International Journal of Cardiology 344 (2021) 127–134 Contents lists available at ScienceDirect International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard Early intravenous nitroglycerin use in prehospital setting and in the emergency department to treat patients with acute heart failure: Insights from the EAHFE Spanish registry Òscar Miró a, b, *, Pere Llorens c, Yonathan Freund d, Beth Davison e, f, Koji Takagi e, f, Pablo Herrero-Puente g, Javier Jacob h, Francisco Javier Martín-Sánchez i, Víctor Gil a, Xavier Rosselló j, k, Aitor Alquézar-Arbé l, Francesc X. Jiménez-Fábrega m, Josep Masip n, Alexandre Mebazaa b, f, o, Gad Cotter e, f, on behalf of the EAHFE Research Group1 a Emergency Department, Hospital Clinic, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Spain b The GREAT (Global Research in Acute Contditions Team) Network, Via Antonio Serra 54, 00191, Roma, Italy c Emergency Department, Short-Stay Unit and Home Hospitalization, Hospital General de Alicante, Spain d Emergency Department, Hôpital Pitié-Salpêtrière, Assistance Publique - Hôpitaux 18 de Paris (APHP), Sorbonne Université, Paris, France e Momentum Research, Inc., Durham, NC, USA f INSERM U-942 (Biotherapy in the critically ill), Paris, France g Emergency Department, Hospital Universitario Central de Asturias, Oviedo, Spain h Emergency Department, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Catalonia, Spain i Emergency Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdISSC), Universidad Complutense de Madrid, Madrid, Spain j Cardiology Department, Health Research Institute of the Balearic Islands (IdISBa), Hospital Universitari Son Espases, Palma, Spain k Centro Nacional de Investigaciones Cardiovasculares (CNIC), Spain l Emergency Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain m Emergency Medical Services, SEM-Catalunya, Barcelona, Catalonia, Spain n Consultant Research Direction, University of Barcelona, Catalonia, Spain o Department of Anaesthesiology and Critical Care Medicine, AP-HP, Saint Louis and Lariboisière University Hospitals, Paris, France. * Corresponding author at: Emergency Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain. E-mail address: omiro@clinic.cat (Ò. Miró). 1 Investigators of the ICA-SEMES (Research group on Acute Heart Failure of the Spanish Society of Emergency Medicine): Marta Fuentes, Cristina Gil (Hospital Universitario de Salamanca), Héctor Alonso, Enrique Pérez-Llantada (Hospital Marqués de Valdecilla de Santander), Francisco Javier Martín-Sánchez, Guillermo Llopis García, Mar Suárez Cadenas (Hospital Clínico San Carlos de Madrid), Òscar Miró, Víctor Gil, Rosa Escoda, Carolina Xipell, Carolina Sánchez, Alba Jerez, Joan Padrosa (Hospital Clínic de Barcelona), María José Pérez-Durá, Eva Salvo (Hospital Politècnic La Fe de Valencia), José Pavón (Hospital Dr. Negrín de Las Palmas de Gran Canaria), Antonio Noval (Hospital Insular de Las Palmas de Gran Canaria), José Manuel Torres (Hospital Reina Sofía de Córdoba), María Luisa López- Grima, Amparo Valero, María Ángeles Juan (Hospital Dr. Peset de Valencia), Alfons Aguirre, Maria Àngels Pedragosa, Silvia Mínguez Masó (Hospital del Mar de Barcelona), María Isabel Alonso, Francisco Ruiz (Hospital de Valme de Sevilla), José Miguel Franco (Hospital Miguel Servet de Zaragoza), Ana Belén Mecina (Hospital de Alcorcón de Madrid), Josep Tost, Marta Berenguer, Ruxandra Donea (Consorci Sanitari de Terrassa), Susana Sánchez Ramón, Virginia Carbajosa Rodríguez (Hospital Universitario Rio Hortega de Valladolid), Pascual Piñera, José Andrés Sánchez Nicolás (Hospital Reina Sofía de Murcia), Raquel Torres Garate (Hospital Severo Ochoa de Madrid), Aitor Alquézar-Arbé, Miguel Alberto Rizzi, Sergio Herrera (Hospital de la Santa Creu y Sant Pau de Barcelona), Javier Jacob, Alex Roset, Irene Cabello, Antonio Haro (Hospital Universitari de Bellvitge de Barcelona), Fernando Richard, José María Álvarez Pérez, María Pilar López Diez (Hospital Universitario de Burgos), Pablo Herrero Puente, Joaquín Vázquez Álvarez, Belén Prieto García, María García García, Marta Sánchez González (Hospital Universitario Central de Asturias de Oviedo), Pere Llorens, Patricia Javaloyes, Víctor Marquina, Inmaculada Jiménez, Néstor Hernández, Benjamín Brouzet, Begoña Espinosa (Hospital General de Alicante), Juan Antonio Andueza (Hospital General Universitario Gregorio Marañón de Madrid), Rodolfo Romero (Hospital Universitario de Getafe de Madrid), Martín Ruíz, Roberto Calvache (Hospital de Henares de Madrid), María Teresa Lorca Serralta, Luis Ernesto Calderón Jave (Hospital del Tajo de Madrid), Beatriz Amores Arriaga, Beatriz Sierra Bergua (Hospital Clínico Lozano Blesa de Zaragoza), Enrique Martín Mojarro, Brigitte Silvana Alarcón Jiménez (Hospital Sant Pau i Santa Tecla de Tarragona), Lisette Travería Bécquer, Guillermo Burillo (Hospital Universitario de Canarias de Tenerife), Lluís Llauger García, Gerard Corominas La Salle. (Hospital Universitari de Vic de Barcelona), Carmen Agüera Urbano, Ana Belén García Soto, Elisa Delgado Padial (Hospital Costa del Sol de Marbella de Málaga), Ester Soy Ferrer (Hospital Josep Trueta de Girona), José Manuel Garrido (Hospital Virgen Macarena de Sevilla), Francisco Javier Lucas- Imbernón (Hospital General Universitario de Albacete), Rut Gaya (Hospital Juan XXIII de Tarragona), Carlos Bibiano, María Mir, Beatriz Rodríguez (Hospital Infanta Leonor de Madrid), José Luis Carballo (Complejo Hospitalario Universitario de Ourense), Esther Rodríguez-Adrada, Belén Rodríguez Miranda (Hospital Rey Juan Carlos de Móstoles de Madrid). https://doi.org/10.1016/j.ijcard.2021.09.031 Received 28 June 2021; Received in revised form 13 September 2021; Accepted 15 September 2021 Available online 20 September 2021 0167-5273/© 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 A R T I C L E I N F O A B S T R A C T Keywords: Background and objective: Although recommended for the treatment of acute heart failure (AHF), the use of Acute heart failure intravenous (IV) nitroglycerin (NTG) is supported by scarce and contradicting evidence. In the current analysis, Nitrates we have assessed the impact of IV NTG administration by EMS or in emergency department (ED) on outcomes of Nitroglycerine AHF patients. Outcome Mortality Methods: We analyze AHF patients included by 45 hospitals that were delivered to ED by EMS. Patients were grouped according to whether treatment with IV NTG was started by EMS before ED admission (preED-NTG), during the ED stay (ED-NTG) or were untreated with IV NTG (no-NTG, control group). In-hospital, 30-day and 365-day all-cause mortality, prolonged hospitalization (>7 days) and 90-day post-discharge combined adverse events (ED revisit, hospitalization or death) were compared in EMS-NTG and ED-NTG respect to control group. Results: We included 8424 patients: preED-NTG = 292 (3.5%), ED-NTG = 1159 (13.8%) and no-NTG = 6973 (82.7%). preED-NTG group had the most severely decompensated cases of AHF (p < 0.001) but it had lower in- hospital (OR = 0.724, 95%CI = 0.459–1.114), 30-day (HR = 0.818, 0.576–1.163) and 365-day mortality (HR = 0.692, 0.551-0.869) and 90-day post-discharge events (HR = 0.795, 0.643–0.984) than control group. ED-NTG group had mortalities similar to control group (in-hospital: OR = 1.164, 0.936–1.448; 30-day: HR = 0.980, 0.819–1.174; 365-day: HR = 0.929, 0.830–1.039) but significantly decreased 90-day post-discharge events (HR = 0.870, 0.780–0.970). Prolonged hospitalization rate did not differ among groups. Five different analyses confirmed these findings. Conclusions: Early prehospital IV NTG administration was associated with lower mortality and post-discharge events, while IV NTG initiated in ED only improved post-discharge event rate. Further studies are needed to assess the role of early prehospital administration of IV NTG to patients with AHF. 1. Introduction attending ED physician decisions. The use of intravenous (IV) nitrates (nitroglycerine, NTG) for the 2.2. Ethics treatment of acute heart failure (AHF) has been debated. Initially, a small study reported improved oxygenation, and reduced need for me­ The EAHFE Registry protocol was approved by a central Ethics chanical ventilation and other adverse events in patients with AHF and Committee at the Hospital Universitario Central de Asturias (Oviedo, significant desaturation when high doses of IV nitrates were adminis­ Spain) with the reference numbers 49/2010, 69/2011, 166/13, 160/15 tered in the prehospital setting [1]. This was followed by a more and 205/17. The present study was carried out in strict compliance with generalized recommendation in the guidelines for the treatment of AHF the Declaration of Helsinki principles. for the use of IV nitrates for longer periods of time in the in-hospital setting during the first days of admission for AHF [2,3]. As pointed, 2.3. Design and variables recorded this recommendation was made without significant supporting data [4]. Of recent, a prospective study (GALACTIC) has found no benefit in the The present analysis included all patients in whom the form of arrival administration of IV nitrates during the first few days of an AHF to ED was registered (this variable was recorded from the EAHFE-3 admission [5]. However, in the GALACTIC study, nitrates were not registry onwards). Of them, we selected those that were delivered to administered intravenously and did not result in reduction of blood the ED by an ambulance provided by emergency medical services (EMS). pressure during the first day of administration, hence their dosing may Patients were classified into three groups: 1) patients receiving IV NTG have been insufficient to affect in significant benefits. In the current which was started by prehospital EMS, before ED arrival (preED-NTG analysis, we have attempted to explore the effects of prehospital Group); 2) patients receiving IV NTG started in ED, after assessment by administration of nitrates on mortality and adverse events in the EAHFE the attending physician (ED-NTG Group); and 3) patients that did not (Epidemiology of AHF in Emergency departments) Spanish registry that receive IV NTG during the urgent management, neither during pre­ includes patients diagnosed with AHF in emergency department (ED) hospital phase by the EMS nor during their stay in the ED (no-NTG consecutively included in sets of 1–2 months cohorts during last 15 Group, controls). Sublingual or oral NTG administration was not years. In addition, we have also explored the effects of IV NTG when this considered. Doses and time duration of IV NTG used by EMS and in the is started in the ED. ED were not recorded. Independent variables consisted on baseline and current episode 2. Methods data prospectively recorded during patients ED stay. Data regarding clinical characteristics of the current AHF episode consisted on pheno­ 2.1. Setting type classification according congestion (wet or dry) and perfusion (cold or warm) [2,8], vitals at ED arrival, laboratory findings and lung The present study is a subanalysis of the EAHFE Registry [6–9]. The congestion in chest X-ray. In addition, the severity of the current episode AHF diagnosis was based on the Framingham clinical criteria [10]. The of decompensation was assessed through the MEESSI score, a clinical initial patient inclusion and data recording was made by the attending score that has demonstrated a very good prediction of the 30-day mor­ emergency physician, and the principal investigator of every center tality in patients with AHF using clinical data recorded in the ED [5,6]. retrospectively reviewed medical reports and was the responsibly for the The MEESSI score is calculated recorded during the first patient final diagnostic adjudication at local level. They revised every case to assessment in the ED. check the compliance criteria of AHF and to confirm diagnosis by measurement of plasma natriuretic peptide and/or echocardiography during ED or hospital stay when possible following the current recom­ 2.4. Outcomes mendations of the ESC Guidelines [2] and this was available in about 92% of cases. The EAHFE Registry does not include any planned inter­ Five outcomes were assessed in the present study. Three outcomes vention, and the management of patients is entirely based on the referred to all-cause mortality (in-hospital and at 30 and 365 days). Vital status of patients was ascertained by consultation of medical records, 128 Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 Table 1 Patients characteristics and comparison among the three groups according to intravenous nitroglycerine was provided by emergency medical services (preED-NTG Group), by emergency physicians in the emergency department (ED-NTG) or not provided at all (No-NTG Group). All patients Missing preED-NTG ED-NTG Group No-NTG Group P value N=8,424 values Group N=1,159 N=6,973 n (%) n (%) N=292 n (%) n (%) n (%) PATIENT BASELINE CHARACTERISTICS Demographic data Age (in years) (median (IQR)) 84 (78-89) 3 (0.0) 80 (72-86) 82 (76-87) 84 (79-89) <0.001 Sex: Male 3,481 (41.3) 18 (0.2) 138 (47.6) 466 (40.2) 2,877 (41.3) 0.07 Comorbidities Hypertension 7,127 (84.8) 15 (0.2) 252 (86.6) 1,010 (87.3) 5,865 (84.3) 0.02 Diabetes mellitus 3,495 (41.6) 17 (0.2) 146 (50.2) 565 (48.9) 2,784 (40.0) <0.001 Coronary artery disease 2,417 (28.7) 15 (0.2) 137 (47.1) 375 (32.4) 1,905 (27.4) <0.001 Chronic kidney failure (creatinine >2 mg/mL) 2,446 (28.7) 15 (0.2) 84 (28.9) 362 (31.3) 2,000 (28.7) 0.20 Cerebrovascular disease 1,175 (14.0) 15 (0.2) 41 (14.1) 165 (14.3) 969 (13.9) 0.95 Atrial fibrillation 4,176 (49.7) 14 (0.2) 104 (35.) 513 (44.3) 3,559 (51.1) <0.001 Peripheral artery disease 820 (9.8) 15 (0.2) 48 (16.5) 162 (14.0) 610 (8.8) <0.001 Heart valve disease 2,141 (25.5) 15 (0.2) 71 (24.4) 310 (26.8) 1,760 (25.3) 0.49 Chronic obstructive pulmonary disease 2,158 (25.7) 17 (0.2) 60 (20.6) 254 (22.0) 1,844 (26.5) 0.001 Dementia 1,304 (15.5) 15 (0.2) 32 (11.0) 137 (11.8) 1,135 (16.3) <0.001 Active neoplasia 1,242 (14.8) 18 (0.2) 40 (13.7) 159 (13.8) 1,043 (15.0) 0.48 Previous episodes of acute heart failure 5,221 (63.8) 244 (2.9) 172 (59.7) 685 (60.3) 4,364 (64.6) 0.007 Baseline status NYHA class III/IV 2,224 (27.6) 380 (4.5) 61 (22.3) 282 (25.1) 1,881 (28.3) 0.01 Left ventricular ejection fraction (LVEF, %) (median (IQR)) 55 (45-64) 3,606 (42.8) 50 (38-60) 55 (42-63) 55 (45-65) <0.001 -LVEF <40% 838 (17.4) 47 (19.3) 131 (19.3) 660 (16.7) -LVEF 40-49% 645 (13.4) 35 (19.3) 96 (14.2) 514 (13.0) -LVEF ≥50% 3,335 (69.2) 99 (54.7) 451 (66.6) 2,785 (70.3) Barthel Index (points)* (median (IQR)) 80 (60-100) 674 (8.0) 90 (65-100) 90 (60-100) 80 (60-100) <0.001 Chronic treatments with disease-modifying drugs at home Beta-blockers 3,563 (43.2) 169 (2.0) 161 (55.7) 516 (44.9) 2,886 (42.3) <0.001 Renin-angiotensin system inhibitors 4,599 (55.7) 164 (1.9) 183 (63.3) 678 (59.0) 3,738 (54.8) 0.001 Mineralcorticosteroid-receptor blockers 1,245 (15.1) 164 (1.9) 39 (13.5) 145 (12.6) 1,061 (15.6) 0.03 CLINCAL CHARACTERISTICS OF THE ACUTE HEART FAILURE EPISODE Clinical phenotype 0 (0) <0.001 Warm & wet 6,572 (78.0) 189 (64.7) 833 (71.9) 5,550 (79.6) Cold & wet 942 (13.5) 83 (28.4) 282 (24.3) 942 (13.5) Warm & dry 465 (5.5) 14 (4.8) 35 (3.0) 416 (6.0) Cold & dry 80 (0.9) 6 (2.1) 9 (0.8) 65 (0.9) Vitals at ED arrival (median (IQR)) Systolic blood pressure 139 (121-158) 76 (0.9) 159 (134-185) 153 (134-175) 137 (120-154) <0.001 Heart rate 86 (72-103) 170 (2.0) 93 (76-110) 88 (75-108) 85 (71-101) <0.001 Pulse-oxymetry 93 (89-96) 164 (1.9) 93 (87-97) 93 (88-96) 94 (90-96) 0.002 Laboratory findings Hemoglobin (g/L) (median (IQR)) 119 (106-133) 72 (0.9) 121 (109-137) 119 (105-134) 119 (106-132) 0.009 Creatinine (mg/dL) (median (IQR)) 1.15 (0.88- 105 (1.2) 1.18 (0.92-1.54) 1.17 (0.90- 1.15 (0.87- 0.13 1.59) 1.60) 1.59) Sodium (mmol/L) 139 (136-141) 200 (2.4) 138 (136-141) 139 (136-141) 139 (136-141) 0.28 Potassium (mmol/L) 4.4 (4.0-4.8) 525 (6.2) 4.3 (3.9-4.8) 4.4 (4.0-4.8) 4.4 (4.0-4.8) 0.88 NT-proBNP (pg/L) (median (IQR)) 4,444 4,196 (49.8) 4,050 4,405 4,456 0.93 (2,089-9,523) (2,167-9,325) (2,070-9,449) (2,088-9,541) Raised troponin (>99th percentile) 2,602 (56.6) 3,825 (45.4) 145 (60.9) 411 (58.6) 2,046 (55.7) 0.07 Lung congestion in chest X-ray Interstitial and/or alveolar edema 1,371 (30.2) 3,890 (46.2) 89 (57.4) 231 (52.0) 1,051 (26.7) <0.001 SEVERITY OF THE ACUTE HEART FAILURE EPISODE MEESSI-AHF risk score 0.004 Predicted 30-day mortality (in %, 95% CI) 8.7 (8.4-9.0) 2,935 (34.8) 11.1 (9.4-13.1) 9.1 (8.4-10.2) 8.5 (8.2-8.9) Low risk category 1,654 (30.2) 51 (24.4) 257 (29.5) 1,349 (30.6) Intermediate risk category 2,325 (42,4) 82 (39.2) 364 (41.8) 1,876 (42.5) High risk category 745 (13.6) 38 (18.2) 132 (15.2) 577 (13.1) Very high risk category 761 (13.9) 38 (18.2) 117 (13.4) 608 (13.8) Bold p values denote statistical significance (p < 0.05). * The higher the score, the better the patient functional status (range of the score: 0 to 100 points). which is electronically accessible in nearly all Spanish communities. In prolonged hospitalization. This outcome was adjudicated when patient addition, we contacted with patients when no clear data was present in had been hospitalized, discharged alive and length of hospitalization the clinical history or access was not possible, as at the time of patient was longer than 7 days, according to previous studies [7,11]. Patients inclusion into the EAHFE Registry they provide phone numbers and directly discharged from the ED and those dying during the index event permission to be called. Death was also ascertained through the Spanish were not considered for this outcome. Finally, the fifth outcome referred database of public health insurance, that covers >99% of Spanish pop­ to adverse event during the 90 days after discharge from the index event. ulation, as every patient dying is immediately retired of such a database We considered as 90-day post-discharge adverse events a combined at the exact time point that death occurs. The forth outcome consisted on variable that included ED revisit due to AHF (with or without 129 Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 Fig. 1. Survival curves for 30-day (left) and 365-day (middle) all-cause mortality and 90-day post-discharge combined adverse event (right) according to intravenous nitroglycerine was provided by emergency medical services (preED-NTG Group), by emergency physicians in the emergency department (ED-NTG) or not provided at all (No-NTG Group). hospitalization), hospitalization due to AHF or death or all-cause death the fourth analysis (sensitivity analysis D), we only included patients (whichever happening first). Every event adjudication was performed at with wet and warm phenotype, as they are those that could potentially local level by the principal investigator of each hospital. have higher benefit to be treated with IV NTG. Finally, the last one (sensitivity analysis E) compared groups of patients paired using a 2.5. Statistical analysis propensity score (PS) matching approach. A PS to be treated with IV NTG was separately calculated for patients of the preED and ED groups Continuous variables are expressed as mean and standard deviation respect to patients of the No-NTG group. With this purpose, we con­ (SD) or median and interquartile range (IQR) if not normally distributed, structed a multivariable model including age, sex, baseline patient and categorical variables as absolute values and percentages. Compar­ characteristics that significantly differed between groups (except those ison among the three groups was carried out using one-way ANOVA for variables included in the MEESSI score), as well as the severity of current continuous variables (or by Kruskal Wallis non-parametrical test if not AHF episode estimated by the MEESSI score. Finally, patients were normally distributed) and the chi square test for categorical variables. paired (1:1) based on a maximum standardized difference of 0.1% in the For comparison of in-hospital mortality and prolonged hospitaliza­ PS. tion, we used odds ratio (OR) with 95% confidence interval (CI) while In the other hand, we carried out a stratified analysis for outcomes in for 30-day and 365-day mortality and 90-day post-discharge combined which statistically significant differences had been detected in the adverse event we used survival tables and curves using the Kaplan-Meier analysis of the whole cohort of patients. Stratification was performed in method and compared by log-rank test, and we calculated hazard ratios the fully adjusted model according to age (< or ≥ 80 years), sex, coro­ (HR) with 95%CI using the Cox regression. In all cases, the no-NTG was nary artery disease and chronic heart failure as previous comorbidity, used as control group. We adjusted OR and HR by baseline differences and first systolic blood pressure record (< or ≥ 120 mmHg), and (by adding age, sex and variables that were unequally distributed among interaction was assessed. groups, p < 0.05, with the exception that those variables that are already Statistical significance was accepted if the p value was less than 0.05. included in the MEESSI score) and by the severity of the current AHF Since this was an exploratory study, a pre-hoc sample size calculation decompensation (using the MEESSI score). Missing values in the vari­ was not made. All calculations were made using SPSS v24.0 software ables included in the adjusted models were replaced using the multiple (IBM, New Castle, NY, USA). imputation technique, generating 5 datasets in which there were no missing values among all the variables included in the adjustment. 3. Results We performed five different sensitivity analyses for every outcome in the fully adjusted model. In the first one (sensitivity analysis A), we Between EAHFE cohort 3 and cohort 6, 8424 patients who were removed from the group of patients receiving IV NTG started by EMS delivered to the hospital by the emergency medical services (EMS) were those in whom, after assessment by the emergency physician in the ED, prospectively enrolled into a registry. Among them, 292 (3.5%) were IV NTG was discontinued. In the second and third ones, we eliminated treated with IV NTG by EMS before admission to the ED (preED-NTG from the three groups all patients with a first systolic blood pressure Group), 1159 (13.8%) were started treated by IV NTG in the ED (ED- below 100 mmHg (sensitivity analysis B) and 100 mmHg (sensitivity NTG Group) and 6973 (82,8%) were not treated by nitrates in either the analysis C), respectively, because they could include, in some extend, EMS or during the ED stay (no-NTG Group, controls) (Supplementary patients in whom IV NTG was incorrectly initiated (in the two groups of Figure). The baseline characteristics of the patients enrolled in by those IV NTG treatment) or patients with more advanced forms of cardiomy­ 3 groups are presented in Table 1. Patients treated by IV NTG, and opathy and poorer prognosis (in the group that not received IV NTG). In especially preED-NTG Group, were younger, they had more diabetes 130 Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 Table 2 (46.4%, p = 0.301). On the other hand, survival curves for 30-day Unadjusted and adjusted outcomes. mortality did not exhibit statistical difference among the three groups Unadjusted ratio Adjusted ratio* as well, with mortality rates of 10.7%, 12.6% and 12.7% for preED-NTG, (95% CI) (95% CI) ED-NTG and no-NTG groups, respectively (log-rank test p = 0.812) In-hospital all-cause mortality (OR) (Fig. 1). Conversely, we observed statistically significant differences in No-NTG Group 1 (reference) 1 (reference) 365-day mortality (29.3%, 34.9% and 36.8%, respectively; log-rank test ED-NTG Group 1.172 1.164 p = 0.031) and 90-day post-discharge combined event (48.1%, 49.1% (0.536–1.254) (0.936–1.448) and 55.7%, respectively; log-rank test p = 0.007) curves, with differ­ preED-NTG Group 0.820 0.724 (0.536–1.254) (0.459–1.114) ences appearing early (by around 30 days from the starting point) and Prolonged hospitalization** (OR) persisting throughout the follow up period (Fig. 1). No-NTG Group 1 (reference) 1 (reference) The unadjusted and adjusted associations with outcomes for preED- ED-NTG Group 0.927 0.908 NTG and ED-NTG groups respect to no-NTG Group are presented in the (0.804–1.070) (0.785–1.050) Table 2. Remarkably, we observed that preED-NTG patients persisted preED-NTG Group 1.043 0.988 (0.804–1.354) (0.758–1.288) with a lower risk of 365-day mortality than controls even after adjust­ 30-day all-cause mortality (HR) ment for differences in baseline characteristics and severity of AHF No-NTG Group 1 (reference) 1 (reference) decompensation (HR = 0.692, 95%CI = 0.551–0.869), as well as with a ED-NTG Group 1.016 0.980 lower risk for 90-day post-discharge combined events (HR = 0.795, 95% (0.855–1.208) (0.819–1.174) preED-NTG Group 0.900 0.818 CI = 0.642–0.984). On the other hand, ED-NTG patients had a lower risk (0.639–1.268) (0.576–1.163) of 90-day post-discharge combined events (HR = 0.870, 95%CI = 365-day all-cause mortality (HR) 0.780–0.970). The five sensitivity analyses showed very similar results No-NTG Group 1 (reference) 1 (reference) for all these associations, although in a few cases statistical significance ED-NTG Group 0.938 0.929 disappeared (Supplementary Table). (0.842–1.045) (0.830–1.039) preED-NTG Group 0.759 0.692 Finally, the subgroup analysis of outcomes for preED-NTG and ED- (0.607–0.948) (0.551–0.869) NTG groups (respect to controls) showed that associations were not 90-day post-discharge combined affected by age (≥ or < 80 years), sex, presence of previous coronary endpoint (HR) artery disease or heart failure, or systolic blood pressure ≥ or < 120 No-NTG Group 1 (reference) 1 (reference) mmHg (Fig. 2). The only exception was the 90-day post-discharge ED-NTG Group 0.867 0.870 (0.779–0.966) (0.780–0.970) combined events for preED-NTG Group that was significantly lower if preED-NTG Group 0.814 0.795 patients had no previous history of heart failure. (0.659–1.004) (0.643–0.984) **Covariables included in the adjustment were sex, hypertension, diabetes 4. Discussion mellitus, coronary artery disease, atrial fibrillation, peripheral artery disease, chronic obstructive pulmonary disease, dementia, previous episodes of acute We found that early starting of IV NTG treatment by EMS was heart failure, left ventricular ejection fraction, chronic treatment with renin- associated with long-term survival of patients with AHF compared with angiotensin system inhibitors and beta-blockers, and MEESSI-AHF risk score. patients in whom IV NTG was not used. In addition, post-discharge Age, Barthel index and NYHA class at baseline were not included as covariates as adverse events among patients who are discharged alive after decom­ they form part of the MEESS-AHFI risk score. pensation are also lower in those administered IV NTG by EMS. For **Prolonged hospitalization (>7 days) was only calculated for hospitalized pa­ patients in whom IV NTG was started in the ED, similar association with tients (i.e., patients directly discharged from the emergency department were not taken into account) who survived to hospitalization (i.e., patients experi­ post-discharge events was observed, although there was no association encing in-hospital mortality were not taken into account). with survival. EMS: emergency medical service; ED: emergency department; NTG: nitroglyc­ These results have to be put in perspective with the currently erine; OR: odds ratio; HR: hazard ratio; CI: confidence interval. available data respect to nitrates use in patients with AHF. In fact, the Bold ORs/HRs denote statistical significance (p < 0.05). administration of IV nitrates to patients with AHF has been recom­ mended by some authorities and in the guidelines for treatment of AHF mellitus and coronary artery disease, peripheral vascular disease, but [2,3] despite lack of significant evidence. A Cochrane review published less atrial fibrillation, lung disease, valvular heart disease and previous in 2013 identified only four randomized controlled trials comparing admission for HF. Less were in NYHA class III/IV but their ejection nitrates with alternative interventions in the management of AHF [12] fraction as lower. Patients who received IV NTG were treated more with and there was no significant difference between nitrate vasodilator betablockers and RAS inhibitors but less by MRA. The majority of pa­ therapy and alternative interventions in the treatment of AHF, with tients were congestive (wet), and hypoperfusion (cold) was more regard to symptom relief and haemodynamic variables. None of them frequently observed in patients treated with IV NTG. Pulmonary reported significant changes in mortality rates. A latter report that congestion was also more severe in patients receiving IV NTG. Similarly, analyzed the impact of NTG administration in the ED to patients with these patients had higher systolic blood pressure and lower pulse- AHF also did not observe any association with short-term survival [13]. oxymetry at ED arrival. Importantly, the MEESSI score, a well vali­ Very recently, to assess the importance of vasodilator therapy in the dated prognostic score for patients admitted to the ED with AHF [5,6], management of AHF, the GALACTIC study has been conducted [4]. In was worst in patients who received IV NTG, and especially worst in this study 781 patients with AHF were randomized to early intensive and preED-NTG Group. sustained vasodilatation versus standard of care during hospitalization. In-hospital mortality was observed in 845 patients (10.0%). In- Both groups received loop diuretics, beta-blockers, aldosterone antag­ hospital mortality in preED-NTG Group (24 deaths, 8.2%) was not sta­ onists, cardiac devices, and routine follow-up. The primary outcome, tistically different from no-NTG Group (689 deaths, 9.9%; p = 0.413), death or AHF rehospitalization at 180 days, occurred at a similar fre­ and the same was observed for in-hospital mortality in ED-NTG group quency between groups (hazard ratio 1.07, p = 0.59). No benefits were (132 deaths, 11.4%; p = 0.127). Among patients that were hospitalized seen in any of the other secondary study endpoints. However, in the and survived to the index AHF episode, prolonged hospitalization was GALACTIC study, nitrates were not administered IV and there was no observed in 48.1% of cases, with no differences between control group substantial difference in blood pressure between the two arms in the first (48.3%) and preED-NTG group (49.4%, p = 0.752) and ED-NTG group day suggesting that the doses of nitrates administered may have not induced the early desired vasodilation. As suggested in our original 131 Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 Fig. 2. Analysis of subgroups and interaction in the fully adjusted model (by baseline characteristics* and MEESSI score) for the association between the admin­ istration of intravenous nitroglycerin by emergency medical services (preED-NTG Group) and by emergency physicians at the emergency department (ED-NTG Group) and outcomes for which significant differences among groups had been found in the analysis of the whole cohort. *Baseline covariables included in the adjustment were sex, hypertension, diabetes mellitus, ischemic cardiomyopathy, atrial fibrillation, peripheral artery disease, chronic obstructive pulmonary disease, dementia, previous episodes of acute heart failure, left ventricular ejection fraction, and chronic treatment with renin- angiotensin system inhibitors and beta-blockers. Age, Barthel index and NYHA class at baseline were not included as covariates as they form part of the MEESSI risk score. Bold p values denote statistical significance (p < 0.05). manuscript proposing nitrated of treatment in AHF [1], nitrates have hospital mortality of 0.724; HR for 30-day mortality of 0.818), this different effects at high and low doses [14]. At low doses, nitrates induce benefits only achieved statistical significance in the long term (HR for only venodilatation, while at higher doses, they induce arterial dilata­ 365-day mortality of 0.691; HR for 90-day post-discharge adverse events tion. Therefore, early administration of high dose of nitrates is likely to of 0.795). This could be due to lack of power for early events in this induce significant afterload reduction, while lower doses administered exploratory study, as the number of patients included in the preED-NTG over time would induce mostly preload reduction, very different effects. Group was small (292). The question of why an early administration of Furthermore, administration of IV nitrates for more than a few hours therapy in the first few hours of presentation would affect decrease in would likely result in tachyphylaxis [15,16]. Hence, the strategies uti­ events, especially mortality over the long run, has not be adequately lized in our initial study [1] and that investigated in the GALACTIC trial answered. Some authors have indeed doubted whether such an outcome [4] were very different. None of the above commented studies evaluated is even possible. However, the current analysis is in line with other the role of early administration of NTG, during the prehospital man­ studies showing longer term mortality benefit or potential benefits from agement. Our results suggest that early administration of IV nitrates may early administration of IV interventions in AHF. Such example includes be of value, and especially in the prehospital arena. the mortality benefit seen with IV serelaxin [21,22] and a recent study Our results are in line with previous studies emphasizing the examining a short term intervention relaying on higher doses of IV ni­ importance of the EMS in the very early treatment of AHF de­ trates in which, despite showing no effect on the primary endpoint, has compensations. A Japanese study reported that transportation time of seen trends towards longer-term mortality benefit in the active arm AHF patients by EMS correlated with risk-adjusted mortality [17], and [23]. The mechanism for such a benefit, if such a benefit indeed exists, the SEMICA-2 study reported that AHF that have received high-intensity are not known, although some authors suggested that early IV admin­ prehospital treatment by EMS teams have a better short-term outcome, istration of some therapies in AHF may reduce the end organ damage especially during the first 7 days [18]. However, the use of EMS and the caused during the first hours of an AHF event and by that affect longer administration of prehospital medication by EMS are low in patients term outcome, due to preservation of longer term organ function [24]. with AHF [19]. A recent international survey involving 104 EMS teams from 18 countries showed that difficulty of diagnosing AHF at scene 4.1. Limitations could be an issue in starting specific medication, as it seems to be moderate compared with other pre-hospital conditions [20]. Addition­ First, as in every observational study, causal relationships cannot be ally, although the prevalence of AHF protocols in EMS is rather high, the inferred. Therefore, the results of the current analysis are limited by the contents seem to vary from country to country; of note, among thera­ retrospective design and therefore the potential bias by indication. peutic actions included in the protocol, the use of IV NTG was the less Similarly, we some key data that could help to better understand the frequent, only present in 57% of protocols, in front of the 93% of sup­ effects of early administration of IV NTG were not recorded, like plementary oxygen, 81% of non-invasive ventilation, or 69% of intra­ response of systolic blood pressure to vasodilator initiation, sequential venous furosemide and opiates [20]. Our results suggest that although assessment of dyspnea or creatinine to identify patients with worsening beneficial effects seem to be present from the beginning (OR for in- heart failure or renal failure, or relevant outcomes as need of intensive 132 Ò. Miró et al. International Journal of Cardiology 344 (2021) 127–134 care. However, as seen in Table 1, patients administered IV nitrates in References the prehospital phase were at higher risk of adverse outcome as measured by higher MEESSI score. Second, the preED-NTG Group was [1] G. Cotter, E. Metzkor, E. Kaluski, Z. Faigenberg, R. Miller, A. Simovitz, O. Shaham, D. Marghitay, M. Koren, A. Blatt, Y. Moshkovitz, R. Zaidenstein, A. Golik, quite limited in size. 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Cardozo, G. Suñén-Cuquerella, B. Alarcón, S. Herrera-Mateo, J.C. Ruibal, A. Alquézar-Arbé, This study was partially supported by grants from the Instituto de V. Gil, R. Donea, M. Berenguer, P. Llorens, B. Villanueva-Cutillas, F.J. Martín- Salud Carlos III supported with funds from the Spanish Ministry of Sánchez, P. Herrero, Ò. Miró, Worsening renal function during an episode of acute heart failure and its relation to short- and long-term mortality: associated factors in Health and FEDER (PI15/01019, PI15/00773, PI18/00393, PI18/ the Epidemiology of Acute heart Failure in Emergency Departments– Worsening 00456) and Fundació La Marató de TV3 (2015/2510). The “Emergen­ Renal Function study, Emergencias 32 (2020) 332–339. cies: Processes and Pathologies” research group of the IDIBAPS receives [10] Ho KKL, K.M. Anderson, W.B. Kannel, W. Grosssman, D. 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