Zdrav Vestn Supl | Heart failure pharmacotherapy guideline implementation I-13 IZVIrnI čLanek/OrIgInaL artIcLe Heart failure pharmacotherapy guideline implementation 1 General Hospital Murska Sobota, Department of internal medicine 2 University Clinic of Respiratory and Allergic Diseases Golnik, Division of Cardiology Korespondenca/ Correspondence: MItja Lainščak, m: mitja. lainscak@guest.arnes.si Ključne besede: srčno popuščanje; smernice; umrljivost; farmakološko zdravljenje Key words: heart failure; guidelines; mortality; pharmacotherapy Citirajte kot/Cite as: Zdrav Vestn 2014; 83 supl: I-13–20 Prispelo: 1. avg. 2013, Sprejeto: 7. okt. 2013 Heart failure pharmacotherapy guideline implementation and survival of patients in a community hospital: a retrospective study Udejanjanje smernic za zdravljenje srčnega popuščanja in preživetje bolnikov v regijski bolnišnici: retrospektivna raziskava Lea Majc Hodošček,1 Mitja Lainščak2 Izvleček Izhodišča: Le malo raziskav je preučevalo udeja- njanje smernic za zdravljenje srčnega popuščanja pri bolnikih v regionalnem okolju. Naš namen je bil preučiti farmakološko zdravljenje bolnikov s srčnim popuščanjem ob odpustu iz bolnišnice in morebitni vpliv na celotno umrljivost. Metode: V retrospektivni raziskavi smo pregle- dali odpustno dokumentacijo hospitaliziranih bolnikov v regionalni bolnišnici, ki so bili od- puščeni ali so umrli z diagnozo srčno popušča- nje v letih 2001–2003. Iz odpustnic smo povzeli osnovne značilnosti in podatke o farmakološkem zdravljenju. Podatke o preživetju smo pridobili iz centralnega registra prebivalstva. Rezultati: Vključili smo 638 bolnikov (73 ± 10 let, 48 % moških, 74 % razreda NYHA III ob sprejemu). Izvid ultrazvočne preiskave srca smo imeli za 61 % bolnikov, pri 70 % bolnikov smo ugotavljali okrnjeno sistolično funkcijo (43 % vseh bolnikov). Ob odpustu so bolniki v pov- prečju prejeli 6 zdravil (1–14 zdravil), od tega 4 zdravila za srčno-žilne bolezni (0–10 zdravil). V opazovanem obdobju smo ugotavljali povečanje predpisovanja zaviralcev adrenergičnih recep- torjev beta, predpisovanje zaviralcev konvertaze angiotenzina pa se v opazovanem obdobju ni spreminjalo. Ciljne odmerke zaviralcev adre- nergičnih receptorjev beta smo svetovali v 4 %, zaviralce ACE pa v 20 %. Kombinacija zdravlje- nja s tremi nevrohormonskimi zdravili, ki smo jo zasledili pri 83 bolnikih (13 %), je bila v mul- tivariantnem modelu povezana z nižjo celotno smrtnostjo (razmerje tveganj 0,69, 95-odstotni interval zaupanja 0,49–0,98). Višji odmerki za- viralcev ACE so bili povezani z boljšim izidom bolezni (razmerje tveganj 0,79, 95-odstotni in- terval zaupanja 0,68–0,93). Zaključki: Udejanjane smernic za zdravljenje bolnikov s srčnim popuščanjem v regijski bol- nišnici se je z raziskavo izkazalo za nezadostno. Farmakološko zdravljenje z nevrohormonskimi zaviralci je bilo povezano z boljšim izidom bo- lezni. Abstract Background: Few studies have investigated implementation of heart failure (HF) pharma- cotherapy in a non-selected community setting. We aimed to investigate pharmacotherapy at dis- charge from hospital and potential associations with all-cause mortality. Methods: In this retrospective study, hospital discharges and deaths from a community hos- pital in the period 2001–2003 were screened for diagnosis of HF. Patient and pharmacotherapy information was retrieved from medical records and survival information was obtained from the Central Population Registry. Results: We included 638 patients (73 ± 10 years, 48 % men, 74 % NYHA class III on admission). Echocardiography report was available for 61 %, and 70 % of those imaged (43 % of total popula- tion) had left ventricular systolic dysfunction. A median of 6 (interquartile range 1–14) drugs, 4 (interquartile range 0–10) being for cardiovas- cular disease, was prescribed at discharge. Over years, prescription rate of beta-blockers (BB) in- creased whereas it remained stable for angioten- sin converting enzyme (ACE) inhibitors. A target dose of BB and ACE inhibitors was prescribed to 4 % and 20 %, respectively. Combined neuro- hormonal antagonist therapy was prescribed to 83 (13 %) of patients, which was associated with lower all-cause mortality risk in a multivariate model (hazard ratio 0.69, 95 % confidence inter- val 0.49–0.98). Higher dose of ACE inhibitors was also associated with better outcome (hazard ratio per tertile: 0.79, 95 % confidence interval 0.68–0.93). I-14 Zdrav Vestn Supl | julij 2014 | Letnik 83 IZVIrnI čLanek/OrIgInaL artIcLe Conclusions: In our non-selected community- based HF cohort, pharmacotherapy was not implemented as appropriate. When applied, pharmacological therapy with neurohormonal antagonists was associated with a better out- come. Introduction Heart failure (HF) is an increasing public health problem imposing a significant bur- den on the patient and health care system. Despite cost-effective pharmacological the- rapy as summarized regularly by the Euro- pean Society of Cardiology (ESC), mortality remains excessive.1-6 Prognosis is particu- larly poor in patients after hospitalization for HF.6-8 Hence, scientific community and policy makers consider hospitalizations as a major preventable event on a HF patient’s journey. On the other hand, an average ho- spital stay of 10 days represents an invalua- ble chance to address open diagnostic issues and to individually tailor patient manage- ment.9 The implementation in clinical prac- tice, however, remains inadequate and there is little data how pharmacotherapy is associ- ated with patient outcomes.6-8,10 In Slovenia, limited data is available on in-hospital HF patient management. Over time, there was a constant improvement in patient assessment and pharmacotherapy, but generally, the guidelines were not fol- lowed as appropriate.5,11-13 This primarily holds true for some agents (e.g. beta-bloc- kers), particularly in conjunction with cer- tain comorbidity, when only limited pro- portion of patients are treated with a target dose.14-16 Evidence regarding reduced mor- tality is robust only for patients with left ventricular systolic dysfunction, whereas no large-scale study reported benefit in patients with preserved left ventricular ejection frac- tion, who make about 50 % of general HF population. Nonetheless, the treatment of underlying cardiovascular disease and risk factors are largely the same as in patients with left ventricular systolic dysfunction.1-4 With little information about HF ma- nagement in Slovenian hospitalized pati- ents, we initiated this retrospective study to obtain an insight into pharmacotherapy at discharge. In addition, we evaluated the associations between pharmacotherapy and long-term outcomes. Methods Study design, patients, and data collection In this retrospective study, all dischar- ges between December 2000 and December 2003 from the Department of Internal Me- dicine at the General Hospital Murska So- bota, a community hospital serving a popu- lation of 125,000 inhabitants, were screened for patient inclusion. We identified eligible patients using the ICD-10 codes I50.0-I50.9 and included those who have been dischar- ged alive. The National Ethics Com mittee revised and approved the study protocol. Data on demographic charac teristics, electrocardiogram, echocardiography, la- boratory parameters and pharmacological management at discharge were retrieved from medical records. Target doses of in- dividual pharmacological agents followed those reported by the ESC guidelines.1 Ena- lapril and carvedilol target dose was used as the reference for angiotensin converting enzyme (ACE) inhibitors and beta-blockers (BB), respectively, for the comparison of daily doses in relation to a target dose. Equi- valent doses of other ACE inhibitors were calculated by multiplying the daily dose by a factor between the target daily dose of the used drug and the target daily dose of enala- pril or carvedilol. Estimated glomerular fil- tration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equa- tion.17 Long-term survival was assessed by cross-referencing patient data with the Cen- tral Population Registry. Our database was censored on 1.11.2008 and no patients were lost to follow-up. Heart failure pharmacotherapy guideline implementation Zdrav Vestn Supl | Heart failure pharmacotherapy guideline implementation I-15 IZVIrnI čLanek/OrIgInaL artIcLe Figure 1: Proportion of patients treated with target dose or ≥50% of target dose. ace – angiotensin converting enzyme; BB – beta blockers. Statistical analysis Continuous variables are presented with mean ± standard deviation (SD) or as me- dian with interquartile range (IQR). Cate- gorical variables are presented as absolute numbers and pro portions. To evaluate the differences between patients according to year of hospitalization, Student’s t-test, the chi-squared test and the Mann–Whitney U-test were used as appropriate. Predictors of BB prescription were estimated by logi- stic regression model. Event-free survival was estimated from Kaplan–Meier curves and compared using the log-rank test. Cox proportion al hazard models were con- structed to study the relationship between pharmacotherapy and all-cause mortality. Combined neurohormonal treatment was defined as a combination of ACE inhibitor/ angiotensin receptor blocker (ARB), BB, and spironolactone. Patients were divided into tertiles of enalapril equivalent daily dose: ≤5mg, 6–10 mg and > 10 mg. To determine independent predictors of all-cause mortali- ty, adjustment for age, gender, comorbidity, and renal function was applied in a mul- tivariate model. We report odds ratios (OR), hazard ratios (HR) and corresponding 95 % confidence intervals (CI). Data collection and all calculations were made using the software package SPSS 18.0 (SPSS Inc., 2009, Chicago, Illinois, USA). For all tests, a P-va- lue of 0.05 or less (two-sided) was conside- red statistically significant. Results We identified 766 eligible patients and after excluding those who died during ho- spitalisation (N = 128), 638 patients (73 ± 10 years, 48 % men, 74 % NYHA class III on admission) were available for analysis (Ta- ble 1). Atrial fibrillation and arterial hyper- tension were most common comorbidities, and 52 % of patients had eGFR < 60ml/min. Echocardiography report was available for 61 % and 70 % of those imaged (43 % of to- tal population) had left ventricular systolic dysfunction. Patients were discharged with a median of 6 (IQR 1–14) drugs, 4 (IQR 0–10) being for cardiovascular disease. No significant differences in the number of drugs or the proportion of patients treated with key pharmacological agents were observed per different left ventricular function (p > 0.2 for all). Over years, the proportion of patients treated with ACEi/ARB remained stable whereas we recorded a decrease in the use of furosemide and digoxin and an increase in the use of BB, which nearly doubled (Table 2). Patients with chronic obstructive pulmo- nary disease (OR 0.35, 95 % CI 0.19–0.64) and those older than 75 years (OR 0.41, 95 % CI 0.28–0.59) were less likely to be prescri- bed with BB. Prescription of either target or ≥ 50 % of target dose of ACE inhibitors and BB increased over years, whereas fur- osemide dosing remained stable. Generally, Heart failure pharmacotherapy guideline implementation I-16 Zdrav Vestn Supl | julij 2014 | Letnik 83 IZVIrnI čLanek/OrIgInaL artIcLe Figure 2a (left): kaplan-Meier survival curves for treatment with combination of neurohormonal antagonists. Figure 2b (right): kaplan-Meier survival curves for treatment per angiotensin converting enzyme daily dose tertile. <10 % of patients received > 25 mg of spiro- nolactone (Figure 1). During an average follow-up of 35 ± 25 months, 396 (62 %) patients died. A neuro- hormonal antagonists combination therapy was prescribed to 83 (13 %) of patients, which was associated with lower all-cause mortali- ty risk (Figure 2a) (HR 0.60, 95 % CI 0.43– 0.86). An increasing dose of ACE inhibitor per tertile of target dose was also associated with lower risk of all-cause mortality (Figure 3) (HR per tertile: 0.76, 95 % CI 0.66–0.87). Heart failure pharmacotherapy guideline implementation Table 1: Patient characteristics by year of hospitalization. Data are given as mean ± standard deviation or number (%). All patients Year 2001 Year 2002 Year 2003 p Number 638 171 193 274 Age (years) 73 ± 10 74 ± 11 72 ± 10 73 ± 10 ns Men 307 (48) 83 (49) 93 (48) 131 (48) ns Ischemic heart disease 135 (21) 30 (17) 43 (22) 62 (23) ns Arterial hypertension 286 (45) 86 (50) 86 (45) 114 (42) ns Atrial fibrillation 335 (53) 92 (54) 120 (58) 123 (45) 0.013 Diabetes mellitus 208 (33) 55 (32) 60 (31) 93 (34) ns Chronic kidney disease 137 (21) 37 (22) 40 (21) 60 (22) ns Chronic obstructive pulmonary disease 106 (17) 32 (19) 35 (18) 41 (15) ns Echocardiography 392 (61) 92 (54) 125 (65) 175 (64) 0,03 Systolic dysfunction 276 (43) 66 (39) 88 (46) 122 (44) <0.01 Haemoglobin (g/l) 133 ± 20 137 ± 19 133 ± 19 131 ± 21 0.005 Potassium (mmol/l) 4.4 ± 0.5 4.4 ± 0.5 4.4 ± 0.5 4.4 ± 0.5 ns Creatinine (umol/l) 113 ± 65 115 ± 75 105 ± 36 118 ± 73 ns Estimated glomerular filtrtion rate (ml/min) 51 ± 20 51 ± 18 53 ± 19 51 ± 21 ns Zdrav Vestn Supl | Heart failure pharmacotherapy guideline implementation I-17 IZVIrnI čLanek/OrIgInaL artIcLe In multivariate models for all-cause morta- lity, treatment with a combination of neuro- hormonal antagonists and with higher daily dose of ACE inhibitors was associated with lower risk for all-cause mortality (Table 3a and 3b). Both findings were independent of left ventricular systolic function. Discussion To our knowledge, this is one of few reports on the prognostic implications of pharmacotherapy in a non-selected commu- nity-based HF cohort. In clinical practice, implementation of HF guidelines remains suboptimal, both in terms of neurohormo- nal antagonist prescription and titration. When applied, however, pharmacological therapy with neurohormonal antagonists was associated with better outcome. Several pan-European surveys and na- tional registries demonstrate constant im- provement in pharmacotherapy patterns over last decade.7,18,19 Our results are in line with previous reports, but show rather unsatisfactory numbers for BB prescription and titration. It needs to be stressed that in- -hospital initiation appears crucial, as pa- tients discharged home as BB naïve have less chances to be on long-term BB therapy when compared to those discharged with BB’s.20 Apparently, several reasons for such clinical practice exist, where advanced age, certain comorbidity (e.g. chronic obstructi- ve pulmonary disease), and patient charac- teristics (blood pressure, heart rate) may be most relevant ones, although little evidence is supportive for such clinical practice.21 Also, it is not trivial to titrate BB in a 14-day manner as previously advised by the guide- lines.1 The largest BB comparative study in the elderly HF patients, the CIBIS-ELD stu- dy, demonstrated that only about a quarter of patients in whom treatment with bisopro- lol or carvedilol was initiated, actually were up-titrated and remained on the target dose if such strict titration scheme was applied.22 Whether target dose is the ultimate goal in BB therapy was recently challenged. In a large meta-analysis, the heart rate was more important than BB target dose,23 which may even be a factor preventing further titration of BB24 or introduction of adjunct therapy with ivabradine,4 which appears to be also safe in elderly25 and those with concomitant COPD.26 Only few studies investigated whether neurohomonal antagonists are associated with clinical benefits in non-selected com- munity HF patients. Additional analyses of the EuroHeart Failure Survey demonstrated that treatment with ACE inhibitors and BB reduced 12-week mortality by at least 20 %.27 An Austrian subsample analysis of 341 pa- tients showed that 81 patients were treated with triple combination of neurohormonal antagonist, which was associated with si- gnificant prognostic benefit.10 Stoerck et al. evaluated 1054 HF patients (61 % with redu- ced left ventricular ejection fraction) and Heart failure pharmacotherapy guideline implementation Table 2: Pharmacological treatment. Data are given as number (%). All patients Year 2001 Year 2002 Year 2003 p Angiotensin converting enzyme inhibitors 495 (77) 139 (81) 151 (78) 205 (75) ns Beta blockers 165 (26) 28 (16) 56 (29) 81 (30) 0.004 Spironolactone 278 (44) 68 (40) 108 (56) 102 (37) <0.001 Angiotensin receptor blockers 24 (4) 4 (2) 8 (4) 12 (4) ns Furosemide 529 (83) 150 (88) 161 (83) 218 (80) ns Thiazides or thiazide like diuretics 60 (9) 12 (7) 21 (11) 27 (10) ns Digoxine 343 (54) 113 (66) 101 (52) 129 (47) <0.001 I-18 Zdrav Vestn Supl | julij 2014 | Letnik 83 IZVIrnI čLanek/OrIgInaL artIcLe reported a median 67 % and 50 % Guideline Adherence Indicator-3 (GAI-3) in patients with and without left ventricular systolic dysfunction.8 In both cohorts, higher GAI- 3 was predictive of better patient outcome. The latter was observed in our cohort and has important clinical implications. Whilst evidence about prognostic benefit of neu- rohormonal antagonists is available for pa- tients with reduced left ventricular ejection fraction, it is rather intuitive that same the- rapy would also confer benefit for those with preserved left ventricular ejection fraction. Although the randomized studies in the fie- ld failed to provide conclusive evidence, in- formation from clinical practice and certain sub analyses of large-scale trials are sugge- stive that such treatment at least should not be withheld in those patients.4 Our findings need to be interpreted in light of certain limitations. As per study de- sign, we relied on data retrieved from medi- cal records, which means that information on comorbidity and diagnostic procedures may not be complete. The inclusion criteri- on of ICD-10 diagnosis can be challenged; yet, this is the usual way implemented in retrospective studies and yields reliable in- formation.28 We are also unaware of poten- tial contraindications that prevented intro- duction or uptitration of pharmacological agents. Finally, only all-cause mortality was Heart failure pharmacotherapy guideline implementation Table 3: Univariable and multivariable predictors of all-cause mortality in subjects a) treated with a combination of neurohormonal antagonists and b) per tertile of angiotensin converting enzyme inhibitor daily dose. Data are presented as hazard ratios with corresponding 95 % confidence intervals. a) treated with a combination of neurohormonal antagonists Univariate Multivariate Men [vs. women] 0.95 [0.78–1.15] 0.91 [0.73–1.14] Age [per 1 year increase] 1.03 [1.02–1.05] 1.03 [1.02–1.04] Ischaemic heart disease 0.83 [0.65–1.06] 0.77 [0.60–0.99] Arterial hypertension 0.69 [0.56–0.84] 0.66 [0.54–0.82] Atrial fibrillation 1.13 [0.92–1.37] 1.05 [0.85–1.29] Diabetes mellitus 0.89 [0.72–1.10] 0.95 [0.76–1.18] Estimated glomerular filtration rate [ per 1ml/min increase] 0.99 [0.98–0.99] 0.99 [0.98–0.99] Combination of neurohormonal antagonists 0.76 [0.66–0.87] 0.69 [0.49–0.98] b) per tertile of angiotensin converting enzyme inhibitor daily dose Univariate Multivariate Men [vs. women] 0.95 [0.78–1.15] 1.01 [0.78–1.31] Age [per 1 year increase] 1.03 [1.02–1.05] 1.03 [1.02–1.05] Ischaemic heart disease 0.83 [0.65–1.06] 0.84 [0.63–1.11] Arterial hypertension 0.69 [0.56–0.84] 0.85 [0.65–1.10] Atrial fibrillation 1.13 [0.92–1.37] 0.97 [0.77–1.23] Diabetes mellitus 0.89 [0.72–1.10] 1.05 [0.82–1.35] Estimated glomerular filtration rate [ per 1ml/min increase] 0.99 [0.98–0.99] 0.99 [0.98–0.99] Angiotensin converting enzyme dose [per tertile] 0.76 [0.66–0.87] 0.79 [0.68–0.93] Zdrav Vestn Supl | Heart failure pharmacotherapy guideline implementation I-19 IZVIrnI čLanek/OrIgInaL artIcLe analysed whereas the influence of pharma- cotherapy on readmissions would also be relevant due to associated costs. Conclusions and clinical implications Our retrospective study gives an insi- ght into HF pharmacotherapy at discharge, which was not satisfactory, neither in terms of agents prescribed nor in daily doses rea- ched. Over years, there was improvement in diagnostic and therapeutic management yet the optimal goals were still not reached. Im- portantly, and irrespective of left ventricular function, treatment with a combination of neurohormonal antagonists and with higher doses of ACE inhibitors was associated with lower all-cause mortality. Therefore, optimi- zation of pharmacotherapy during hospital stay should be pursued when ample oppor- tunity exists. Whenever possible, patients should be referred to specialized HF clinics for adequate counselling and further therapy optimization with periodical follow-up.29-31 In conjunction with that, higher standards of HF management across all levels of care, starting with the awareness, aetiological treatment, and multidisciplinary approach, should be applied according to local needs and potentials.32,33 References 1. Task force for the diagnosis and treatment of chronic heart failure of the European Society of Cardiology. Guidelines for the diagnosis and tre- atment of chronic heart failure. Eur Heart J 2001; 22: 1527–60. 2. Swedberg K, Cleland J, Dargie H, Drexler H, Fol- lath F, Komajda M, et al. Guidelines for the dia- gnosis and treatment of chronic heart failure: full text (update 2005). Eur Heart J 2005; 26: 1115–40. 3. Dickstein K, Cohen-Solal A, Filippatos G, McMu- rray JJ, Ponikowski P, Poole-Wilson PA, et al. ESC Guidelines for the diagnosis and treatment of acu- te and chronic heart failure 2008. Eur J Heart Fail 2008; 10: 933–89. 4. McMurray JJ, Adamopoulos S, Anker SD, Auri- cchio A, Bohm M, Dickstein K, et al. ESC Gui- delines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chro- nic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012; 14: 803–69. 5. Lainscak M, Horvat A, Keber I. The manage- ment of patients with heart failure in a Slovenian community hospital: what has changed between 1997 and 2000? Wien Klin Wochenschr 2003; 115: 334–9. 6. Maggioni A, Anker SD, Dahlstrom U, Filippatos G, Ponikowski P, Zannad F, et al. Are hospitalized or ambulatory patients with heart failure treated in accordance with ESC guidelines? Evidence from 12,440 patients of the ESC Heart Failure Long- -Term Registry. Eur J Heart Fail 2013; 15: 1173–84. 7. Tavazzi L, Senni M, Metra M, Gorini M, Caccia- tore G, Chinaglia A, et al. Multicenter prospective observational study on acute and chronic heart failure: one-year follow-up results of IN-HF (Itali- an Network on Heart Failure) Outcome Registry. Circ Heart Fail 2013; 6: 473–81. 8. Stoerck S, Hense HW, Zentgraf C, Uebelacker I, Jahns U, Ertl G, et al. Pharmacotherapy according to treatment guidelines is associated with lower mortality in a community-based sample of pati- ents with chronic heart failure: a prospective co- hort study. Eur J Heart Fail 2008; 10: 1236–45. 9. Lainscak M, Cleland JG, Lenzen MJ, Nabb S, Ke- ber I, Follath F, et al. Recall of lifestyle advice in patients recently hospitalised with heart failure: a EuroHeart Failure Survey analysis. Eur J Heart Fail 2007; 9: 1095–103. 10. Hulsmann M, Berger R, Mortl D, Pacher R. In- fluence of age and in-patient care on prescription rate and long-term outcome in chronic heart fai- lure: a data-based substudy of the EuroHeart Fai- lure Survey. Eur J Heart Fail 2005; 7: 657–61. 11. Kariz S, Grom I. Trends in management of pati- ents hospitalized for heart failure in a community hospital, 1996–2004. Slov Kardiol 2005; 2(Suppl 1): 51. 12. Keber I, Lainscak M, Horvat A, Dobovisek J. Obravnava bolnikov s srčnim popuščanjem v splošni in univerzitetni bolnišnici v letu 1997. Zdrav Vestn 2003; 78: 135–40. 13. Lainscak M, Kerbev M, Horvat A, Benko D, Klanc- nik Gruden M, et al. Results of EuroHeart Failure survey in Slovenia: pharmacological management of heart failure. Slov Kardiol 2004; 1: 22–7. 14. Lainscak M, Majc Hodoscek L, Düngen HD, Rau- chhaus M, Doehner W, Anker SD, et al. The bur- den of chronic obstructive pulmonary disease in patients hospitalized with heart failure. Wien Klin Wochenschr 2009; 121: 309–13. 15. Lainscak M, Cleland JG, Lenzen MJ, Follath F, Ko- majda M, Swedberg K. International variations in the treatment and co-morbidity of left ventricular systolic dysfunction: data from the EuroHeart Fai- lure Survey. Eur J Heart Fail 2007; 9: 292–9. 16. Lainscak M, Moullet C, Schön N, Tendera M. Tre- atment of chronic heart failure with carvedilol in daily practice: the SATELLITE survey experience. Int J Cardiol 2007; 122: 149–55. 17. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet Heart failure pharmacotherapy guideline implementation I-20 Zdrav Vestn Supl | julij 2014 | Letnik 83 IZVIrnI čLanek/OrIgInaL artIcLe in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70. 18. Komajda M, Follath F, Swedberg K, Cleland J, Aguilar JC, Cohen-Solal A, et al. The EuroHeart Failure survey programme—a survey on the qua- lity of care among patients with heart failure in Europe; part 2: treatment. Eur Heart J 2003; 24: 464–75. 19. Nieminen MS, Brutsaert D, Dickstein K, Drexler H, Follath F, Harjola V-P, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acu- te heart failure patients: description of population. Eur Heart J 2006; 27: 2725–36. 20. Gattis WA, O’Connor C, Gallup DS, Hasselblad V, Gheorghiade M. Predischarge initiation of carve- dilol in patients with edcompensated heart failur. J Am Coll Cardiol 2004; 43: 1534–41. 21. Lainscak M, Podbregar M, Kovacic D, Rozman J, von Haehling S. Differences between bisoprolol and carvedilol in patients with chronic heart fai- lure and chronic obstructive pulmonary disease: a randomized trial. Respir Med 2011; 105 Suppl 1: S44-S49. 22. Düngen HD, Apostolovic S, Inkrot S, Tahirovic E, Töpper A, Mehrhof F, et al; on behalf of the CIBIS- -ELD investigators and Project Multicentre Trials in the Competence Network Heart Failure. Titra- tion to target dose of bisoprolol vs. carvedilol in elderly patients with heart failure: the CIBIS-ELD trial. Eur J Heart Fail 2011; 13: 670–80. 23. McAlister FA, Wiebe N, Ezekowitz JA, Leung AA, Armstrong PW. Meta-analysis: beta-blocker dose, heart rate reduction, and death in patients with heart failure. Ann Intern Med 2009; 150: 784–94. 24. Gelbrich G, Edelmann F, Inkrot S, Lainscak M, Apostolovic S, Neskovic AN, et al. Is target dose the treatment target? Uptitrating beta-blockers for heart failure in the elderly. Int J Cardiol 2012; 155: 160–6. 25. Tavazzi L, Swedberg K, Komajda M, Böhm M, Borer JS, Lainscak M, et al. Efficacy and safety of ivabradine in chronic heart failure across the age spectrum: insights from the SHIFT study. Eur J Heart Fail 2013, 2013; 15: 1296–303. 26. Tavazzi L, Swedberg K, Komajda M, Böhm M, Borer JS, Lainscak M, et al. Clinical profiles and outcomes in patients with chronic heart failure and chronic obstructive pulmonary disease: an efficacy and safety analysis of SHIFT study. Int J Cardiol 2013; 170: 182-8. 27. Velavan P, Khan NK, Goode K, Rigby AS, Loh PH, Komajda M, et al. Predictors of short term morta- lity in heart failure – Insight from the Euro Heart Failure Survey. Int J Cardiol 2010; 138: 63–9. 28. Pfister R, Michels G, Wilfred J, Luben R, Wareham NJ, Khaw KT. Does ICD-10 hospital discharge code I50 identify people with heart failure? A vali- dation study within the EPIC-Norfolk study. Int J Cardiol 2013, 2013; 168: 4413–4. 29. Lainscak M, Keber I. Patients’ knowledge and beta blocker treatment improve prognosis of patients from a heart failure clinic. Eur J Heart Fail 2006; 8: 187–90. 30. Lainscak M, Cleland JG, Lenzen MJ, Keber I, Go- ode K, Follath F, et al. Nonpharmacologic mea- sures and drug compliance in patients with heart failure: data from the EuroHeart Failure Survey. Am J Cardiol 2007; 99(6B): 31D-37D. 31. McDonagh TA, Blue L, Clark AL, Dahlström U, Ekman I, Lainscak M, et al; on behalf of Heart Failure Association Committee on Patient Care. European Society of Cardiology Heart Failure Association Standards for delivering heart failure care. Eur J Heart Fail 2011; 13: 235–41. 32. Seferovic PM, Stoerk S, Filippatos G, Mareev V, Kavoliuniene A, Ristic AD, et al. Organization of Heart failure Management in European Soci- ety of Cardiology Member Countries: Position Statement of the Heart Failure Association of the European Society of Cardiology in Collaboration with the Heart Failure National Societies/Working Groups. Eur J Heart Fail 2013, 2013; 15: 947–59. 33. Lainscak M, Letonja M, Kovacic D, Hodoscek LM, Marolt A, Bartolic CM, et al. General public awareness of heart failure: results of questionnaire survey during Heart Failure Awareness Day 2011. Arch Med Sci 2014; 10: 355–60.