ESC HEART FAILURE ORIGINAL RESEARCH ARTICLE ESC Heart Failure 2020; 7: 26–36 Published online 9 January 2020 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12567 Management of Heart Failure with Reduced Ejection Fraction after ESC 2016 Heart Failure Guidelines: The Linx Registry Fernando de Frutos1*, Sonia Mirabet2, Luis Ortega-Paz3, Irene Buera4, Sara Darnés5, Nuria Farré6, Bernardo Perez,7 Raquel Adeliño8, Ramón Bascompte9, Jordi Pérez-Rodón10, Xavier Aparicio11, Mario Sutil-Vega12, Adriana Soto13, Mercedes Faraudo14, Miguel Cainzos-Achirica1 and Nicolás Manito1 1 Department of Cardiology, Hospital Universitari de Bellvitge, Barcelona, Spain; 2Department of Cardiology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 3 Department of Cardiology, Hospital Clinic, Barcelona, Spain; 4Department of Cardiology, Hospital de Viladecans, Barcelona, Spain; 5Department of Cardiology, Hospital de Figueres, Girona, Spain; 6Department of Cardiology, Hospital del Mar, Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), and Department of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain; 7Department of Cardiology, Hospital de Granollers, Barcelona, Spain; 8 Department of Cardiology, Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 9Department of Cardiology, Hospital Universitari Arnau de Vilanova, Lleida, Spain; 10 Department of Cardiology, Hospital Universitari Vall d’Hebrón, Universitat Autònoma de Barcelona, Vall d’Hebrón Institut de Recerca, CIBER-CV, Barcelona, Spain; 11 Department of Cardiology, Hospital de Mataró, Barcelona, Spain; 12Department of Cardiology, Corporacio Sanitaria Parc Taulí, Barcelona, Spain; 13Department of Cardiology, Hospital de Martorell, Barcelona, Spain; 14Department of Cardiology, Hospital Moises Broggi, Barcelona, Spain Abstract Aims In May 2016, a new version of the European Society of Cardiology (ESC) Guidelines for the management of heart failure (HF) was released. The aim of this study was to describe the management of HF with reduced ejection fraction after the pub- lication of ESC Guidelines. Methods and results The Linx registry is a multicentre, observational, cross-sectional study from 14 Catalan hospitals that enrolled 1056 patients with HF and reduced left ventricular ejection fraction (≤40%) from 1 February to 30 April 2017 in out- patient cardiology clinics. Results were compared between hospitals according to their level of complexity in our own registry and compared with previously published registries similar to ours. Sacubitril/valsartan was prescribed to 23.9% of patients in our population, as a consequence, use of angiotensin-converting enzyme inhibitor and angiotensin receptor blockers in mono- therapy decreased to 48.1% and 16.9%, respectively, and prescription of beta-blockers (91.8%), mineralocorticoid receptor an- tagonists (72.7%), and ivabradine (21.4%) remained similar to previous registries. Target doses of beta-blockers (25.4%), angiotensin-converting enzyme inhibitors (24.9%), angiotensin receptor blockers (7.7%), sacubitril/valsartan (8.1%), and min- eralocorticoid receptor antagonists (19.7%) were accomplished in a low proportion of patients. Our results also suggest that prescription and up-titration of class I HF drugs were greater in hospitals with higher level of complexity. Conclusions The Linx registry shows an appropriate adherence to pharmacological recommendations from ESC HF Guide- lines despite a low proportion of patients reached target doses. Almost one-quarter of patients were under treatment with sacubitril/valsartan a few months after ESC HF Guidelines recommendations. Keywords Chronic heart failure; Guidelines; Heart failure; Management; Sacubitril/valsartan Received: 7 July 2019; Revised: 30 October 2019; Accepted: 4 November 2019 *Correspondence to: Fernando de Frutos, Department of Cardiology, Hospital Universitari de Bellvitge, 19th Floor, Feixa Llarga s/n, 08907 L’Hospitalet de Llobregat, Barcelona, Spain. Email: fdefrutos@alumni.unav.es Introduction Although in Western countries there is currently a trend to- Heart failure (HF) is a global health issue with a prevalence wards a reduction in the incidence of HF with reduced ejec- between 1% and 2% in Western countries,1,2 an estimated tion fraction [HFrEF; left ventricular ejection fraction (LVEF) 26 million affected worldwide,3 and one of the leading ≤40%],5 it still represents almost one-third of incident HF sources of health care resource use and expenditure.4 cases6 and has a mortality rate of 8.8% at 1 year.7 © 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any me- dium, provided the original work is properly cited and is not used for commercial purposes. Management of Heart Failure after ESC 2016 Guidelines 27 Pharmacological management of HFrEF aims to regulate which patients were included in the study will be considered the physiological compensatory response to low cardiac the ‘index’ visit. output, which in the long-term prompts maladaptive cardiac remodelling finally leading to chronic HF.8 Blocking the adren- Data collection ergic and the renin–angiotensin–aldosterone systems has been the classical target of HF drugs.9–11 In addition, drugs Information on demographic characteristics, HF aetiology, key that reduce heart rate through inhibition of sinoatrial cardiac HF clinical variables (e.g. LVEF and New York Heart Association myocites, such as ivabradine,12 or increase plasma levels of functional class), and relevant co-morbidities was collected by natriuretic peptides through inhibition of neprilysin, such as local researchers using the local medical records. Information sacubitril/valsartan,13 have shown clinical benefits in the last on vital signs and electrocardiographic parameters was ob- decade. tained from the information generated in the most recent In May 2016, a new version of the European Society of Car- outpatient clinic visit before study entry. Data on blood sam- diology (ESC) Guidelines for the management of acute and ple tests [including levels of N-terminal pro-B type natriuretic chronic HF was released.14 The document included updated peptide (NT-proBNP)] and echocardiographic parameters recommendations regarding the diagnosis, pharmacological were obtained from the most recent tests before study entry. and invasive treatment of these patients, such as introduc- Data on pharmacological therapies [including beta- tion of sacubitril/valsartan as a class I therapy, or recommen- blockers, angiotensin-converting enzyme inhibitors (ACEI), dations for the early initiation of key HF drugs. angiotensin receptor blockers (ARBs), mineralocorticoid re- To our knowledge, no major registries of HFrEF outpatients ceptor antagonists (MRAs), ARNIs, and ivabradine, among have been published after the publication of ESC 2016 Guide- others], their doses, and use of key HF devices [cardiac lines.14 The purpose of the present study was thus to (i) de- resynchronization therapy (CRT) and implantable cardioverter scribe the characteristics of a large population HFrEF defibrillator (ICD)] were collected by local researchers at the patients recruited after ESC 2016 Guidelines14 release, (ii) end of the index visit. compare the pharmacological and invasive management of HFrEF patients by level of hospital complexity, and (iii) com- pare this management with those from previous registries. Definition of hospital type In order to compare the clinical characteristics and pharmaco- logical management between hospitals according to their level Methods of complexity, we classified recruiting centres in three catego- ries: primary, secondary, and tertiary. Hospitals providing nei- Study design and population ther interventional cardiology nor cardiac surgery were classified as primary centres (six), hospitals providing interven- tional cardiology but not cardiac surgery were classified as sec- The Linx registry is a multicentre, observational, cross- ondary centres (three), and hospitals providing both were sectional study from 14 Catalan hospitals (Figure 1) aimed classified as tertiary centres (five). This classification has been at assessing the impact of the new ESC 2016 Guidelines14 in widely used in previously published HF registries.15 the management of HFrEF outpatients in the real-world setting. For the Linx registry, patients were prospectively enrolled Statistical analyses from the outpatient cardiology clinics of each participating hospital from 1 February to 30 April 2017. This included gen- Descriptive statistics were used to summarize the characteris- eral cardiology clinics (mostly in primary hospitals) as well as tics of the study participants, including therapies and drug specialized HF clinics (typically in tertiary hospitals). Inclusion doses. Categorical variables are presented as number and criteria were a diagnosis of HF according ESC 2016 Guide- percentage, continuous variables with normal distribution lines14 and reduced LVEF (defined by LVEF ≤40% in the most are presented using mean and standard deviation, and non- recent echocardiography during follow-up). Exclusion criteria normal continuous variables are presented using median were age under 18 years old, use of left ventricular assist de- and interquartile range. vices, or heart transplantation before study entry. All of these In the comparative analyses by level of hospital complex- patients were included in the present analysis. ity, these characteristics were compared using chi-squared Patients included in the Linx registry were managed tests for categorical variables, and ANOVA and non- according to the local HFrEF management protocols; at the parametric tests for continuous variables, as appropriate. time of inclusion, there were no regulatory restrictions to The proportion of patients in whom target doses of each prescription of angiotensin receptor neprilysin inhibitor key HF pharmacotherapy were achieved (according to ESC (ARNI). For the present analysis, the outpatient clinic visit in 2016 Guidelines14) was also calculated, overall and by ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 28 F. de Frutos et al. Figure 1 Hospital geographical location. 1. Hospital Universitari de Bellvitge (L’Hospitalet de Llobregat), 2. Hospital Clinic (Barcelona), 3. Hospital Universitari Germans Trias i Pujol (Badalona), 4. Hospital de la Santa Creu i Sant Pau (Barcelona), 5. Hospital Universitari Vall d’Hebron (Barcelona), 6. Hospital Universitari Arnau de Vilanova (Lleida), 7. Hospital del Mar (Barcelona), 8. Corporació Sanitària Parc Taulí (Sabadell), 9. Hospital de Figueres (Figueres), 10. Hospital de Granollers (Granollers), 11. Hospital Moisès Broggi (Sant Joan Despí), 12. Hospital Sant Joan de Deu de Martorell (Martorell), 13. Hospital de Mataró (Mataró), 14. Hospital de Viladecans (Viladecans). 1–5 tertiary hospitals, 6–8 secondary hospitals, 9–14 primary hospitals. hospital type. As a graphical, intuitive summary, these pro- Results portions were plotted using a radial graph or ‘radar chart’.26 Although this graph has not been common in HF research, Study participants it allows accommodating in one single image multiple data (in the present analysis, multiple data on target dose use) in Between 1 February and 30 April 2017, 1056 HFrEF patients a more efficient way than traditional bar charts. It also allows were prospectively enrolled in the registry; 604 calculating the area of the polygon, and the proportion over patients (57.2%) were recruited from tertiary hospitals, 144 the total area, as summary measures. Specifically, we calcu- patients (13.6%) from secondary hospitals, and 308 patients lated the proportion over the total area for four polygons, (29.2%) from primary hospitals. as a percentage of the maximum theoretical target dose: overall (i.e. all hospitals), tertiary, secondary, and primary hospitals. More details on the calculations performed for Demographic characteristics and clinical profile of the radial graph are presented in the Supporting Information, the study participants Data S1. We also compared the overall proportions of users of each Table 1 summarizes the characteristics of 1056 HFrEF patients drug type and of HF devices in the Linx registry, with the included in the registry. Overall, mean age was 66.5 years, results of the Spanish cohort of the ESC Heart Failure Long- and 78.9% of patients were men. Ischaemic cardiomyopathy term Registry,16 a similar multicentre registry including 1526 was the most frequent aetiology of HF (42.3%), followed by Spanish HFrEF patients, published before the release of the idiopathic dilated cardiomyopathy (32.7%). Median LVEF ESC 2016 Guidelines. Proportions were compared again using was 30%, and only 14.5% of patients were asymptomatic, the chi-squared statistic. while more than half (58.4%) had mild HF symptoms (New Finally, we plotted the present results together with the York Heart Association II). Median NT-proBNP was 1861 results from similar, previously published landmark European pg/mL, and 66.5% of patients had a previous admission for HFrEF registries conducted since 2003, as means to provide HF. Left bundle branch block was present in 33.6% of pa- historical context to the present findings.7,17–19 tients. With regard to co-morbidities, 40% of patients had All statistical analyses were centralized in one of the atrial fibrillation, 34.7% had chronic kidney disease, and recruiting centres and were performed using Excel version 16 23.7% had chronic obstructive pulmonary disease. (Microsoft, Redmond, Washington, USA) and Stata software In hospitals with higher level of complexity, patients were version 15.0 (StataCorp, College Station, Texas, USA). A two- younger, and ischaemic cardiomyopathy was more frequent tailed P value <0.05 was considered statistically significant. than in less complex centres. There were no differences ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 Management of Heart Failure after ESC 2016 Guidelines 29 Table 1 Demographics and clinical profile of patients Overall (N = 1056) Tertiary (N = 604) Secondary (N = 144) Primary (N = 308) P value Demographics Age (years) 66.5 (12.3) 64.3 (12.3) 67.1 (12.1) 70.4 (11.5) <0.001 Male sex 815 (78.9) 481 (80.8) 98 (74.2) 236 (77.1) 0.162 HF aetiology <0.001 Ischaemic 404 (42.3) 232 (46.0) 55 (38.2) 117 (38.1) Valvular 70 (7.3) 33 (6.6) 13 (9.0) 24 (7.8) Hypertensive 22 (2.3) 9 (1.8) 7 (4.9) 6 (1.95) Alcoholic 29 (3.0) 18 (3.6) 4 (2.8) 7 (2.3) Other toxics 18 (1.9) 8 (1.6) 10 (5.1) 2 (0.6) Non-compaction 26 (2.7) 20 (4.0) 3 (2.1) 3 (1.0) Mixed 41 (4.3) 27 (5.4) 2 (1.4) 12 (3.9) IDC 312 (32.7) 140 (27.8) 44 (30.6) 128 (41.7) Others 33 (3.5) 17 (3.4) 8 (5.6) 18 (2.6) LVEF (%) 30 (25, 35) 31 (25, 35) 30 (25, 35) 30 (25, 35) 0.552 NYHA class <0.001 I 153 (14.5) 65 (10.8) 32 (22.2) 56 (18.2) II 616 (58.4) 341 (56.6) 92 (63.9) 183 (59.6) III 265 (25.1) 183 (30.4) 19 (13.2) 63 (20.5) IV 20 (1.9) 14 (2.3) 1 (0.7) 5 (1.6) Previous admission 701 (66.5) 396 (65.6) 115 (79.9) 190 (61.9) 0.001 Vital signs SBP (mmHg) 117.6 (18.6) 115.0 (18.2) 120.9 (17.6) 121.1 (19.0) <0.001 DBP (mmHg) 70.9 (11) 71.7 (10.0) 69.8 (11.3) 69.78 (12.5) 0.020 HR (b.p.m.) 68.9 (12.6) 67.7 (11.6) 70.5 (14.8) 70.4 (13.3) 0.002 Cardiovascular risk factors Current smoker 136 (12.9) 71 (11.8) 24 (16.7) 41 (13.4) 0.275 Previous smoker 559 (53.7) 337 (56.5) 65 (45.8) 157 (51.8) 0.051 Hypertension 700 (66.4) 389 (64.4) 96 (66.7) 215 (70.0) 0.235 Diabetes mellitus 419 (39.7) 231 (38.3) 60 (41.7) 128 (41.7) 0.528 Dyslipemia 648 (61.5) 371 (61.4) 83 (57.6) 194 (63.4) 0.503 Co-morbidities OSAS 132 (12.5) 80 (13.3) 19 (13.1) 33 (10.8) 0.551 COPD 250 (23.7) 126 (20.9) 40 (27.8) 84 (27.5) 0.041 Stroke 97 (9.2) 66 (10.9) 10 (6.9) 21 (6.9) 0.081 Vasculopathy 117 (11.1) 70 (11.6) 12 (8.3) 35 (11.4) 0.522 CKD 366 (34.7) 211 (34.9) 44 (30.8) 111 (36.3) 0.516 AF <0.001 No 632 (60.0) 379 (62.8) 83 (57.6) 170 (55.7) Paroxistic 91 (8.6) 43 (7.1) 22 (15.3) 26 (8.5) Persist/perman. 144 (13.7) 68 (11.3) 31 (21.5) 45 (14.8) Non-defined 186 (17.6) 114 (18.9) 8 (5.7) 64 (21.0) Biomarkers Haemoglobin (g/dL) 13.4 (1.9) 13.4 (1.8) 13.5 (2.3) 13.3 (1.9) 0.725 Creatinine (mg/dL) 1.1 (0.9, 1.4) 1.1 (0.9, 1.5) 1.1 (0.9, 1.4) 1.1 (0.9, 1.4) 0.619 BNP (pg/mL) 296 (200, 891) 306 (204, 956) 219 (136.9, 335) 1782 (484, 3080) 0.012 NT-proBNP (pg/mL) 1861 (694, 4307) 1418 (635, 4108) 2957 (1182, 4794) 2390 (1022.5, 4424.5) 0.006 Ferritin (ng/mL) 154.5 (72, 284) 143.5 (65, 280) 145 (72, 328) 180 (94, 294) 0.268 TSI (%) 20.3 (15, 28) 21 (15, 29) 18.7 (14.5, 26) 20 (15.6, 28) 0.260 ECG Rhythm <0.001 Sinus 715 (68.4) 444 (74.0) 93 (64.6) 178 (58.9) AF 227 (21.7) 118 (19.7) 31 (21.5) 78 (25.8) Paced 99 (9.5) 34 (5.7) 19 (13.2) 46 (15.2) Atrial flutter 5 (0.5) 4 (0.7) 1 (0.7) 0 (0) LBBB 353 (33.6) 194 (32.1) 48 (33.3) 111 (36.5) 0.425 Echocardiography LVEDD (mm) 63.1 (8.8) 63.8 (9) 62.8 (8.0) 61.8 (8.6) 0.005 E/A 1 (0.7, 1.8) 1.1 (0.7, 2.0) 0.9 (0.7, 1.4) 0.8 (0.6, 1.5) <0.001 LA (mm) 47.3 (8.5) 47.1 (8.8) 47.8 (8.6) 47.4 (7.7) 0.671 MR mod/sev 375 (35.9) 223 (37.2) 37 (25.9) 115 (38.0) 0.026 PH 267 (25.9) 173 (29.1) 27 (19.7) 67 (22.3) 0.019 AF, atrial fibrillation; BNP, brain natriuretic peptide; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; DBP, di- astolic blood pressure; ECG, electrocardiogram; HF, heart failure; HR, heart rate; IDC, idiopathic dilated cardiomyopathy; LA, left atrium; LBBB, left bundle branch block; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; MR, mitral regurgi- tation; NT-proBNP, N-terminal pro-B type natriuretic peptide; NYHA, New York Heart Association; OSAS, obstructive sleep apnoea syn- drome; PH, pulmonary hypertension; SBP, systolic blood pressure; TSI, transferrin saturation index. ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 30 F. de Frutos et al. between hospital types in terms of sex distribution or median except for valsartan and carvedilol, which were the most fre- LVEF. The burden of co-morbidities was also similar across quently used ARB and beta-blocker, respectively, in second- groups, except for atrial fibrillation and for chronic obstruc- ary hospitals. tive pulmonary disease, which were more frequent in hospi- tals with lower complexity. Median NT-proBNP levels were higher in secondary hospitals, whereas the lowest levels were Target doses of key heart failure drugs those of tertiary hospitals. Mean systolic blood pressure and mean heart rate were slightly lower in patients from tertiary The proportion of patients in whom target doses of each hospitals compared with the other centres. key HF pharmacotherapy were achieved (according to ESC 2016 Guidelines14) is displayed in Figure 3, overall and by level of hospital complexity. Overall, target doses of ACEI Pharmacological management and devices and beta-blockers were achieved in approximately 25% of patients, MRA in 20%, while for ARB and ARNI, target Figure 2 shows the pharmacological and invasive manage- doses were achieved only in less than 10% of patients. ment of our study population. Overall, beta-blockers were Although tertiary hospitals achieved target doses of ARBs, used in 91.8% of patients, ACE-I in 48.1%, ARB in 16.9%, MRAs, ivabradine, and ARNI more frequently than the other sacubitril/valsartan in 23.9%, MRA in 72.7%, and ivabradine centres, for beta-blockers and ACEI, target doses were in 21.4% patients. CRT and ICD were used in 15.6% and achieved more frequently in secondary hospitals. On the other 26.3% of patients, respectively. hand, the lowest adherence to guideline-recommended target In the comparative analyses by level of complexity, beta- doses was observed in primary centres (graph area 1.7%). blockers were more frequently prescribed in tertiary hospi- tals, while renin–angiotensin inhibitors globally were more Comparison with prior registries frequently prescribed in secondary centres. Primary hospitals had the highest proportion of patients under treatment with Table 4 compares the observations from our registry to a sim- sacubitril/valsartan (37.2%), whereas there was a trend to- ilar Spanish registry16 published before the release of the ESC wards higher prescription of MRAs in hospitals with higher 2016 Guidelines. In Linx, the use of ACEI, ARBs, and any level of complexity (75.7% in secondary hospitals and 78.1% renin–angiotensin inhibitors (ACE-I, ARB, or ARNI) was slightly in tertiary hospitals). lower than in the 2015 registry (before commercialization of There was a trend towards greater use of devices (ICD and sacubitril/valsartan). There was also a statistically significant CRT) in hospitals with higher complexity; and patients from decrease in the use of digoxin after the ESC 2016 Guide- tertiary and secondary hospitals had undergone percutane- lines.14 No other statistically significant differences were ob- ous coronary revascularization more frequently. served between the two studies. Table 2 displays the combinations of drug prescription among patients. Overall, 62.7% of patients were under treat- ment with triple therapy (beta-blockers + renin–angiotensin Temporal trends inhibitors + MRA). In line with the results showed in the pre- vious paragraphs, there was also a trend towards higher pro- The temporal trends in pharmacological and device manage- portion of patients under triple therapy in hospitals with ment of outpatients with HFrEF in Europe from 2003 higher level of complexity. (SWEDE-HEART registry17) to the present (Linx) are presented in Figure 4, which summarizes the observations from key, comparable, European HFrEF observational studies. The pro- Specific drugs and drug doses portion of patients treated with beta-blockers and ACEI/ARBs remained stable over time (around 90%), until commercializa- Table 3 describes the use of specific drugs within each family, tion of sacubitril/valsartan, which, as evidenced in our regis- and their mean doses, overall and by level of complexity. try, has been associated with a marked decrease in the use Overall, the most frequently prescribed drugs within each of ACEI. MRA use has steadily increased in the last decade, family were enalapril among ACEI (73.4%, mean dose 12 so has the use of ICD and CRT. mg/day), bisoprolol among beta-blockers (54.9%, mean dose 5.6 mg/day), losartan among ARBs (40.6%, mean dose 78 mg/day), and eplerenone among MRAs (65.8%, mean dose 29.7 mg/day). Mean dose of sacubitril/valsartan was 144.8 Discussion mg/day, and mean dose of ivabradine was 11 mg/day. The observations with regard to the most frequently used The Linx registry shows that after the release of the ESC 2016 drug subtypes were also true across all levels of complexity, Guidelines,14 use of beta-blockers remained very high in ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 Management of Heart Failure after ESC 2016 Guidelines 31 Figure 2 Drugs and devices. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; CRT, cardiac resynchronization therapy; ICD, implantable cardioverter defibrillator; MRA, mineralocorticoid receptor antagonist; PCI, percu- taneous coronary intervention. Table 2 Combinations of drug prescription Overall (N = 1056) Tertiary (N = 604) Secondary (N = 144) Primary (N = 308) P value BB (monotherapy) 60 (5.7%) 26 (4.3%) 2 (1.4%) 32 (10.5%) <0.001 MRA (monotherapy) 6 (0.6%) 5 (0.8%) 0 (0%) 1 (0.3%) 0.40 iRA (monotherapy) 24 (2.3%) 5 (0.8%) 3 (2.1%) 16 (5.3%) <0.001 ACE-I 10 (1%) 3 (0.5%) 2 (1.4%) 5 (1.6%) 0.21 ARB 3 (0.3%) 1 (0.2%) 0 (0%) 2 (0.7%) 0.33 ARNI 9 (0.9%) 1 (0.2%) 1 (0.7%) 7 (2.3%) 0.004 BB + iRA (bitherapy) 190 (18.2%) 94 (15.7%) 29 (20.1%) 67 (22.1%) 0.048 BB + ACE-I 109 (10.5%) 58 (9.8%) 18 (12.5%) 33 (10.9%) 0.612 BB + ARB 34 (3.2%) 16 (2.7%) 9 (6.3%) 9 (3%) 0.087 BB + ARNI 34 (3.2%) 9 (1.5%) 2 (1.4%) 23 (7.6%) <0.001 BB + MRA (bitherapy) 50 (4.8%) 28 (4.7%) 9 (6.3%) 13 (4.3%) 0.66 iRA + MRA (bitherapy) 46 (4.4%) 20 (3.3%) 5 (3.5%) 21 (7%) 0.035 ACE-I + MRA 25 (2.4%) 15 (2.5%) 4 (2.8%) 6 (2%) 0.841 ARB + MRA 8 (0.8%) 2 (0.3%) 1 (0.7%) 5 (1.7%) 0.097 ARNI + MRA 11 (1.1%) 2 (0.4%) 0 (0%) 9 (3%) <0.001 BB + iRA + MRA (triple therapy) 653 (62.7%) 415 (69.2%) 95 (66%) 143 (48%) <0.001 BB + ACE-I + MRA 328 (31.8%) 226 (38.3%) 51 (35.4%) 51 (17.1%) <0.001 BB + ARB + MRA 119 (11.4%) 85 (14.1%) 13 (9%) 21 (7%) 0.004 BB + ARNI + MRA 179 (17.2%) 89 (14.8%) 31 (21.5%) 59 (20.1%) 0.047 ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blockers; iRA, renin–angiotensin inhibitors; MRA, mineralocorticoid receptor antagonist. ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 32 F. de Frutos et al. Table 3 Drug prescription and doses (mg/day) Overall Tertiary Secondary Primary P value ACE-I Enalapril (n, %) 373 (73.4%) 262 (79.6%) 51 (65.4%) 60 (59.4%) <0.001 Mean dose (SD) 12 (9) 12.2 (8.4) 14.7 (11.4) 8.7 (7.8) — Ramipril (n, %) 118 (23.2%) 58 (17.6%) 23 (29.5%) 37 (36.6%) — Mean dose (SD) 4.5 (2.8) 4.6 (2.8) 5.3 (3.1) 4.0 (2.6) — Lisinopril (n, %) 9 (1.8%) 6 (1.8%) 1 (1.3%) 2 (2%) — Mean dose (SD) 13.1 (15.4) 11.3 (14.3) 5 (0) 22.5 (24.7) — Captopril (n, %) 1 (0.2%) 0 (0%) 0 (0%) 1 (1%) — Mean dose (SD) 25 (0) — — 25 (0) — Perindopril (n, %) 5 (1%) 1 (0.3%) 3 (3.9%) 1 (1.0%) — Mean dose (SD) 3.6 (2.6) 8 (0) 2 (0) 4 (0) — Others (n, %) 2 (0.4%) 2 (0.6%) 0 (0%) 0 (0%) — ARB Valsartan (%) 63 (37.1%) 39 (35.8%) 16 (66.7%) 8 (21.6%) 0.002 Mean dose (SD) 120.7 (85.1) 115.6 (76.3) 110.9 (83.6) 320 (0) — Losartan (%) 69 (40.6%) 44 (40.4%) 5 (20.8%) 20 (54%) — Mean dose (SD) 78 (46.6) 80.4 (44.0) — 68.8 (57.9) — Candesartan (%) 26 (15.3%) 20 (18.4%) 2 (8.3%) 4 (10.8%) — Mean dose (SD) 21.8 (16.9) 22.2 (17.8) — 18 (2.8) — Olmesartan (%) 6 (3.5%) 1 (0.9%) 1 (4.2%) 4 (10.8%) — Mean dose (SD) 40 (0) — — 40 (0) — Irbesartan (%) 5 (2.9%) 5 (4.6%) 0 (0%) 0 (0%) — Mean dose (SD) 150 (0) 150 (0) — — — Telmisartan (%) 1 (0.6%) 0 (0%) 0 (0%) 1 (2.7%) — Mean dose (SD) 80 (0) — — 80 (0) — Beta-blockers Bisoprolol (%) 519 (54.9%) 268 (48.6%) 66 (48.3%) 185 (71.4%) <0.001 Mean dose (SD) 5.6 (3.3) 6.4 (3.4) 6.5 (3.8) 4.1 (2.4) — Carvedilol (%) 390 (41.2%) 258 (46.8%) 69 (50.7%) 63 (24.3%) — Mean dose (SD) 26.6 (18.4) 26.2 (17.4) 33.2 (21.3) 20.8 (16.6) — Metoprolol (%) 1 (0.1%) 1 (0.2%) 0 (0%) 0 (0%) — Mean dose (SD) 100 (0) 100 (0) — — — Nevibolol (%) 35 (3.7%) 24 (4.4%) 0 (0%) 11 (4.3%) — Mean dose (SD) 4.5 (2.5) 4.7 (2.9) — 4 (1.5) — Others (%) 1 (0.1%) 0 (0%) 1 (0.7%) 0 (0%) MRA Spironolactone (%) 262 (34.2%) 161 (34.2%) 31 (28.4%) 70 (37.6%) 0.275 Mean dose (SD) 28.2 (18.1) 27.6 (18.7) 27.8 (16.7) 29.6 (17.3) — Eplerenone (%) 504 (65.8%) 310 (65.8%) 78 (71.6%) 116 (62.4%) — Mean dose (SD) 29.7 (12.5) 31.1 (13.6) 29.9 (11.7) 26.1 (8.7) — Ivabradine Mean dose (SD) 11 (3.3) 10.9 (3.6) 11.2 (2.9) 11.1 (2.9) — Sacubitril/valsartan Mean dose (SD) 144.8 (94) 160.5 (101) 144.1 (94.4) 130.4 (85.4) — ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; n, num- ber; SD, standard deviation. HFrEF patients, while there was a marked decrease in the use despite optimal medical treatment. The proportion reached of ACE-I/ARBs in monotherapy, which was likely the 24% in our population and was even higher in primary hos- consequence of a marked increase in the use of pitals. Given the recent publication of safety data showing sacubitril/valsartan. When considering hospital complexity, that early initiation of ARNI might be feasible and tolera- we observed that beta-blockers, MRAs, and devices were ble,20 this proportion is likely to keep growing in the com- more frequently used in tertiary hospitals (where the popula- ing years. Further studies will provide valuable insights on tion was younger and median NT-proBNP levels were lower), this question. while sacubitril/valsartan was more frequently used in pri- Our results also suggest a trend towards a better adherence mary hospitals. In all centres, achievement of the target drug to ESC HF Guideline recommendations in hospitals with higher doses recommended by the ESC 2016 Guidelines14 was low. level of complexity. Whether these disparities are the conse- Our first main finding is the very high uptake of quence of differences in the clinical profiles of the patient pop- sacubitril/valsartan, only a few months after ESC 2016 ulations from each type of hospital, or of other factors, cannot Guidelines14 recommendation to replace ACE-I for ARNI in be concluded from the available data. Nevertheless, some dif- ambulatory patients with HFrEF who remain symptomatic ferences in demographic and clinical characteristics were ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 Management of Heart Failure after ESC 2016 Guidelines 33 Figure 3 Target dose. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhib- itor; MRA, mineralocorticoid receptor antagonist. Table 4 Drugs prescription comparison with previous registries hospitals, although in a recently published registry (GWTG- from Spain HF)24 this trend was not confirmed. ESC Heart Failure We also observed a low proportion of patients meeting the 17 Long-term Registry recommended target doses of most class I HFrEF therapies. A (LVEF ≤ 40%) Linx registry potential explanation to this finding, as discussed in the ESC (N = 1526) (N = 1056) P value 2016 Guidelines,14 is the fact that some of the clinical trials ACE-I (%) 64.6 48.1 <0.001 ARB (%) 29.1 16.9 <0.001 in which those target doses were defined were conducted be- ARNI (%) — 23.9 — fore the availability of modern therapies such as eplerenone or ACE-I + ARB + ARNI (%) 92.6 86.9 <0.001 sacubitril/valsartan, among others. Also, the patient popula- Beta-blockers (%) 93.3 91.8 0.15 MRA (%) 74.5 72.7 0.31 tions included in those studies tended to be young and to have Diuretics (%) 83.3 83.5 0.89 few co-morbidities; conversely, in our real-life patient popula- Digoxin (%) 22 14.1 <0.001 tion, the prevalence of key co-morbidities such as chronic kid- Ivabradine (%) 19.7 21.4 0.29 Nitrates (%) 16.8 19.7 0.06 ney disease or chronic obstructive pulmonary disease was high. In addition, it is important to note that information on ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin drug use, drug doses, and device use was recorded at study en- receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; ESC, European Society of Cardiology; LVEF, left ventricular ejection try (i.e. not necessarily at end of titration). This means that fraction; MRA, mineralocorticoid receptor antagonist. many patients might have been treated with additional thera- pies, might have had some drug doses titrated, or might have observed across centres—e.g. patients from tertiary hospitals been treated with specific HF devices later in time (i.e. during were younger, which might explain a higher tolerance to beta- follow-up in the cardiology clinic), as part of standard pharma- blockers, and therefore the more frequent use of this drug cological titration and progressive therapeutic optimization. group; and patients from secondary and primary hospitals Therefore, the present observations regarding target doses were older and had more co-morbidities, such as chronic ob- and device use should be interpreted cautiously. structive pulmonary disease. Despite the fact that there are Importantly, our findings regarding the very low proportion no previous studies comparing management of HFrEF outpa- of patients meeting target doses are consistent with those tients by hospital type, some studies21–23 also suggest better from prior registries.7,17–19,25 Indeed, achieving target doses outcomes in patients admitted for HF in higher volume of pharmacological therapies proven to reduce mortality ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 34 F. de Frutos et al. Figure 4 The temporal trends in pharmacological and device management of outpatients with heart failure with reduced ejection fraction in Europe. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor neprilysin inhibitor; BB, beta-blockers; CRT, cardiac resynchronization therapy; ESC-HF-LT, European Society of Cardiology Heart Failure Long-Term Registry; ICD, implantable cardioverter de- fibrillator; MRA, mineralocorticoid receptor antagonist. remains as a major challenge for the management of patients practice. Finally, the detailed information on drug dosage with chronic HFrEF as recently described in CHAMP-HF regis- captured in Linx allowed evaluating adherence to guideline try.25 Compared with clinical practice in the USA, we found recommendations. no differences in achieving target doses of ACE-I/ARB (20.6% vs. 17.5%) or beta-blockers (25.4% vs. 27.6%), but we found fewer patients in target doses regarding ARNI (8.1% vs. 14%) Study limitations and MRA (19.7% vs. 76.6%). The greater proportion of target doses of MRA might be partly explained by a much lower pro- One of the major limitations of the registry comes from the portion of patients prescribed with MRA (72.7% vs. 33.1%) cross-sectional design, which limits causal inference based on that might select a group of patients with better renal the observed differences. Another limitation is the absence function. of information in the registry describing the reason for not pre- scribing or up-titrating medication or devices. It is highly likely that formal contraindications as well as limited tolerance to specific drugs would explain most of these scenarios. Finally, Study strengths although participating hospitals are spread around Catalonia, most patients were recruited from the metropolitan area of To our knowledge, this is the first registry to evaluate the Barcelona, so patients from rural areas might have been real-world management of HFrEF in the outpatients setting underrepresented. in Europe since the publication of the ESC 2016 HF Guide- lines. Moreover, because Linx is a multicentre, large registry, this maximized statistical power and the generalizability of the conclusions. In addition, because not only tertiary but Conclusions also secondary and primary centres were included, we were able to compare hospitals by level of complexity, and this in- The Linx registry shows an appropriate adherence to pharma- creased generalizability of our overall findings even further. cological recommendations from ESC 2016 HF Guidelines de- Although secondary and primary centres are usually under- spite that target doses of class I HF drugs were low in our represented in clinical trials and observational studies, they population. These findings are consistent with the observa- actually manage a large number of patients in routine clinical tions from prior observational, real-life studies. On the other ESC Heart Failure 2020; 7: 26–36 DOI: 10.1002/ehf2.12567 Management of Heart Failure after ESC 2016 Guidelines 35 hand, almost one-quarter of chronic HFrEF patients were un- Funding der treatment with sacubitril/valsartan a few months after ESC 2016 HF Guidelines recommendation, prompting the re- The Linx registry was sponsored by the Catalan Society of duction of ACE-I/ARB use in this patient population. Use of Cardiology. sacubitril/valsartan was even greater in primary hospitals. Fi- nally, use of beta-blockers, MRA, and ivabradine remained similar to the prescription rates observed in previous Spanish HFrEF registries and was particularly high in tertiary centres. Supporting information Additional supporting information may be found online in the Supporting Information section at the end of the article. Contributions Data S1. Supplementary appendix. All authors contributed to patient inclusion and approved the final version of the manuscript. 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