ejhf30

European Journal of Heart Failure (2014) 16, 103111doi:10.1002/ejhf.30

Co-morbidities in patients with heart failure:an analysis of the European Heart Failure PilotSurveyVincent M. van Deursen1, Renato Urso2, Cecile Laroche3, Kevin Damman1,Ulf Dahlstrm4, Luigi Tavazzi5, Aldo P. Maggioni6, and Adriaan A. Voors1,*1Department of Cardiology, University of Groningen, Groningen, The Netherlands; 2Pharmacology Unit Giorgio Segre, University of Siena, Siena, Italy; 3EORP Department,ESC, Sophie Antipolis, France; 4Department of Cardiology, Linkoping University Hospital, Linkoping, Sweden; 5GVM Care and Research, Ettore Sansavini Health ScienceFoundation, Maria Cecilia Hospital, Cotignola, Italy; and 6ANMCO Research Center, Florence, Italy

Received 27 March 2013; revised 6 June 2013; accepted 14 June 2013

Aims Co-morbidities frequently accompany heart failure (HF), contributing to increased morbidity and mortality, and animpairment of quality of life.We assessed the prevalence, determinants, regional variation, and prognostic implicationsof co-morbidities in patients with chronic HF in Europe.

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

Methodsand results

A total of 3226 European outpatients with chronic HF were included in this analysis of the European Society ofCardiology (ESC) Heart Failure Pilot Survey. The following co-morbidities were considered: diabetes, hyper- andhypothyroidism, stroke, COPD, sleep apnoea, chronic kidney disease (CKD), and anaemia. Prognostic implications ofco-morbidities were evaluated using population attributable risks (PARs), and patients were divided into geographicregions. Clinical endpoints were all-cause mortality and HF hospitalization. The majority of patients (74%) had a leastone co-morbidity, the most prevalent being CKD (41%), anaemia (29%), and diabetes (29%). Co-morbidities wereindependently associated with higher age (P < 0.001), higher NYHA functional class (P < 0.001), ischaemic aetiology ofHF (P < 0.001), higher heart rate (P = 0.011), history of hypertension (P < 0.001), and AF (P < 0.001). Only diabetes,CKD, and anaemia were independently associated with a higher risk of mortality and/or HF hospitalization. Therewere marked regional differences in prevalence and prognostic implications of co-morbidities. Prognostic implicationsof co-morbidities (PARs) were: CKD = 41%, anaemia = 37%, diabetes = 14%, COPD = 10%, and

104 V. M. van Deursen et al.

elderly (>65 years) patients with heart failure, the prevalence of co-morbidities was 96%.5 It was calculated that patients with >5 co-morbidities are responsible for 81% of all hospital days experiencedby all heart failure patients. However, regional differences have notbeen studied and determinants of multiple co-morbidities remainunknown.The present study examines multiple co-morbidities in a broad

spectrum of patients with chronic heart failure. We focus onthe prevalence, determinants, regional variation, and prognosticimplications of co-morbidities in a broad spectrum of patients withchronic heart failure in Europe.

MethodsThe HF Pilot Survey of the EURObservational Research Programme(EORP) of the European Society of Cardiology (ESC) was a prospec-tive, multicentre, observational survey.9 The aim was to include abroad spectrum of patients with heart failure from outpatient clin-ics and those admitted to a hospital. Outpatients were diagnosedwith chronic heart failure according to the clinical judgement of acardiologist. Admitted patients had pre-existing heart failure or new-onset heart failure requiring i.v. therapy. A total of 5118 patients wereincluded, 1892 (37%) in-hospital patients with acute heart failure and3226 (63%) outpatients with chronic heart failure, recruited from 136cardiology centres in 12 European countries. These countries wereselected on the basis of previous performances in the Euro Heart Sur-veys and geographical distribution. The National Cardiology Societiesof each country agreed to participate in the programme and were askedto select hospitals of different levels of complexity. The aim was toinvolve a broad spectrum of cardiology units. The number of partici-pating centres for each country was decided according to the numberof inhabitants of that country. We used all 3226 outpatients to obtaina representative chronic heart failure population for analysis.

RegionsFour geographical regions were defined as follows: Western Europeancountries [Austria (n = 86), France (n = 37), Germany (n = 138), andThe Netherlands (n = 76)], Eastern European countries [Romania (n =120) and Poland (n = 243)], Southern European countries [Greece (n= 115), Italy (n = 1387), and Spain (n = 532)), and Northern Europeancountries [Denmark (n = 174), Norway (n = 126), and Sweden (n =201)].

Co-morbiditiesCo-morbidities were determined based on the case record formas assessed by the treating physician. We used all non-cardiac co-morbidities that were assessed in this survey. Co-morbidities consistedof diabetes (n = 3223), thyroid dysfunction (n = 3171), stroke (n =3206), COPD (n = 3202), sleep apnoea (either in medical history orself-reported, n = 3197), chronic kidney disease [CKD; defined asestimated GFR (eGFR)

Co-morbidities in heart failure 105

Table 1 Baseline characteristics, according to patients with zero or one co-morbidity and patients with more thanone co-morbidity

All patients(n = 3226)

1 co-morbidiy(n = 1417)

>1 co-morbidity(n = 1167)

P-value

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

Age (years) 66 14 63 14 71 11


Table 2 Prevalence of co-morbidities in patients withheart failure with reduced ejection fraction and inpatients with heart failure with preserved ejectionfraction

HFrEF(LVEF 3 co-morbidities had an even higher mortality rate(HR 9.33, 95% CI 5.1416.96, P < 0.001), and were re-hospitalizedmore frequently (HR 4.74, 95% CI 3.107.23, P < 0.001) thanpatients without co-morbidities.

Geographical regionsIn Figure 2 the prevalence of co-morbidities is divided into Euro-pean regions. Eastern European patients (n = 363) had less CKD(28% vs. 39, 43, and 42%) compared with Northern (n = 501),Southern (n = 2025), and Western (n = 337) European regions,respectively. The prevalence of anaemia was much lower in East-ern European patients (17% vs. 29, 32, and 24%). Northern Euro-pean patients had a much lower prevalence of diabetes (16%vs. 32, 33, and 29%) compared with Southern, Western, andEastern European regions, respectively. Geographical differenceswere minimal for hyperthyroidism, stroke, and COPD. Hypothy-roidism was twice as common in Southern and Western European

Table 3 Univariate and multivariate associations between co-morbidities and all-cause mortality

No. of deaths (%) Univariate Multivariate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

HR (95% CI) P-value HR (95 % CI) P-value. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Chronic kidney disease 130 (5%) 2.77 (2.083.69)


(a)

(b)

Figure 1 (A) Mortality among groups of multiple co-morbidities. Groups are defined as 0 co-morbidities, 13 co-morbidities, and >3co-morbidities. (B) Heart failure hospitalization among groups of multiple co-morbidities. Groups are defined by 0 co-morbidities, 13 co-morbidities, and >3 co-morbidities.

countries (both 10% vs. 5 and 6%). Sleep apnoea was diag-nosed more often in Western European countries (10% vs. 2, 2,and 4%).Overall, patients from the Northern European countries had

fewer co-morbidities (72%) than those from Western Europeancountries (77%), followed by those from Eastern (78%) and South-ern European countries (80%).

DiscussionThis study examines multiple co-morbidities in a broad spectrumof patients in chronic heart failure. In this pilot survey, we foundthat the majority of patients had a least one co-morbidity, andthe number of co-morbidities increased with the severity of heartfailure. Diabetes, CKD, and anaemia had the highest prevalence .

............................................. and were independently associated with both mortality and heart

failure hospitalization.

Prevalence of co-morbiditiesChronic kidney disease, anaemia, and diabetes were the mostcommon co-morbidities in our chronic heart failure patients, alongwith COPD and stroke. These findings are consistent with otherreports.1114

In the absence of active screening, we found a much lowerprevalence for sleep apnoea in our population, in stark contrast tothe prevalence of up to 60% reported in the recent literature.1522

This discrepancy underscores the need for better screening forco-morbidities, particularly in cases where symptoms overlap withthose of heart failure. The same holds true for COPD, whereprevalence is reported up to 50%.23,24 In another study, only 43% of

2013 The AuthorsEuropean Journal of Heart Failure 2013 European Society of Cardiology


Figure 2 The prevalence of multiple co-morbidities per geographical regions in Europe (East, North, South, and West).

patients with evidence of COPD during spirometry self-reportedhaving COPD.25

We found that hypothyroidism had a higher prevalence com-pared with hyperthyroidism. This could be due to the effect ofamiodarone therapy on thyroid dysfunction. In patients with per-sistent AF, hypothyroidism has been reported to have a prevalenceof 31% in those treated with amiodarone compared with 7% in thecontrol group.26

We found a high prevalence of co-morbidities in patients withchronic heart failurenearly half had two or more co-morbidities.In a cross-sectional study of 122 630 patients with heart failure,the prevalence of co-morbidities was even higher.5 This differenceis probably due to the greater number of co-morbidities assessedin the cross-sectional study.

Determinants of co-morbiditiesThe literature shows a high prevalence of co-morbidities in patientswith heart failure. Although co-morbidities might cause heartfailure, it is reasonable to believe that heart failure itself mightbe a cause of multiple other co-morbidities.6 This is supported bythe finding that the prevalence of co-morbidities is associated withthe severity of heart failure, measured with the NYHA functionalclassification.27 In addition to neurohormonal changes and thenegative effect of heart failure medication, haemodynamic factorscould also play a pathophysiological role.13,2831

We found that patients with co-morbidities were older andhad more advanced heart failure, reflected by a higher NYHA ..

.................................................................................. class and a higher prevalence of hypertension and AF, although

a causal relationship cannot be established based on the data.Patients with heart failure of ischaemic aetiology had moreco-morbidities, and patients with more co-morbidities hadmore clinical signs of congestion (elevated JVP or peripheraloedema). This is consistent with our previous findings thatcongestion plays a pathophysiological role in renal and liverdysfunction.13,31 Organs in heart failure may also be affected byimpaired haemodynamics, reflected by elevated venous pressure,among other factors.6

Importantly, we found that patients with co-morbidities wereless likely to be receiving evidence-based therapies, such asACE inhibitors, ARBs, and beta-blockers. In accordance, previousstudies have shown that sicker patients are more likely to have sideeffects or contraindications.3234

Population attributable riskThe term attributable risk is the difference in the rate of acondition (for instance mortality) between an exposed populationand an unexposed population (presence or absence of a co-morbidity). Attributable risk was first described in 1953 andhas been used since.10,35 Interestingly, attributable risks combineincidence with effect. For our analyses, PAR can be describedas the reduction in mortality that would be observed if thepopulation was entirely unexposed to a certain co-morbidity,compared with the mortality pattern in patients without that co-morbidity.



When co-morbidities were considered separately, we foundthat CKD and anaemia had the highest PAR. All-cause mortalitycould also be attributed to diabetes and stroke, while other co-morbidities lacked a significant PAR. The high PARs for CKD andanaemia are driven by the combination of high prevalence and astrong association with mortality.

Prognosis and co-morbiditiesPrevious studies have shown a strong association between co-morbidities and adverse clinical outcomes.3,4,11 It has been cal-culated that patients with 5 co-morbidities are responsible for81% of all hospital days experienced by all heart failure patients.5

Our findings confirm that patients with increasing numbers of co-morbidities have an increasing risk of both mortality and heartfailure hospitalization.Accordingly, we found that CKD, anaemia, and diabetes

remained significantly and independently related to all-causemortality and heart failure hospitalizations. This is in accordancewith other studies reporting on CKD and anaemia separately.This supports a causal relationship between heart failure andco-morbidities, linking them to disease severity.Diabetes was also associated with a poorer prognosis in heart

failure. In acute heart failure, diabetic patients had worse outcomecompared with non-diabetics.36 The relationship with prognosis isless clear in patients with chronic heart failure.3739

Regarding sleep apnoea, we did not find an association withoutcome in the present study, although other studies show thatsleep apnoea is associated with increased mortality.40,41 We believethat this difference can be explained by under-reporting due toa lack of screening, as explained previously. Other studies showthat, after adjustment for confounders, sleep apnoea doubles themortality risk in patients with heart failure.40,41

Geographical regionsPatients from the Northern European countries were less likely tohave co-morbidities, followed by Western, Eastern, and SouthernEuropean countries, in ascending order. This was largely drivenby diabetes, which had a low prevalence in Northern Europeancountries compared with the other regions. However, patientsfrom Eastern European countries were less likely to have CKD andanaemia. Hypothyroidism was slightly more commonly diagnosedin Southern and Western Europe, while sleep apnoea was morecommonly diagnosed in Western Europe.In addition to prevalence, there were also marked regional

differences in the prognostic implications of co-morbidities. InEastern and Northern European patients, all-cause mortalitywas less attributable to diabetes, COPD, and CKD, comparedwith Southern and Western European patients. In Southern andNorthern European countries, mortality was less attributable tostroke. ..

...................................................................................................................................................................... Limitations

As is the case for all surveys, the voluntary participation andrecruitment of patients imposes limitations that must be acknowl-edged. First, as mentioned in the main article,9 this pilot studytried to balance the methodological need for consecutive enrol-ment with the practical feasibility by reducing the workload forcentres with limited recruitment to 1 day per week for 8months.Secondly, the study population may not represent the general heartfailure population. Participating centres were selected proportion-ally to the size of the population of the participating countries,accounting for the different technological levels of the cardiologycentres invited to participate. Another important limitation is thatthe diagnosis of heart failure was made by the treating physician,and both diagnosis and events were not adjudicated.There are many potential explanations for the regional dif-

ferences observed. These include a lack of screening for co-morbidities in various regions of Europe, or imperfect represen-tativeness of the regional populations. Hospital care practices alsodiffer between countries and centres. However, the observed dif-ferences may also be real and thus related to the heterogeneousEuropean epidemiology, with regional variation in prevalence, car-diovascular risk factors, and cardiovascular event rates.42

ConclusionThis is the first study to examine multiple co-morbidities in a broadspectrum of patients with chronic heart failure. This pilot surveyshowed that the majority of patients had a least one co-morbidity,with CKD, anaemia, and diabetes being most prevalent, and thatthe number of co-morbidities increased with the severity of heartfailure. Diabetes, CKD, and anaemia were independently associatedwith both mortality and HF hospitalization. However, there weremarked differences in prevalence and prognostic implications of co-morbidities across various European regions.

FundingThe Survey was funded by the ESC. No industrial support was used.Each participating National Cardiology Society was granted 10000 to help with the organizational needs regarding the nationalnetwork implementation. At present, the following companies aresupporting the EURObservational Research programme: GOLD:Boehringer Ingelheim International, Menarini International, Sanofi-Aventis Group, Laboratoires Servier; SILVER: Amgen; BRONZE:Boston Scientific International.

Conflicts of interest: A.A.V. received consultancy fees and/orresearch grants from Alere, Bayer, Cardio3Biosciences, Celladon,Ceva, Novartis, Servier, Torrent, and Vifor; is a Clinical Estab-lished Investigator of the Dutch Heart Foundation (2006T37); issupported by a grant from the Dutch Heart Foundation enti-tled: Approaching Heart Failure by Translational Research of RNAmechanisms (ARENA); and is leader of a project funded by theEuropean Commission (FP7-242209-BIOSTAT-CHF), entitled: asystems BIOlogy Study to TAilered Treatment in Chronic Heart



Failure (BIOSTAT-CHF) which is supported by a grant fromthe European Commission: FP7-242209-BIOSTAT-CHF. A.P.M.received consultancy fees and/or research grants from: Amgen,Bayer, Cardiorentis, Novartis, and Vifor. All other authors have noconflicts to declare.

References1. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk

V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY,Maggioni AP, Parkhomenko A, Pieske BM, Popescu BA, Ronnevik PK, Rutten FH,Schwitter J, Seferovic P, Stepinska J, Trindade PT, Voors AA, Zannad F, Zeiher A,Bax JJ, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-BrentanoC, Hasdai D, Hoes A, Kirchhof P, Knuuti J, Kolh P, McDonagh T, Moulin C, ReinerZ, Sechtem U, Sirnes PA, Tendera M, Torbicki A, Vahanian A, Windecker S, BonetLA, Avraamides P, Ben Lamin HA, Brignole M, Coca A, Cowburn P, Dargie H,Elliott P, Flachskampf FA, Guida GF, Hardman S, Iung B, Merkely B, Mueller C,Nanas JN, Nielsen OW, Orn S, Parissis JT, Ponikowski P. ESC guidelines for thediagnosis and treatment of acute and chronic heart failure 2012: the Task Forcefor the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 ofthe European Society of Cardiology. Developed in collaboration with the HeartFailure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803869.

2. van der Meer P, Voors AA, Lipsic E, van Gilst WH, van Veldhuisen DJ. Erythro-poietin in cardiovascular diseases. Eur Heart J 2004;25:285291.

3. Hillege HL, Nitsch D, Pfeffer MA, Swedberg K, McMurray JJ, Yusuf S, Granger CB,Michelson EL, Ostergren J, Cornel JH, de Zeeuw D, Pocock S, van VeldhuisenDJ, Candesartan in Heart Failure: Assessment of Reduction in Mortality andMorbidity (CHARM) Investigators. Renal function as a predictor of outcome in abroad spectrum of patients with heart failure. Circulation 2006;113:671678.

4. Macchia A, Monte S, Romero M, DEttorre A, Tognoni G. The prognosticinfluence of chronic obstructive pulmonary disease in patients hospitalized forchronic heart failure. Eur J Heart Fail 2007;9:942948.

5. Braunstein JB, Anderson GF, Gerstenblith G, Weller W, Niefeld M, HerbertR, Wu AW. Noncardiac comorbidity increases preventable hospitalizations andmortality among Medicare beneficiaries with chronic heart failure. J Am Coll Cardiol2003;42:12261233.

6. van Deursen VM, Damman K, van der Meer P, Wijkstra PJ, Luijckx GJ, van BeekA, van Veldhuisen DJ, Voors AA. Co-morbidities in heart failure. Heart Fail Rev2012; doi:10.1007/s10741-012-9370-7, in press.

7. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, WehrensXH, Deswal A. Impact of noncardiac comorbidities on morbidity and mortality ina predominantly male population with heart failure and preserved versus reducedejection fraction. J Am Coll Cardiol 2012;59:9981005.

8. Saczynski JS, Go AS, Magid DJ, Smith DH, McManus DD, Allen L, Ogarek J,Goldberg RJ, Gurwitz JH. Patterns of comorbidity in older adults with heartfailure: the Cardiovascular Research Network PRESERVE study. J Am Geriatr Soc2013;61:2633.

9. Maggioni AP, Dahlstrom U, Filippatos G, Chioncel O, Leiro MC, Drozdz J,Fruhwald F, Gullestad L, Logeart D, Metra M, Parissis J, Persson H, PonikowskiP, Rauchhaus M, Voors A, Nielsen OW, Zannad F, Tavazzi L, Heart FailureAssociation of ESC (HFA). EURObservational Research Programme: the HeartFailure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 2010;12:10761084.

10. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A,Pais P, Varigos J, Lisheng L, INTERHEART Study Investigators. Effect of potentiallymodifiable risk factors associated with myocardial infarction in 52 countries (theINTERHEART study): casecontrol study. Lancet 2004;364:937952.

11. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J, Hillege HL, vanVeldhuisen DJ, van der Meer P. Anemia and mortality in heart failurepatients a systematic review and meta-analysis. J Am Coll Cardiol 2008;52:818827.

12. Damman K, Voors AA, Hillege HL, Navis G, Lechat P, van Veldhuisen DJ, DargieHJ, CIBIS-2 Investigators and Committees. Congestion in chronic systolic heartfailure is related to renal dysfunction and increased mortality. Eur J Heart Fail2010;12:974982.

13. Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL.Increased central venous pressure is associated with impaired renal function andmortality in a broad spectrum of patients with cardiovascular disease. J Am CollCardiol 2009;53:582588.

14. Voors AA, van der Horst IC. Diabetes: a driver for heart failure. Heart2011;97:774780.

15. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100male patients. The final report. Int J Cardiol 2006;106:2128. ..

...................................................................................................................................................................................................................... 16. Javaheri S, Parker TJ, Liming JD, Corbett WS, Nishiyama H, Wexler L,

Roselle GA. Sleep apnea in 81 ambulatory male patients with stable heart fail-ure. Types and their prevalences, consequences, and presentations. Circulation1998;97:21542159.

17. Javaheri S, Parker TJ, Wexler L, Michaels SE, Stanberry E, Nishyama H, RoselleGA. Occult sleep-disordered breathing in stable congestive heart failure. AnnIntern Med 1995;122:487492.

18. Vazir A, Hastings PC, Dayer M, McIntyre HF, Henein MY, Poole-Wilson PA,Cowie MR, Morrell MJ, Simonds AK. A high prevalence of sleep disorderedbreathing in men with mild symptomatic chronic heart failure due to leftventricular systolic dysfunction. Eur J Heart Fail 2007;9:243250.

19. Lanfranchi PA, Somers VK, Braghiroli A, Corra U, Eleuteri E, Giannuzzi P.Central sleep apnea in left ventricular dysfunction: prevalence and implicationsfor arrhythmic risk. Circulation 2003;107:727732.

20. Oldenburg O, Lamp B, Faber L, Teschler H, Horstkotte D, Topfer V. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporarystudy of prevalence in and characteristics of 700 patients. Eur J Heart Fail2007;9:251257.

21. Ferrier K, Campbell A, Yee B, Richards M, OMeeghan T, Weatherall M,Neill A. Sleep-disordered breathing occurs frequently in stable outpatients withcongestive heart failure. Chest 2005;128:21162122.

22. Herrscher TE, Akre H, Overland B, Sandvik L, Westheim AS. High prevalence ofsleep apnea in heart failure outpatients: even in patients with preserved systolicfunction. J Card Fail 2011;17:420425.

23. Hawkins NM, Petrie MC, Jhund PS, Chalmers GW, Dunn FG, McMurray JJ.Heart failure and chronic obstructive pulmonary disease: diagnostic pitfalls andepidemiology. Eur J Heart Fail 2009;11:130139.

24. Hawkins NM, Jhund PS, Simpson CR, Petrie MC, Macdonald MR, Dunn FG,Macintyre K, McMurray JJ. Primary care burden and treatment of patients withheart failure and chronic obstructive pulmonary disease in Scotland. Eur J HeartFail 2010;12:1724.

25. Iversen KK, Kjaergaard J, Akkan D, Kober L, Torp-Pedersen C, Hassager C,Vestbo J, Kjoller E, ECHOS Lung Function Study Group. The prognostic impor-tance of lung function in patients admitted with heart failure. Eur J Heart Fail2010;12:685691.

26. Batcher EL, Tang XC, Singh BN, Singh SN, Reda DJ, Hershman JM, SAFE-T Investigators. Thyroid function abnormalities during amiodarone therapy forpersistent atrial fibrillation. Am J Med 2007;120:880885.

27. Edelmann F, Stahrenberg R, Gelbrich G, Durstewitz K, Angermann CE, DungenHD, Scheffold T, Zugck C, Maisch B, Regitz-Zagrosek V, Hasenfuss G, Pieske BM,Wachter R. Contribution of comorbidities to functional impairment is higher inheart failure with preserved than with reduced ejection fraction. Clin Res Cardiol2011;100:755764.

28. Zelis R, Sinoway LI, Musch TI, Davis D, Just H. Regional blood flow in congestiveheart failure: concept of compensatory mechanisms with short and long timeconstants. Am J Cardiol 1988;62:2E8E.

29. Levine TB, Olivari MT, Garberg V, Sharkey SW, Cohn JN. Hemodynamicand clinical response to enalapril, a long-acting converting-enzyme inhibitor, inpatients with congestive heart failure. Circulation 1984;69:548553.

30. Saxena PR, Schoemaker RG. Organ blood flow protection in hypertension andcongestive heart failure. Am J Med 1993;94:4S12S.

31. van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, VoorsAA. Abnormal liver function in relation to hemodynamic profile in heart failurepatients. J Card Fail 2010;16:8490.

32. Lenzen MJ, Boersma E, Reimer WJ, Balk AH, Komajda M, Swedberg K, FollathF, Jimenez-Navarro M, Simoons ML, Cleland JG. Under-utilization of evidence-based drug treatment in patients with heart failure is only partially explained bydissimilarity to patients enrolled in landmark trials: a report from the Euro HeartSurvey on Heart Failure. Eur Heart J 2005;26:27062713.

33. Komajda M, Lapuerta P, Hermans N, Gonzalez-Juanatey JR, van Veldhuisen DJ,Erdmann E, Tavazzi L, Poole-Wilson P, Le Pen C. Adherence to guidelines is apredictor of outcome in chronic heart failure: the MAHLER survey. Eur Heart J2005;26:16531659.

34. Peters-Klimm F, Muller-Tasch T, Schellberg D, Remppis A, Barth A, Holzapfel N,Junger J, Herzog W, Szecsenyi J. Guideline adherence for pharmacotherapy ofchronic systolic heart failure in general practice: a closer look on evidence-basedtherapy. Clin Res Cardiol 2008;97:244252.

35. Levin ML. The occurrence of lung cancer in man. Acta Unio Int Contra Cancrum1953;9:531541.

36. Berry C, Brett M, Stevenson K, McMurray JJ, Norrie J. Nature and prognosticimportance of abnormal glucose tolerance and diabetes in acute heart failure.Heart 2008;94:296304.

37. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ,Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM,



Robinson CA, Ezzati M, Global Burden of Metabolic Risk Factors of ChronicDiseases Collaborating Group (Blood Glucose). National, regional, andglobal trends in fasting plasma glucose and diabetes prevalence since 1980:systematic analysis of health examination surveys and epidemiological stud-ies with 370 country-years and 2.7 million participants. Lancet 2011;378:3140.

38. Tomova GS, Nimbal V, Horwich TB. Relation between hemoglobin a(1c) andoutcomes in heart failure patients with and without diabetes mellitus. Am J Cardiol2012;109:17671773.

39. Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated witha marked increase in mortality in patients with advanced heart failure. Am HeartJ 2005;149:168174. ..

........................ 40. Damy T, Margarit L, Noroc A, Bodez D, Guendouz S, Boyer L, Drouot X,

Lamine A, Paulino A, Rappeneau S, Stoica MH, Dubois-Rande JL, Adnot S,Hittinger L, dOrtho MP. Prognostic impact of sleep-disordered breathing andits treatment with nocturnal ventilation for chronic heart failure. Eur J Heart Fail2012;14:10091019.

41. Jilek C, Krenn M, Sebah D, Obermeier R, Braune A, Kehl V, Schroll S, MontalvanS, Riegger GA, Pfeifer M, Arzt M. Prognostic impact of sleep disordered breathingand its treatment in heart failure: an observational study. Eur J Heart Fail2011;13:6875.

42. Nichols M, Townsend N, Scarborough P, Luengo-Fernandez R, Leal J, Gray A,Rayner M. European Cardiovascular Disease Statistics 2012. Brussels: EuropeanSociety of Cardiology; Sophia Antipolis: European Heart Network; 2012.


ejhf30

Documents