Journal of Clinical Medicine Article Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria Anna Camps-Vilaró 1,2 , Juan F. Delgado-Jiménez 2,3,4 , Núria Farré 5,6,7 , Helena Tizón-Marcos 5,6 , Jesús Álvarez-García 2,7,8 , Juan Cinca 2,7,8 , Irene R. Dégano 1,2,9, *,† and Jaume Marrugat 1,2, *,† 1 REGICOR Study Group, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain; acamps@imim.es 2 CIBER of Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; juan.delgado@salud.madrid.org (J.F.D.-J.); jalvarezg@santpau.cat (J.Á.-G.); JCinca@santpau.cat (J.C.) 3 Department of Cardiology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain 4 Faculty of Medicine, Complutense University of Madrid (UCM), 28040 Madrid, Spain 5 Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; NFarreLopez@parcdesalutmar.cat (N.F.); htizon@psmar.cat (H.T.-M.) 6 Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain 7 Faculty of Medicine, Universitat Autónoma de Barcelona (UAB), 08193 Barcelona, Spain 8 Department of Cardiology, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain 9 Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), 08500 Vic, Spain * Correspondence: iroman@imim.es (I.R.D.); jmarrugat@imim.es (J.M.); Tel.: +349-3316-0714 (I.R.D.); +349-3316-0733 (J.M.) † These authors contributed equally to this work.  Received: 9 June 2020; Accepted: 30 June 2020; Published: 3 July 2020  Abstract: Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II–IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 . In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II–IV, and have a GFR ≥ 30 mL/min/1.73 m2 , respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin. Keywords: heart failure; reduced ejection fraction; cardiovascular disease; cardiovascular therapy; dapagliflozin; sodium-glucose cotransporter-2 inhibitor; epidemiology; prevalence 1. Introduction Heart failure (HF) is a clinical syndrome caused by a structural or functional heart abnormality leading to a reduction of cardiac output or an increase in intracardiac pressure. Characterization of J. Clin. Med. 2020, 9, 2089; doi:10.3390/jcm9072089 www.mdpi.com/journal/jcm J. Clin. Med. 2020, 9, 2089 2 of 15 HF is usually based on the ejection fraction (EF): preserved (≥50%), mid-range (40–49%), or reduced (<40%) [1]. Although HF is increasingly treatable and preventable, it remains one of the main causes of morbidity, mortality, and high healthcare costs. Incidence and prevalence of HF increase with population aging. Greater prevalence is related to increased survival, due to successful HF treatment, and higher incidence is related to the increasing population prevalence of atrial fibrillation, hypertension, obesity, and diabetes [1–3]. In 2018, HF caused 19,142 deaths in Spain [4]. While the morbidity and mortality of patients with reduced EF (40–60% of HF patients) [5–7] have decreased, thanks to improved clinical management in recent decades [8], the average total cost per patient with HF in Spain was €12,995–18,220 in 2010, with the largest cost item (59.1–69.8%) being non-professional care [9]. The total HF-patient healthcare expenditure as a percentage of the annual healthcare budget is 1.5% in all of Spain and 7.1% in Catalonia, with the highest cost in both cases related to hospitalizations [10,11]. Prevalence, clinical characteristics, and prognosis of HF differ according to EF category. Time series based on data from hospitalized patients suggest a more pronounced decrease in HF incidence and show higher all-cause mortality but fewer comorbidities in patients with reduced EF, compared to preserved EF [1]. Comorbidities are a key component in the management of patients with HF, as treatments for accompanying pathologies can worsen HF prognosis [1]. Two of the most common comorbidities are diabetes (20–40%) and chronic kidney disease (10–30%) [12,13]. Both are associated with more hospitalizations and higher mortality in HF patients [14]. The good quality of HF mortality data in Spain contrasts with the lesser-known prevalence of the disease. Several studies have analysed the population prevalence of HF in Spain, providing estimations that vary considerably (2.7–6.8%) for the population older than 44 years [14–16]. Most of these figures exceed the estimations in adult populations of Europe (1–2%) [1,17,18] and North America (2.2–2.4%) [2,19]. Moreover, no data are available on the prevalence of HF with reduced EF and comorbidities, the patient profile associated with the highest HF mortality. Although advances in HF treatment have significantly reduced mortality risk in clinical trials, particularly in patients with reduced EF, the real-life impact of improved treatment has been more modest [20]. One new option is dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor with solid clinical evidence in patients with type 2 diabetes mellitus (T2D) that also markedly reduces hospitalization for HF [21]. Dapagliflozin has reduced cardiovascular mortality and hospitalization for HF, compared to a placebo, as an additional treatment in patients with chronic HF and reduced EF, with and without T2D [22]. In view of these promising results, it would be useful to determine the target population for this new treatment indication, based on the criteria used in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study [22]. Spain did not participate in the DAPA-HF study; therefore, there is a great interest to know the impact of the DAPA-HF study criteria in the Spanish population. The aim of this study was to estimate the population in Spain, stratified by its autonomous communities, that meets the DAPA-HF criteria for dapagliflozin indication: HF and reduced EF (≤40%), functional class II–IV of the New York Heart Association (NYHA), and glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m2 , all with and without T2D. 2. Materials and Methods 2.1. Study Design and Population To determine the number of patients with HF with reduced EF, in NYHA functional class II–IV, and with normal or moderate kidney function (≥ 30 mL/min/1.73 m2 ), we carried out a systematic literature search in PubMed of English or Spanish cross-sectional, cohort, population-based, or other epidemiological studies. To this end, we selected articles that contained the terms “heart failure” in the title; “prevalence” or “burden” in the title or abstract; “ejection fraction”, “systole”, or “systolic” in the J. Clin. Med. 2020, 9, 2089 3 of 15 title or abstract; and “general population” or “healthy” in the title or abstract (search date: September 1, 2017). This systematic search was updated on April 15, 2020, and supplemented with articles provided by experts [12,13,20–24]. Patients’ eligibility criteria for the population candidates for dapagliflozin treatment are summarized in Table 1. Full details are provided in the design paper [25]. Table 1. Summary of inclusion and exclusion criteria of the DAPA-HF study [25]. Inclusion Criteria (1) Provision of signed informed consent prior to any study specific procedures (2) Men or women, aged ≥18 years at the time of consent (3) Diagnosis of HF with left ventricular EF ≤ 40%, which has been present for at least 12 months prior to enrolment (4) Diagnosis of symptomatic HF (NYHA functional class II–IV), within the previous 2 months (5) Optimally treated with pharmacological and/or device therapy for HF (6) NT-proBNP ≥ 600 pg/mL (or if hospitalised for HF within the previous 12 months, NT-proBNP ≥ 400 pg/mL) at enrolment. Patients with atrial fibrillation or atrial flutter must have a level ≥900 pg/mL, irrespective of history of HF hospitalization Exclusion Criteria (1) Treatment with SGLT2 inhibitors within 8 weeks prior to enrolment, or previous intolerance of an SGLT2 inhibitor (2) Diagnosis of type 1 diabetes mellitus (3) Symptomatic hypotension or systolic blood pressure <95 mmHg (4) Recent worsening HF or other cardiovascular events or procedures (5) Severe (GFR < 30 mL/min/1.73m2 by CKD-EPI equation), unstable, or rapidly progressing renal disease at the time of randomization (6) Other conditions likely to prevent patient participation in the trial or greatly limit life expectancy DAPA-HF: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; HF: heart failure; EF: ejection fraction; NYHA: New York Heart Association; NT-proBNP: N-terminal proB-type natriuretic peptide; GFR: glomerular filtration rate; CKD-EPI: Chronic Kidney Disease-Epidemiology Collaboration; SGLT2: sodium-glucose cotransporter-2. 2.2. Estimation of Population Prevalence and Number of Patients with Heart Failure in Spain Our analysis applied the prevalence of HF reported for individuals older than 44 years in the largest and most recent representative population study [14] to the entire Spanish population and to each autonomous community’s population, according to the 2019 Spanish National Statistics Institute data [26]. 2.3. Estimation of Ejection Fraction ≤ 40% and New York Heart Association Functional Class II–IV Prevalence in the Heart Failure Population in Spain The proportion of HF patients with EF ≤ 40% and NYHA functional class II–IV was determined according to the average percentages observed in the most recent Spanish registries of patients with chronic HF [6,7,27–29]. The study designs, in reverse chronological order, are summarized as follows: Prospective cohort studies: • RICA (National Registry for Heart Failure), carried out in internal medicine units in 52 public and private hospitals [27]; • REDINSCOR (Spanish Network for Heart Failure), carried out in HF units in 18 hospitals [27]; • BADAPIC (Database of Patients with Heart Failure), involving 62 centres with specific HF units or clinics [6]; Cross-sectional studies: • INCA (Heart Failure Study), involving 415 primary care physicians and 93 cardiologists [7]; J. Clin. Med. 2020, 9, 2089 4 of 15 • EPISERVE (Heart Failure in Outpatients), carried out by 181 primary care physicians, 172 cardiologists, and 154 internal medicine physicians [28]; • GALICAP (Galician Study of Heart Failure in Primary Care), involving 149 primary care physicians distributed in eight areas of Galicia [29]. 2.4. Estimation of Glomerular Filtration Rate ≥ 30 mL/min/1.73 m2 Prevalence in the Heart Failure Population in Spain The proportion of patients with GFR ≥ 30 mL/min/1.73 m2 was estimated from the most generalizable data, obtained from patients with chronic HF in 28 Spanish hospitals included in the European Society of Cardiology (ESC) Heart Failure Long-Term Registry [23]. The prevalence of GFR ≥ 30 mL/min/1.73 m2 was applied to the estimated HF population with EF ≤ 40% and with NYHA functional class II–IV (obtained in Section 2.3). A sensitivity analysis with the total REDINSCOR prevalence of EF, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 was done to determine the reliability of our estimates (Tables S1–S3). 2.5. Estimation of Type 2 Diabetes Mellitus Prevalence in the Heart Failure Population in Spain Finally, the prevalence of patients with and without T2D was obtained from a specific analysis of a chronic HF cohort provided by REDINSCOR investigators. The cohort characteristics have been described previously [27,30]. We calculated the prevalence of patients with and without diabetes who met the criteria for HF with EF ≤ 40%, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 (Tables S1 and S2). 2.6. Statistical Analysis The arithmetic means of reduced EF and NYHA functional class II–IV estimations were obtained. The 95% confidence interval (CI) for the described estimations were obtained by assuming a Poisson distribution of patient counts. Analysis was carried out using R software, version 4.0.0. 3. Results 3.1. Estimation of Population Prevalence and Number of Patients with Heart Failure in Spain Table 2 describes the prevalence of HF in Spain and in Europe, as reported in the largest, most recent, and most representative population-based candidate studies. The 2012 study by Farré et al. [14] was considered the most appropriate for estimating prevalence in Spain, since it included a representative population of more than 88,000 people and the results closely resembled those of similar studies in Europe. Applying the prevalence of specific ages used by Farré et al. [14] to current Spanish population in the same age groups yielded a prevalence of approximately 2.6% in the group older than 44 years, or 594,684 (95% CI: 593,175–596,196) patients with HF. Table 2. Summary of the heart failure prevalence by age group in population studies in Spain and Europe. Year of Study Age, Years Age Group Prevalence, By Years Country/Region Women,% Publication Population (SD) Total 45–54 55–64 65–74 ≥75 Farré et al. 2017 Catalonia 88,195 77 (12) 55.0% 2.70% 0.30% 0.90% 2.50% 8.80% [14] Anguita et al. 2008 Spain 1776 64 (12) 55.9% 6.80% 1.30% 5.50% 8.00% 16.1% [15] 40–49 50–59 60–69 70–79 ≥80 Cortina et al. 2001 Asturias 391 60 (13) 53.6% 5.00% <1.00% 2.00% 5.00% 13.0% 18.0% [16] 0–49 50–59 60–69 70–79 80–89 ≥90 J. Clin. Med. 2020, 9, 2089 5 of 15 Table 2. Cont. Year of Study Age, Years Age Group Prevalence, By Years Country/Region Women,% Publication Population (SD) Total 45–54 55–64 65–74 ≥75 Ohlmeier et al. 2015 Germany 6,284,194 39 (21) 48.2% 1.70% 0.10% 1.28% 3.88% 10.8% 25.9% 45.7% [17] 19–54 55–64 65–74 75–84 85–99 Parén et al. 2014 Sweden 144,925 - 48.9% 1.99% 0.13% 1.06% 3.20% 9.23% 20.4% [18] 45–64 65–74 ≥75 Murphy et al. 2004 Scotland 307,741 - 50.6% 0.71% 0.38% 2.30% 6.53% [31] 55–64 65–74 75–84 ≥85 Bleumink et al. 2004 Rotterdam 7983 70 (10) 61.0% 6.70% - 0.90% 4.00% 9.70% 17.4% [32] 25–49 50–59 60–69 70–79 ≥80 Ceia et al. [33] 2002 Portugal 5434 68 (15) 62.7% 4.36% 1.36% 2.93% 7.63% 12.7% 16.1% SD: standard deviation. 3.2. Estimation of Ejection Fraction ≤ 40% and New York Heart Association Functional Class II–IV Prevalence in the Heart Failure Population in Spain Characteristics of patients with HF included in the selected Spanish studies are shown in Table 3. The average proportion of HF patients with EF ≤ 40% was 52.4%, of which 84.0% had NYHA functional class II–IV. Applying these percentages to the estimated number of patients with HF in Spain, 311,614 (95% CI: 310,522–312,709) patients would have EF ≤ 40%, and 261,756 (95% CI: 260,755–262,760) patients would also have NYHA functional class II–IV. Table 3. Studies of patients with heart failure in Spain. Year of Study Age, Years Type of Heart Geographical Reduced NYHA Study Women, % Specialty Publication Population (SD) Failure Area EF Class II–IV Internal RICA [27] 2017 1396 79 (8) 54.0% chronic Spain 39.5% 80.2% medicine REDINSCOR 2017 2150 70 (10) 31.0% chronic Spain Cardiology 79.6% 100% 1 [27] BADAPIC [6] 2010 4720 65 (12) 29.0% chronic Spain Cardiology 63.4% 100% 1 Primary care INCA [7] 2009 2161 71 (11) 44.4% chronic Spain and 38.3% 84.0% cardiology Primary care, Spain, cardiology, EPISERVE [28] 2008 2249 72 (10) 45.0% - except La 55.0% 90.4% and internal Rioja medicine GALICAP [29] 2007 1195 76 (10) 52.1% - Galicia Primary care 38.6% 81.5% Mean 52.4% 84.0% 1Data not included in the calculation of NYHA functional class II–IV average. RICA: National Registry for Heart Failure; REDINSCOR: Spanish Network for Heart Failure; BADAPIC: Database of Patients with Heart Failure; INCA: Heart Failure Study; EPISERVE: Heart Failure in Outpatients; GALICAP: Galician Study of Heart Failure in Primary Care; SD: standard deviation; Reduced EF: ejection fraction less than 40–50%; NYHA: New York Heart Association. The Spanish population and the number of patients with HF, by age group and by autonomous community, are shown in Table 4. In Table 5, these data are disaggregated by EF ≤ 40%, and by the combination of EF ≤ 40% and NYHA functional class II–IV. J. Clin. Med. 2020, 9, 2089 6 of 15 Table 4. Total population in Spain according to 2019 data from the National Statistics Institute [26], and the number of patients with heart failure in Spain and its autonomous communities, according to prevalence data published by Farré et al. [14]. General Population (by Age Group) Heart Failure Prevalence (by Age Group) Total 45–54 55–64 65–74 Total 45–54 55–64 65–74 75+ Autonomous Communities 0.30% 0.90% 2.50% 8.80% Andalucía 3,895,025 1,341,487 1,093,149 770,187 690,202 93,855 4024 9838 19,255 60,738 Aragón 674,882 207,355 180,224 136,185 151,118 18,947 622 1622 3405 13,298 Principado de Asturias 589,263 164,027 161,384 131,949 131,903 16,851 492 1452 3299 11,607 Illes Balears 529,589 194,110 145,007 103,545 86,927 12,126 582 1305 2589 7650 Canarias 1,048,012 390,823 293,621 199,438 164,130 23,244 1172 2643 4986 14,443 Cantabria 307,255 93,358 85,403 65,351 63,143 8239 280 769 1634 5557 Castilla y León 1,347,618 376,632 361,698 275,863 333,425 40,623 1130 3255 6897 29,341 Castilla-La Mancha 974,147 320,338 265,833 180,457 207,519 26,127 961 2392 4511 18,262 Catalunya 3,593,591 1,188,206 946,935 738,057 720,393 93,933 3565 8522 18,451 63,395 Comunitat Valenciana 2,437,743 799,940 658,274 508,440 471,089 62,491 2400 5924 12,711 41,456 Extremadura 537,686 166,131 151,011 104,505 116,039 14,682 498 1359 2613 10,211 Galicia 1,484,698 424,418 377,370 322,257 360,653 44,463 1273 3396 8056 31,737 Comunidad de Madrid 3,099,482 1,074,013 826,152 609,975 589,342 77,769 3222 7435 15,249 51,862 Región de Murcia 648,115 234,820 176,760 123,046 113,489 15,358 704 1591 3076 9987 Comunidad Foral de Navarra 317,203 102,519 84,911 64,649 65,124 8419 308 764 1616 5731 País Vasco 1,156,253 347,445 312,977 247,706 248,125 31,887 1042 2817 6193 21,835 La Rioja 158,846 49,143 43,080 32,058 34,565 4378 147 388 801 3042 Ciudad Autónoma de Ceuta 32,632 12,059 10,246 5676 4651 680 36 92 142 409 Ciudad Autónoma de Melilla 30,008 11,057 9737 5077 4137 612 33 88 127 364 All Communities 22,862,048 7,497,881 6,183,772 4,624,421 4,555,974 594,684 22,494 55,654 115,611 400,926 95% CI 22,852,679–22,871,420 7,492,516–7,503,249 6,178,900–6,188,647 4,620,208–4,628,637 4,551,792–4,560,158 593,175–596,196 22,202–22,789 55,194–56,117 114,947–116,278 399,687–402,168 CI: Confidence interval. J. Clin. Med. 2020, 9, 2089 7 of 15 Table 5. Total number of patients in Spain and its autonomous communities with heart failure and ejection fraction ≤ 40%, as well as the number of heart failure patients with average ejection fraction ≤ 40% and in New York Heart Association functional class II–IV (based on data summarized in Table 3). Heart Failure + Ejection Fraction ≤ 40% (by Age Group) Heart Failure + Ejection Fraction ≤ 40% + NYHA Class II–IV (by Age Group) Total 45–54 55–64 65–74 75+ Total 45–54 55–64 65–74 75+ Autonomous Communities 52.4% 52.4% 52.4% 52.4% 84.0% 84.0% 84.0% 84.0% Andalucía 49,180 2109 5155 10,089 31,827 41,311 1771 4330 8475 26,734 Aragón 9928 326 850 1784 6968 8340 274 714 1499 5853 Principado de Asturias 8830 258 761 1729 6082 7417 217 639 1452 5109 Illes Balears 6354 305 684 1356 4008 5337 256 574 1139 3367 Canarias 12,180 614 1385 2613 7568 10,231 516 1163 2195 6357 Cantabria 4317 147 403 856 2912 3627 123 338 719 2446 Castilla y León 21,287 592 1706 3614 15,375 17,881 497 1433 3036 12,915 Castilla-La Mancha 13,690 504 1254 2364 9569 11,500 423 1053 1986 8038 Catalunya 49,221 1868 4466 9669 33,219 41,346 1569 3751 8122 27,904 Comunitat Valenciana 32,745 1258 3104 6661 21,723 27,506 1056 2608 5595 18,247 Extremadura 7693 261 712 1369 5351 6462 219 598 1150 4495 Galicia 23,299 667 1780 4222 16,630 19,571 560 1495 3546 13,970 Comunidad de Madrid 40,751 1688 3896 7991 27,176 34,231 1418 3273 6712 22,828 Región de Murcia 8048 369 834 1612 5233 6760 310 700 1354 4396 Comunidad Foral de Navarra 4411 161 400 847 3003 3706 135 336 711 2523 País Vasco 16,709 546 1476 3245 11,442 14,035 459 1240 2726 9611 La Rioja 2294 77 203 420 1594 1927 65 171 353 1339 Ciudad Autónoma de Ceuta 356 19 48 74 214 299 16 41 62 180 Ciudad Autónoma de Melilla 321 17 46 67 191 269 15 39 56 160 All Communities 311,614 11,787 29,163 60,580 210,085 261,756 9901 24,497 50,887 176,471 95% CI 310,522–312,709 11,576–12,001 28,830–29,499 60,100– 61,063 209,189–210,984 260,755–262,760 9708–10,097 24,192–24,805 50,447–51,330 175,650–177,295 NYHA: New York Heart Association; CI: Confidence interval. J. Clin. Med. 2020, 9, 2089 8 of 15 3.3. Estimation of Glomerular Filtration Rate ≥ 30 mL/min/1.73 m2 Prevalence in the Heart Failure Population in Spain According to the prevalence of chronic HF patients with GFR ≥ 30 mL/min/1.73 m2 described by Crespo-Lerio [23], we estimated the number of HF patients with the combination of EF ≤ 40%, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 (Table 6). In Spain, an estimated 245,789 (95% CI: 244,819–246,762) patients would have these characteristics. Table 6. Total number of patients with heart failure ejection fraction ≤ 40%, New York Heart Association functional class II–IV, and glomerular filtration rate ≥ 30 mL/min/1.73 m2 in Spain and its autonomous communities [23]. HF + EF ≤ 40% + NYHA Class II–IV + GFR ≥ 30 (by Age Group) Total 45–54 55–64 65–74 75+ Autonomous Communities 93.9% 93.9% 93.9% 93.9% Andalucía 38,791 1663 4066 7958 25,104 Aragón 7831 257 670 1407 5496 Principado de Asturias 6965 203 600 1363 4797 Illes Balears 5012 241 539 1070 3162 Canarias 9607 485 1092 2061 5970 Cantabria 3405 116 318 675 2297 Castilla y León 16,790 467 1345 2850 12,127 Castilla-La Mancha 10,798 397 989 1865 7548 Catalunya 38,823 1473 3522 7626 26,202 Comunitat Valenciana 25,828 992 2449 5254 17,134 Extremadura 6068 206 562 1080 4220 Galicia 18,377 526 1404 3330 13,117 Comunidad de Madrid 32,143 1332 3073 6303 21,435 Región de Murcia 6348 291 658 1271 4128 Comunidad Foral de Navarra 3480 127 316 668 2369 País Vasco 13,179 431 1164 2559 9025 La Rioja 1810 61 160 331 1257 Ciudad Autónoma de Ceuta 281 15 38 59 169 Ciudad Autónoma de Melilla 253 14 36 52 150 All Communities 245,789 9297 23,002 47,783 165,707 95% CI 244,819–246,762 9,110–9,487 22,707–23,300 47,357–48,212 164,911–166,506 HF: heart failure; EF: ejection fraction; NYHA: New York Heart Association; GFR: glomerular filtration rate. (mL/min/1.73 m2 ); CI: Confidence interval. A sensitivity analysis with REDINSCOR estimates (Table S3), however, showed that the estimated number of patients who met the clinical characteristics of participants in the DAPA-HF trial were 353,658 (95% CI: 352,494–354,825). 3.4. Estimation of Type 2 Diabetes Mellitus Prevalence in the Heart Failure Population in Spain The number of HF patients with EF ≤ 40%, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 , with and without T2D, are shown in Table 7 by age group and autonomous community. With these prevalence data, Spain would have 115,473 (95% CI: 114,809–116,140) patients with T2D and 130,316 (95% CI: 129,610–131,025) without T2D who would meet the diagnostic criteria of HF with EF ≤ 40%, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 . Figure 1 summarizes the sequence of patient selection by the prevalence of patient characteristics or comorbidities analysed, as well as the estimated number of patients with and without each characteristic in Spain. J. Clin. Med. 2020, 9, 2089 9 of 15 Table 7. Total number of patients with heart failure, ejection fraction ≤ 40%, New York Heart Association functional class II–IV, and glomerular filtration rate ≥ 30 mL/min/1.73 m2 , with or without type 2 diabetes mellitus, in Spain and its autonomous communities, according to prevalence data from the REDINSCOR registry (Tables S1 and S2). HF + EF ≤ 40% + NYHA Class II–IV + GFR ≥ 30 + Diabetes (by Age Group) HF + EF ≤ 40% + NYHA Class II–IV + GFR ≥ 30 (No Diabetes) (by Age Group) Total 45–54 55–64 65–74 75+ Total 45–54 55–64 65–74 75+ Autonomous Communities 28.7% 40.7% 49.2% 48.2% 71.3% 59.3% 50.8% 51.8% Andalucía 18,157 478 1654 3914 12,111 20,634 1185 2412 4044 12,993 Aragón 3690 74 273 692 2652 4141 183 398 715 2845 Principado de Asturias 3288 58 244 671 2314 3677 145 356 693 2483 Illes Balears 2340 69 219 526 1525 2672 172 320 544 1636 Canarias 4477 139 444 1014 2880 5130 345 648 1047 3090 Cantabria 1603 33 129 332 1108 1803 82 188 343 1189 Castilla y León 7934 134 547 1402 5851 8856 333 798 1448 6277 Castilla-La Mancha 5075 114 402 917 3641 5724 283 587 947 3906 Catalunya 18,248 423 1433 3751 12,641 20,576 1050 2090 3875 13,561 Comunitat Valenciana 12,131 285 996 2584 8266 13,697 707 1453 2670 8868 Extremadura 2855 59 228 531 2036 3213 147 333 549 2184 Galicia 8688 151 571 1638 6328 9689 375 833 1692 6789 Comunidad de Madrid 15,074 383 1250 3100 10,341 17,069 949 1823 3203 11,094 Región de Murcia 2968 84 267 625 1991 3380 207 390 646 2136 Comunidad Foral de Navarra 1636 37 128 329 1143 1843 91 187 339 1226 País Vasco 6210 124 473 1259 4,354 6969 307 691 1301 4671 La Rioja 852 18 65 163 607 957 43 95 168 651 Ciudad Autónoma de Ceuta 130 4 16 29 82 151 11 23 30 88 Ciudad Autónoma de Melilla 117 4 15 26 73 136 10 21 27 78 All Communities 115,473 2672 9355 23,503 79,943 130,316 6625 13,647 24,280 85,764 95% CI 114,809–116,140 2573–2774 9167–9546 23,205–23,804 79,391–80,498 129,610–131,025 6467–6786 13,420–13,877 23,977–24,586 85,192–86,339 HF: heart failure; EF: ejection fraction; NYHA: New York Heart Association; GFR: glomerular filtration rate (mL/min/1.73 m2 ); CI: Confidence interval. J. Clin. Med. 2020, 9, 2089 10 of 15 J. Clin. Med. 2020, 9, x FOR PEER REVIEW 11 of 16 Spanish population n = 47,100,396 Population < 45 years old n = 24,238,348 (51.5%) Population ≥ 45 years old n = 22,862,048 Population without HF n = 22,267,364 (97.4%) Patients with HF n = 594,684 Patients with EF > 40% n = 283,070 (47.6%) Patients with EF ≤ 40% n = 311,614 Patients with NYHA = I n = 49,858 (16.0%) Patients with NYHA = II–IV n = 261,756 Patients with GFR < 30 n = 15,967 (6.10%) Patients with GFR ≥ 30 n = 245,789 Patients with T2D Patients without T2D n = 115,473 n = 130,316 Figure 1. Flow chart of the Spanish population older than 44 years with heart failure (HF), Figure 1.fraction ejection Flow chart of40%, (EF) ≤ the Spanish New Yorkpopulation older than(NYHA) Heart Association 44 yearsfunctional with heartclass failure (HF), II–IV, ejection glomerular fraction (EF) ≤ 40%, New York Heart Association 2 (NYHA) functional class II–IV, glomerular filtration filtration rate (GFR) ≥ 30 mL/min/1.73 m , and type 2 diabetes mellitus (T2D), according to the estimation rate (GFR) specified in ≥the 30Methods mL/min/1.73 m², and type 2 diabetes mellitus (T2D), according to the estimation section. specified in the Methods section. 4. Discussion 4. Discussion 4.1. Main Findings 4.1. Main AmongFindings all Spanish patients with HF, the estimated prevalence of patients older than 44 years with Among reducedallEF, NYHA Spanish functional patients with class II–IV, HF, the and with estimated normal of prevalence or patients moderate kidney older than function 44 years (≥30 mL/min/1.73 m 2 ) was about 41.3%. Since the population was selected to meet the clinical with reduced EF, NYHA functional class II–IV, and with normal or moderate kidney function (≥ 30 characteristics mL/min/1.73 of participants m²) was about in the DAPA-HF 41.3%. Sincetrial, theit population is conceivable that selected was these patients mightthe to meet alsoclinical benefit from the positive characteristics of cardiovascular participants in effects attributedtrial, the DAPA-HF to dapagliflozin, in addition it is conceivable to its that these glucose-lowering patients might also benefits. benefit from the positive cardiovascular effects attributed to dapagliflozin, in addition to itswith This new therapeutic indication would benefit the defined HF patient population, and glucose- without loweringT2D, as shown benefits. Thisin the therapeutic new DAPA-HF clinical trial would indication [22]. Regardless of defined benefit the the presence of T2D population, HF patient and the risk of with and without T2D, as shown in the DAPA-HF clinical trial [22]. Regardless of the presenceless worsening HF, death from cardiovascular causes and hospitalizations for HF were significantly of T2D and the risk of worsening HF, death from cardiovascular causes and hospitalizations for HF J. Clin. Med. 2020, 9, 2089 11 of 15 frequent among DAPA-HF participants who received dapagliflozin, compared to those who received a placebo. In the DAPA-HF study, dapagliflozin represents the first in a new class of drug for HF with reduced EF. The DAPA-HF study results introduce the opportunity to further study the potential cardiovascular benefits of SGLT2 inhibitors. Prior studies with empagliflozin [34] and canagliflozin [35] showed a reduction in the relative risk of HF hospitalization in T2D patients, suggesting that the observed benefit is not restricted to a particular drug, but is rather a class effect. The Canagliflozin Cardiovascular Assessment Study (CANVAS) showed that canagliflozin reduced the overall risk of HF events in patients with T2D and high cardiovascular risk. No clear difference in effects on HF with reduced versus preserved events was noted [36]. In addition, the Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) study with dapagliflozin included a reanalysis of retrospectively-obtained EF. The clinical benefit of dapagliflozin was found to be strong in reduced EF in the subset of patient with available EF. In patients with HF without reduced EF, there was only a reduction of hospitalizations, but not in total or cardiovascular mortality [37]. The former was confirmed in the DAPA-HF study. The dapagliflozin effect on mortality in HF-preserved EF patients remains to be conclusively answered 4.2. Reliability of Prevalence Estimates Based on updated demographic information and a comprehensive literature review to obtain reliable prevalence data, we selected the most recent population-based cross-sectional study, in which Farré et al. analysed data from 88,000 individuals representative of the population of Catalonia, with an estimated a 2.7% HF prevalence in people older than 44 years [14]. Due to slight regional differences in age group population distribution, our estimations yielded 2.6% prevalence when applied to all of Spain. The estimations obtained by Farré et al. are also close to European and North American figures, and are more recent than the larger prevalence estimates reported in the meta-analysis by Hernáez et al. [24] and the 2008 Heart Failure Prevalence Study in Spain (PRICE) by Anguita et al. [15]. Given the diversity of hospital departments and primary care settings participating in the published studies, our estimated prevalence of HF patients with reduced EF and NYHA functional class II–IV (52.4% and 84.0%, respectively) reflects the mean values of the main published Spanish registries [6,7,27–29]. The obtained prevalence values are in good agreement with the most recent European publications [5,38] in the Southern Europe population. Spanish cardiology departments were well-represented in these European studies, carried out in the context of the ESC Heart Failure Long-Term Registry, which had indicated that the prevalence of reduced EF in patients with chronic HF predominantly admitted to cardiology departments would be around 60%. This is slightly higher than our study’s estimate, which was based on HF data from cardiology units, internal medicine, and primary care settings. The Linx Registry, one of the most recent HF studies in Spain, also had a large sample of patients and was carried out in cardiology departments in Catalonia. In that registry, de Frutos et al. [39] estimated that the prevalence of NYHA functional class II–IV in patients with HF and EF ≤ 40% was 85.5%, remarkably close to the estimate obtained in the present study. We used the 6.1% prevalence of GFR < 30 mL/min/1.73 m2 among chronic HF patients, reported by Crespo-Leiro et al. [23], based on data from 28 Spanish hospitals included in the ESC Heart Failure Long-Term Registry. This is the most recent publication with HF data from Spain, includes the largest series of Spanish patients, and is the only study to provide GFR data generalizable to the HF population. The 6.1% prevalence is among the lowest published in recent decades in Spain, although it is close to the REDINSCOR registry prevalence of 5.5% in HF units within cardiology departments (Tables S1 and S2). 4.3. Potential Translational Perspective The results of the DAPA-HF study demonstrated that the primary composite outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio = 0.74; 95% CI: 0.65–0.85; p < 0.001). The largest number of events J. Clin. Med. 2020, 9, 2089 12 of 15 of worsening HF was hospitalizations. Of the patients receiving dapagliflozin, 231 (9.7%) were hospitalized for HF, compared with 318 patients (13.4%) receiving the placebo (hazard ratio = 0.70; 95% CI: 0.59–0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) who received dapagliflozin, and in 273 (11.5%) who received the placebo (hazard ratio = 0.82; 95% CI: 0.69 to 0.98) [22]. Under the placebo group incidence assumptions, among all 245,789 patients of the estimated Spanish target population, the primary outcome would occur in 52,107 patients, 32,936 patients would be hospitalized for HF, and 28,266 patients would die from cardiovascular causes. With dapagliflozin therapy, the expected annual reduction would consist of 5996 hospitalized patients for HF and 3079 deaths from cardiovascular causes. 4.4. Strengths and Limitations The main strength of this study is that it combines the estimates from recently published HF prevalence data, enriched by a specific analysis of the REDINSCOR registry database to estimate HF with reduced EF, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 , with and without T2D prevalence in the Spanish population. However, we decided not to use the estimates based on REDINSCOR database, because the REDINSCOR registry could be biased toward the profile of patients admitted to HF units in cardiology departments, which could depart from the general HF patient population characteristics. All patients included in the REDINSCOR registry had a NYHA class >I, and the mean estimate of patients with reduced EF was 73%, considerably different from the average of the main Spanish registries that we summarize in Table 3. A sensitivity analysis with REDINSCOR patient characteristics is presented in Table S3, showing rather higher figures than its corresponding Table 6 results. The study also has several limitations. First, we did not take into account the N-terminal pro B-type natriuretic peptide (NT-proBNP) eligibility criteria prevalence in our estimates, due to the absence of prevalence information in the literature and to the probably small reduction in the number of eligibility patients. Second, among the Spanish studies summarized in Table 3, the definition of reduced EF varied from EF ≤ 40% to EF ≤ 50%. Furthermore, the GALICAP and EPISERVE studies did not differentiate between chronic and acute HF. Third, we had to assume that the prevalence of NYHA functional class II–IV was the same for reduced, mid-range, and preserved EF, owing to the absence of stratified information in the literature. Likewise, we had to assume that the prevalence of GFR ≥ 30 mL/min/1.73 m2 was the same for each type of EF and NYHA functional class, and for all age groups considered in our study. Fourth, the prevalence of diabetic and non-diabetic patients in the REDINSCOR registry could be biased toward the profile of patients admitted to HF units in cardiology departments. Finally, our study does not report prevalence by sex, as the published studies did not provide this stratified information. We firmly support stratification by sex in all future studies, in order to identify the best treatment guidelines to apply in the whole population. 5. Conclusions In this population analysis, we estimated that approximately 245,789 Spanish patients would meet the inclusion criteria of the DAPA-HF: EF ≤ 40%, NYHA functional class II–IV, and GFR ≥ 30 mL/min/1.73 m2 , as well as 115,473 with T2D. The magnitude of this population highlights the need to introduce effective and safe new drugs to reduce morbidity and mortality in these patients. Supplementary Materials: The following are available online at http://www.mdpi.com/2077-0383/9/7/2089/s1, Table S1: Number of patients with the four selection criteria of the DAPA-HF study in the REDINSCOR cohort in Spain. Table S2: Average prevalence of the four main selection criteria of the DAPA-HF study in the REDINSCOR cohort in Spain. Table S3: Total number of patients with heart failure, ejection fraction ≤ 40%, New York Heart Association functional class II–IV, and glomerular filtration rate ≥ 30 mL/min/1.73 m2 in Spain and its autonomous communities, according to prevalence data from the REDINSCOR registry (Tables S1 and S2). J. Clin. Med. 2020, 9, 2089 13 of 15 Author Contributions: Conceptualization, J.F.D.-J., J.M.; methodology, J.F.D.-J., I.R.D., and J.M.; validation, all authors; formal analysis, A.C.-V. and I.R.D.; investigation, A.C.-V., I.R.D., J.F.D.-J., and J.M.; resources, N.F., H.T.-M., J.C., J.Á.-G., and J.M.; data curation, A.C.-V., I.R.D., and J.M.; writing—original draft preparation, A.C.-V., I.R.D., J.F.D.-J, and J.M.; writing—review and editing, all authors; visualization, A.C.-V., I.R.D., and J.M.; supervision, J.M.; project administration, J.M.; funding acquisition, J.M. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by Spain’s Ministry of Science and Innovation (Madrid, Spain), co-financed with European Union European Regional Development Funds (ERDF) (CIBERCV CB16/11/00229), as well as the Health Department of the Generalitat de Catalunya (Barcelona, Spain) through the Agència de Gestió d’Ajuts Universitaris de Recerca de Catalunya (AGAUR) (Barcelona, Spain) (2017SGR222), the Strategic Plan for Research and Health Innovation (PERIS) (Barcelona, Spain) (SLT006/17/00029 to I.R.D.), and the Private Foundation Daniel Bravo Andreu (Barcelona, Spain) (J.Á.-G.). CIBER of Cardiovascular Diseases (CIBERCV) is an initiative of the Instituto de Salud Carlos III (Madrid, Spain). Acknowledgments: We appreciate the English language editing done by Elaine Lilly, PhD, of Writer’s First Aid. Conflicts of Interest: J.F.D.-J. reports consultancy fees from AstraZeneca; N.F. reports grants and consultancy fees from Novartis, Bayer, Rovi, and AstraZeneca; J.Á.-G. reports consultancy fees from AstraZeneca, Boehringer Ingelheim, and Lilly; J.M. reports grants and consultancy fees from AstraZeneca, Sanofi, Shire, Gilead, Daichii-Sankyo, Genincode, and Ferrer. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, and interpretation of data; in the writing of the manuscript; and in the decision to publish the results. References 1. 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