multiple defects) and several complications and interventions that had occurred prior to the age of 18 were included, because they either potentially increase the risk of HF or were considered clinically important (Table 1) [10,21].

Table 1 Candidate risk factors for first HF-admission in adulthood, by status of HF-admission. HF-admission (n = 274)

No HF-admission (n = 10,534)

n

%

n

%

p-value

Patient characteristics Male gender Multiple defects Right-sided defect* Main defect Ventricular septal defect Atrial septal defect* Aortic coarctation Tetrology of Fallot* Aortic stenosis Pulmonary stenosis* Bicuspid aortic valve AVSD Marfan syndrome TGA* Patent arterial duct Ebstein malformation* ccTGA* PA + VSD* FUH/DILV Other*

139 191 155

51 70 57

5128 5134 4500

49 49 43

25 53 10 42 20 b10 11 17 b10 16 b10 b10 b10 b10 16 35

9 (1) 19 (3) 4 (1) 15 (5) 7 (2) b4 (b1) 4 (b1) 6 (1) b4 (b1) 6 (1) b4 (2) b4 (2) b4 (3) b4 (6) 6 (16) 13 (5)

1873 1677 1025 884 901 789 678 466 441 421 227 156 103 111 86 696

18 16 10 8 9 7 6 4 4 4 b4 b4 b4 b4 b4 7

Complications in childhood Condunction disturbances SVA Ventricular arrhythmias Endocarditis TIA/CVA Pulmonary hypertension Eisenmenger syndrome

11 16 b10 b10 b10 b10 b10

4 6 b4 b4 b4 b4 b4

337 217 38 74 24 63 14

b4 b4 b4 b4 b4 b4 b4

ns b0.05 ns b0.05 ns ns ns

Interventions in childhood Surgery Reoperation Percutaneous intervention Valve replacement† Pacemaker implantation ICD implantation

131 46 19 b10 b10 b10

48 17 7 b4 b4 b4

4774 1103 667 305 124 b10

45 10 6 b4 b4 b4

b0.15 b0.05 ns ns b0.05 ns

ns b0.05 b0.05

b0.15

Due to privacy legislation numbers b10 are not revealed. Between parentheses the percentages are given within rows. AVSD = atrioventricular septal defect; TGA = transposition of the great arteries; ccTGA = congenitally corrected transposition of the great arteries; PA + VSD = pulmonary atresia with ventricular septal defect; FUH/DILV = univentricular heart/double inlet left ventricle; SVA = supraventricular arrhythmias; TIA/CVA = cerebrovascular accident/transient ischaemic attack; ICD = implantable cardioverter defibrillator. * Right-sided heart defect. For ‘other defect’, only part was classified as right-sided, depending on the defect. † Percutaneous or surgical.

A.C. Zomer et al. / International Journal of Cardiology 168 (2013) 2487–2493 Table 2 Independent risk factors for first HF-admission in adulthood.

Patient characteristics Multiple defects Main defect Ventricular septal defect Atrial septal defect Aortic coarctation Tetrology of Fallot Aortic stenosis Pulmonary stenosis Bicuspid aortic valve AVSD Marfan syndrome TGA Patent arterial duct Ebstein malformation ccTGA PA + VSD FUH/DILV Other Interventions in childhood Surgery Reoperation Pacemaker implantation

HR

95% CI

2.2

1.7–2.9

– 1.1 0.4 2.1 1.9 0.6 0.7 2.7 0.8 5.0 0.6 0.7 5.2 3.0 11.4 3.1

– 0.7–1.7 0.2–0.9 1.3–3.6 1.0–3.4 0.3–1.4 0.4–1.5 1.5–5.1 0.3–2.2 2.5–9.9 0.2–1.7 0.2–2.2 1.8–15.4 1.2–7.4 5.9–22.0 2.2–6.1

2.5 1.8 3.1

1.8–3.5 1.2–2.6 1.5–6.3

Abbreviations as in Table 1. HR = hazard ratio; 95% CI = 95% confidence interval. Candidate risk factors of mortality after first HF-admission were identified based on review of the literature [9,16,17], clinical relevance, and routine availability in the initial hours of hospital presentation. These included patient characteristics (gender, main defect; left-sided or right-sided, the presence of multiple defects, and age at admission), presentation features (e.g. blood pressure, heart rate, and EKG parameters) or other data abstractable from the clinical record in the first hours of hospital presentation (e.g. laboratory values and medical history; Table 3). Low serum haemoglobin was defined as b7.8 mmol/l (12.6 g/dL) for men and b7.3 mmol/l (11.8 g/dL) for women. High serum creatinine was defined as >100 μmol/l (1.13 mg/dL) for men and >80 μmol/l (0.90 mg/dL) for women. Mean blood pressure was calculated using the following formula: (2 ∗ diastolic blood pressure (mmHg) + systolic blood pressure (mmHg)) / 3 [22]. Outcome was three-year mortality after first HF-admission in adulthood. 2.4. Statistical analyses Age at inclusion, age at first surgery, age at admission, follow-up duration and heart rate were summarized using medians (range). Complications and interventions up to the age of

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18 years, and clinical parameters at admission were presented as frequencies and proportions, or as mean ± standard deviation. For the assessment of three-year mortality after first HF-admission only patients with prospective follow-up after their first HF-admission were considered (n = 86). If clinical parameters (potential risk factors for mortality after HF-admission) were missing, these were imputed using multiple imputation techniques (10 repeated imputations) [23]. Clinical parameters were missing in the range of 1–47% (median = 22%). The characteristics of patients with missing data were not significantly different from patients without. Candidate variables that were associated with first HF-admission and three-year mortality after first HF-admission on univariate analysis (p b 0.15) were included as potential risk factors in multivariable Cox proportional hazards models. Variables in the multivariable model were subsequently excluded in a backward stepwise fashion. Results were expressed as hazard ratios (HR) with 95% confidence intervals (CI); 95% CI not including 1.0, corresponding to two-sided P-values of 0.05 or less, were considered statistically significant. Analyses were performed using SPSS version 18.0 (SPSS Inc. Chicago, IL, USA). All analyses have been performed according to the privacy legislation in The Netherlands.

3. Results Of 10,808 patients available for analysis, 5268 (49%) were male and median age was 37.0 years (range 18 to 92) at end of follow-up. During a median follow-up period of 21 years, 274 patients (2.5%) were admitted for HF. Median age at first HF-admission was 46.7 years (range 19.2 to 90.9) and 51% were male. The cumulative observed risk of admission for HF in adulthood was 1.2% at the age of 40 years and 5.8% at the age of 60 years. The overall incidence of first HF-admission at adult age was 1.2 (95% CI 1.1–1.3) per 1000 patient-years. Table 1 shows the candidate risk factors for first HF-admission. Among others, right-sided heart defect was identified as a univariate risk factor (p b 0.05). Independent risk factors of HF-admission included multiple defects, the main congenital heart defect, and three types of interventions in childhood: surgery, reoperations and pacemaker implantation (Table 2). Patients with univentricular hearts, and congenitally and surgically corrected transposition of the great arteries had the highest risk of being admitted for HF compared to patients with ventricular septal defect (HR = 11.4; 95% CI, 5.9–22.0, HR = 5.2; 95% CI, 1.8–15.4 and HR = 5.0; 95% CI, 2.5–9.9 respectively). Of the 274 patients admitted for HF, 59 subjects (22%) were admitted twice, 22 subjects (8%) were admitted three times and 41 subjects (15%) were admitted four times or more for HF. Cumulative risk of readmission for HF was 23% after one year. Patients admitted for HF for the first time

Fig. 1. Causes of death of adult patients with CHD who died after HF-admission within one year (n = 21), and within three years (n = 30). PHF = progressive heart failure.

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had a five-fold higher risk of mortality compared to all other patients not admitted for HF (HR = 5.3; 95% CI 4.2–6.9). Of the 86 patients analysed for three-year mortality after first HF-admission, 21 patients (24%) died within one year and 30 patients (35%) died within three years after HF-admission. Mean follow-up duration from first HF-admission to death or end of follow-up was 3.1 years. Fig. 1 depicts causes of death in these patients. Over 90%

of patients died from cardiovascular causes. Candidate risk factors for three-year mortality after first HF-admission are presented in Table 3. Table 4 shows the independent risk factors for three-year mortality, which include male gender, pacemaker implantation, number of admission days, non-cardiac medication use and high serum creatinine. Fig. 2 shows the survival curve of male and female patients after first HF-admission.

Table 3 Candidate risk factors for three-year mortality after first HF-admission in adult patients with CHD (n = 86), by status of mortality. Deceased b 3 years (n = 30)

Patient characteristics Male gender Multiple defects Right-sided defect* Main defect Ventricular septal defect Atrial septal defect* Aortic coarctation Tetrology of Fallot* Aortic stenosis Pulmonary stenosis* Bicuspid aortic valve AVSD Marfan syndrome TGA* Patent arterial duct Ebstein malformation* ccTGA* PA + VSD* FUH/DILV Other* Age at admission, years (mean ± SD) Medical history Surgery Age of first surgery, years (median, range) Palliative intervention Reoperation Ventricular arrhythmias Conduction disturbance TIA/CVA Pulmonary hypertension/Eisenmenger Implantable cardioverter defibrillator Pacemaker implantation Hospitalization data Number of admission days (median, range) Medication at admission† - Diuretics - Ace-inhibitor - Beta blocker - Anti-arrhythmics - Non-cardiac medication Aetiology of HF† - Arrhythmia - Valve regurgitation or stenosis - Pulmonary hypertension - Other/unknown Clinical findings at admission Blood pressure, mmHg (mean ± SD)† - Systolic - Diastolic Mean blood pressure in mmHg (mean ± SD)† Heart rate in b.p.m. (median, range)† Laboratory values and EKG Low serum haemoglobin (mmol/l)† High serum creatinine (μmol/l)† Rhythm† - Supraventricular arrhythmia - Ventricular arrhythmia Bundle branch block (n = 55)†,‡

p-value§

Survived > 3 years (n = 56)

n

%

n

%

18 26 15

60 87 50

24 42 31

43 75 55

b0.15 ns ns

4 7 1 2 2 0 0 3 0 1 1 1 1 0 3 4 49.7 ± 3.9

13 23 3 7 7 0 0 10 0 3 3 3 3 0 10 13

4 2 2 11 5 1 3 4 1 6 1 0 1 1 3 11 44.4 ± 1.7

7 4 4 20 9 2 5 7 2 11 2 0 2 2 5 20

ns

21 11.1 ( 0.0–66.0) 5 15 5 7 2 4 2 16

70

45 8.9 (0.0–66.7) 18 24 7 11 4 2 5 15

80

17 50 17 23 7 13 7 53

8 (1–127)

b0.15

32 43 13 20 7 4 9 27

b0.05

5 (1–38)

23/25 12/25 7/25 10/25 20/25

92 48 23 40 80

34/44 11/44 23/44 17/44 24/44

77 25 52 39 55

6/23 7/23 6/23 4/23

26 30 26 17

10/44 7/44 2/44 26/44

23 16 5 59

117.8 ± 5.4 /17 64.6 ± 3.2 /17 82.3 ± 3.7 /17 99 (60-174)/20

ns ns ns ns ns ns ns b0.15 ns b0.05

129.9 ± 4.7 /32 71.8 ± 2.4 /32 91.2 ± 2.8 /32 88 (65-180)/35

ns b0.15 b0.15 ns b0.15

ns

ns ns ns ns

4/15 9/22

27 41

3/31 4/35

10 11

b0.15 b0.05

6/21 0/21 9/12

29 0 75

15/37 0/37 14/29

41 0 48

ns ns ns

Abbreviations as in Table 1. * Right-sided heart defect. For ‘other defect’, only part was classified as right-sided, depending on the defect . † The denominator represents the number of patients for which data were present. ‡ Patients with ventricular pacemaker rhythm were excluded from analyses. § P value is given for univariate analyses after multiple imputation.

A.C. Zomer et al. / International Journal of Cardiology 168 (2013) 2487–2493 Table 4 Independent risk factors for three-year mortality after first HF-admission in adult patients with CHD. HR

95% CI

Patient characteristics Male gender

2.41

1.06–5.49

Medical history and clinical findings Pacemaker implantation Number of admission days (per day) Non-cardiac medication use High serum creatinine (μmol/l)

3.63 1.02 2.58 2.40

1.66–7.96 1.01–1.04 1.00–6.68 1.03–5.59

HR = hazard ratio; 95% CI = 95% confidence interval.

4. Discussion This comprehensive study is the first to show estimates of prevalence and incidence of HF-admission in adults with CHD. Of nearly 11,000 adult CHD patients 2.5% were admitted for HF during a median follow-up of 21 years. The incidence of first HF-admission was 1.2 per 1000 patient years, with increasing risk of HF-admission with increasing age. Main defect, multiple defects, surgery and pacemaker implantation in childhood were identified as risk factors of first HF-admission in adulthood. Mortality risk is substantially increased after first HF-admission. To our knowledge this is the first study to assess risk factors of mortality after first HF-admission in adults with CHD. The presented risk factors in this study might be used as a first step towards identifying patients at high risk of HF-admission and of mortality after HF-admission. Although our reported incidence of HF-admissions (1.2 per 1000 patient years) may seem low, the incidence of HF in the general population for adults in the same age category as our patient population is only 0.1 per 1000 (not even one-tenth of the incidence of HF-admissions in our study population) [24], which emphasises the fact that HF is a significant problem in our young patient population. The incidence of HF itself in adults with CHD is actually higher, since not all patients with HF are admitted. Only few studies have focused on the occurrence of HF in adults with CHD and on determining risk factors for HF, and nearly all have

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concentrated on patients with single or systemic right ventricles, who seem to have a higher chance of ventricular dysfunction [9,10,21,25]. In line with this, we found that patients with univentricular hearts, and congenitally and surgically corrected transposition of the great arteries had the highest risk of being admitted for HF in adulthood. Moreover, multiple defects and surgical interventions (surgery and reoperations) proved to be risk factors of HF-admission, which was also found by Graham et al. and Norozi et al. [9,21]. Finally, pacemaker implantation was identified as a risk factor. Nothroff et al. reported this too, and suggested that this was related to a prolonged QRS complex duration and chronotropic incompetence in adult CHD patients with a pacemaker [26]. Risk factors of (short-term) mortality in patients admitted for HF secondary to acquired heart disease has been identified in several studies [16,17]. This is the first study aiming to provide risk factors of mortality in adult CHD patients after HF-admission. Mortality rates after first HF-admission in adult CHD patients were slightly lower than the mortality rates described for patients with HF secondary to acquired heart disease [15–17]. This may be due to a pathophysiological difference in the two different patient populations. As suggested from our results, right-sided HF is more important in adults with CHD than left-sided HF, while for patients with acquired heart disease this is most often left-sided HF [27,28]. Moreover, patients with HF secondary to acquired heart disease are considerably older and have more comorbidity, which likely contributes to a higher mortality rate in these patients [16]. As expected, the large majority of adult CHD patients admitted for HF died from cardiovascular causes, especially from HF and arrhythmia [29], which is also seen in adults with HF secondary to acquired heart disease [30,31]. Male gender appeared to be a risk factor of mortality after HF-admission; a finding which is supported by the published literature on overall survival in patients with CHD [14,32–34]. Additionally, non-cardiac medication use was identified as risk factor, which might be interpreted as a proxy for comorbidity. Studies including patients with HF secondary to acquired heart disease already showed the importance of comorbidity for the prognosis after HF-admission [16,17]. 4.1. Limitations Adult patients who died prior to enrolment in the CONCOR registry are not accounted for in this study. Because of the retrospective nature of this study, our results are dependent on the accuracy of recorded data. Nevertheless, if clinical data were not recorded, these missing values were imputed, since analyzing datasets with imputed data has shown to be more efficient than analyzing only complete cases [23,35,36]. It is possible that we missed some HF-admissions, as it has been shown that quite some patients admitted for HF are discharged with a different discharge diagnosis [37]. This may have resulted in an underestimation of the number of HF-admissions in this study. Unfortunately, we were unable to take some factors into account that could have influenced the risk of mortality after HF-admission, such as the traditional cardiovascular risk factors (smoking, hypercholesterolemia, and diabetes) [38], neurohormonal activation [39,40], echocardiographic measurements, the number of outpatient visits, and non-cardiovascular comorbidities such as cancer or pulmonary disease. Finally, we did not have any data on outpatient visits for HF. Therefore HF-patients not admitted to the hospital were not accounted for in this study. 4.2. Clinical implications and future perspectives

Fig. 2. Survival curve of female (n = 44) and male (n = 42) patients after first HF-admission.

Considering the low median age of our total study population at end of follow-up and the increasing risk of HF-admission with increasing age, it is to be expected that the proportion of CHD patients admitted for HF will increase in the near future. This emphasizes the importance of identifying risk factors of HF-admission and of adverse outcome after HF-admission in this population. Patients who have

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single or systemic right ventricles, multiple defects, (multiple) surgery and pacemaker implantation in medical history have the highest chance of being admitted for HF. Although none of the risk factors are directly modifiable, the clinician should be alert when one of his patients has multiple of these risk factors. A more intensified follow-up or more aggressive treatment against arrhythmias or valve disease (the two most common causes of HF in these patients) might be needed to prevent HF(-admission) in these patients. Not only is pacemaker implantation a risk factor of HF-admission, but it is also a risk factor of mortality after admission. A regular check for optimal settings of the pacemaker might be indicated. If chronotropic incompetence is indeed part of the pathophysiology of HF in these patients as Nothroff et al. suggested [26], then the maximum pacing rate should not be set too low. Of course, in some cases it may be that necessity of a pacemaker is a sign of severity of the underlying defect, rather than a risk factor itself. Male gender, renal failure and non-cardiac medication use (as proxy for comorbidity) were also identified as risk factors for mortality after HF-admission. Patients with several risk factors, who are at high risk of mortality after HF-admission, might as well benefit from closer follow-up and early medical intervention to prevent major adverse events. Up to date, it is still unclear if the traditional HF drug therapies, which are mostly based on neurohormonal blockade, have the same beneficial effects in patients with CHD as in patients with HF secondary to acquired heart disease. However, also in patients with CHD, neurohormonal activation has been related to ventricular dysfunction [39,40]. Large studies are needed to determine what medical treatment will be best in CHD patients with HF [41,42]. 5. Conclusions The incidence of HF-admission in adults with CHD is 1.2 per 1000 patient-years, which is much higher than in the general population. Moreover, it is to be expected that the proportion of CHD patients admitted for HF will increase in this aging population. Mortality risk is substantially increased after HF-admission. This all emphasises the importance to identify patients at high risk of HF-admission and mortality after HF-admission, who might benefit from closer follow-up and earlier medical or surgical interventions. The presented risk factors in this study might be used as a first step towards identifying these high-risk patients. Acknowledgements We thank all the Dutch medical institutions and their study coordinators for participating in the CONCOR project. Furthermore, we thank Lia Engelfriet, Irene Harms and Sylvia van den Busken of the Interuniversity Cardiology Institute of the Netherlands for their dedicated support of the CONCOR project. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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