Time for Reactive System Modeling

Reactive systems interact with their environment by reading inputs and computing and feeding back outputs in reactive cycles that are also called ticks. Often they are safety critical systems and are increasingly modeled with highlevel modeling tools. The concepts of the corresponding modeling languages are typically aimed to facilitate formal reasoning about program constructiveness to guarantee deterministic output and are explicitly abstracted from execution time aspects. Nevertheless, the worst-case execution time of a tick can be a crucial value, where exceedance can lead to lost inputs or tardy reaction to critical events. This thesis proposes a general approach to interactive timing analysis, which enables the feedback of detailed timing values directly in the model representation to support timing aware modeling. The concept is based on a generic timing interface that enables the exchangeability of the modeling as well as the timing analysis tool for the flexible implementation of varying tool chains. The proposed timing analysis approach includes visual highlighting and modeling pragmatics features to guide the user to timing hotspots for timing related model revisions

Denotational Fixed-Point Semantics for Constructive Scheduling of Synchronous Concurrency

The synchronous model of concurrent computation (SMoCC) is well established for programming languages in the domain of safety-critical reactive and embedded systems. Translated into mainstream C/Java programming, the SMoCC corresponds to a cyclic execution model in which concurrent threads are synchronised on a logical clock that cuts system computation into a sequence of macro-steps. A causality analysis verifies the existence of a schedule on memory accesses to ensure each macro-step is deadlock-free and determinate. We introduce an abstract semantic domain I(D, P) and an associated denotational fixed point semantics for reasoning about concurrent and sequential variable accesses within a synchronous cycle-based model of computation. We use this domain for a new and extended behavioural definition of Berry’s causality analysis in terms of approximation intervals. The domain I(D, P) extends the domain I(D) from our previous work and fixes a mistake in the treatment of initialisations. Based on this fixed point semantics the notion of Input Berry-constructiveness (IBC) for synchronous programs is proposed. This new IBC class lies properly between strong (SBC) and normal Berry-constructiveness (BC) defined in previous work. SBC and BC are two ways to interpret the standard constructive semantics of synchronous programming, as exemplified by imperative SMoCC languages such as Esterel or Quartz. SBC is often too restrictive as it requires all variables to be initialised by the program. BC can be too permissive because it initialises all variables to a fixed value, by default. Where the initialisation happens through the memory, e.g., when carrying values from one synchronous tick to the next, then IBC is more appropriate. IBC links two levels of execution, the macro-step level and the micro-step level. We prove that the denotational fixed point analysis for IBC, and hence Berry’s causality analysis, is sound with respect to operational micro-level scheduling. The denotational model can thus be viewed as a compositional presentation of a synchronous scheduling strategy that ensures reactiveness and determinacy for imperative concurrent programming

Sequentially Constructive Concurrency: A Conservative Extension of the Synchronous Model of Computation

Synchronous languages ensure deterministic concurrency, but at the price of heavy restrictions on what programs are considered valid, or constructive. Meanwhile, sequential languages such as C and Java offer an intuitive, familiar programming paradigm but provide no guarantees with regard to deterministic concurrency. The sequentially constructive model of computation (SC MoC) presented here harnesses the synchronous execution model to achieve deterministic concurrency while addressing concerns that synchronous languages are unnecessarily restrictive and difficult to adopt. In essence, the SC MoC extends the classical synchronous MoC by allowing variables to be read and written in any order as long as sequentiality expressed in the program provides sufficient scheduling information to rule out race conditions. This allows to use programming patterns familiar from sequential programming, such as testing and later setting the value of a variable, which are forbidden in the standard synchronous MoC. The SC MoC is a conservative extension in that programs considered constructive in the common synchronous MoC are also SC and retain the same semantics. In this paper, we identify classes of variable accesses, define sequential constructiveness based on the concept of SC-admissible scheduling, and present a priority-based scheduling algorithm for analyzing and compiling SC programs

Sex- and age-related differences in the management and outcomes of chronic heart failure: an analysis of patients from the ESC HFA EORP Heart Failure Long-Term Registry

Aims: This study aimed to assess age- and sex-related differences in management and 1-year risk for all-cause mortality and hospitalization in chronic heart failure (HF) patients. Methods and results: Of 16 354 patients included in the European Society of Cardiology Heart Failure Long-Term Registry, 9428 chronic HF patients were analysed [median age: 66 years; 28.5% women; mean left ventricular ejection fraction (LVEF) 37%]. Rates of use of guideline-directed medical therapy (GDMT) were high (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, beta-blockers and mineralocorticoid receptor antagonists: 85.7%, 88.7% and 58.8%, respectively). Crude GDMT utilization rates were lower in women than in men (all differences: P\ua0 64 0.001), and GDMT use became lower with ageing in both sexes, at baseline and at 1-year follow-up. Sex was not an independent predictor of GDMT prescription; however, age >75 years was a significant predictor of GDMT underutilization. Rates of all-cause mortality were lower in women than in men (7.1% vs. 8.7%; P\ua0=\ua00.015), as were rates of all-cause hospitalization (21.9% vs. 27.3%; P\ua075 years. Conclusions: There was a decline in GDMT use with advanced age in both sexes. Sex was not an independent predictor of GDMT or adverse outcomes. However, age >75 years independently predicted lower GDMT use and higher all-cause mortality in patients with LVEF 6445%

Time for Reactive System Modeling : Interactive Timing Analysis with Hotspot Highlighting

Modeling tools typically provide no information about timing properties and costly parts of the system under development. In this paper we propose a generic approach to integrate timing analysis and modeling tools. This approach includes visual highlighting to guide the user to worst-case execution time hotspots, detailed timing information for specific model elements, and the separation of di↵erent types of timing val- ues. Our solution includes both a way to keep track of model elements subject to timing analysis during the compilation process, and a flexible and formally defined timing analysis interface for communicating timing information between a high-level modeling tool and a lower-level timing analysis tool. We present a complete open-source, Eclipse-based pro- totype tool chain that is evaluated both using a systematic benchmark suite and a user study. QC 20170124</p

Association between loop diuretic dose changes and outcomes in chronic heart failure: observations from the ESC-EORP Heart Failure Long-Term Registry

Aims: Guidelines recommend down-titration of loop diuretics (LD) once euvolaemia is achieved. In outpatients with heart failure (HF), we investigated LD dose changes in daily cardiology practice, agreement with guideline recommendations, predictors of successful LD down-titration and association between dose changes and outcomes. Methods and results: We included 8130 HF patients from the ESC-EORP Heart Failure Long-Term Registry. Among patients who had dose decreased, successful decrease was defined as the decrease not followed by death, HF hospitalization, New York Heart Association class deterioration, or subsequent increase in LD dose. Mean age was 66 ± 13 years, 71% men, 62% HF with reduced ejection fraction, 19% HF with mid-range ejection fraction, 19% HF with preserved ejection fraction. Median [interquartile range (IQR)] LD dose was 40 (25–80) mg. LD dose was increased in 16%, decreased in 8.3% and unchanged in 76%. Median (IQR) follow-up was 372 (363–419) days. Diuretic dose increase (vs. no change) was associated with HF death [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.12–2.08; P = 0.008] and nominally with cardiovascular death (HR 1.25, 95% CI 0.96–1.63; P = 0.103). Decrease of diuretic dose (vs. no change) was associated with nominally lower HF (HR 0.59, 95% CI 0.33–1.07; P = 0.083) and cardiovascular mortality (HR 0.62,. 95% CI 0.38–1.00; P = 0.052). Among patients who had LD dose decreased, systolic blood pressure [odds ratio (OR) 1.11 per 10 mmHg increase, 95% CI 1.01–1.22; P = 0.032], and absence of (i) sleep apnoea (OR 0.24, 95% CI 0.09–0.69; P = 0.008), (ii) peripheral congestion (OR 0.48, 95% CI 0.29–0.80; P = 0.005), and (iii) moderate/severe mitral regurgitation (OR 0.57, 95% CI 0.37–0.87; P = 0.008) were independently associated with successful decrease. Conclusion: Diuretic dose was unchanged in 76% and decreased in 8.3% of outpatients with chronic HF. LD dose increase was associated with worse outcomes, while the LD dose decrease group showed a trend for better outcomes compared with the no-change group. Higher systolic blood pressure, and absence of (i) sleep apnoea, (ii) peripheral congestion, and (iii) moderate/severe mitral regurgitation were independently associated with successful dose decrease. © 2020 European Society of Cardiolog

Acute heart failure congestion and perfusion status – impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry

Aims: Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. Methods and results: We included 7865 AHF patients classified at admission as: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), ‘wet-cold’ (19.8%) and ‘dry-cold’ (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in ‘dry-warm’, 3.8% in ‘wet-warm’, 9.1% in ‘dry-cold’ and 12.1% in ‘wet-cold’ patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.78 (1.43–2.21) and ‘wet-cold’ vs. ‘wet-warm’ 1.33 (1.19–1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.46 (1.31–1.63) and ‘wet-cold’ vs. ‘wet-warm’ 2.20 (1.89–2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. Conclusion: Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes. © 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiolog

Acute heart failure congestion and perfusion status – impact of the clinical classification on in-hospital and long-term outcomes; insights from the ESC-EORP-HFA Heart Failure Long-Term Registry

none614siAims: Classification of acute heart failure (AHF) patients into four clinical profiles defined by evidence of congestion and perfusion is advocated by the 2016 European Society of Cardiology (ESC)guidelines. Based on the ESC-EORP-HFA Heart Failure Long-Term Registry, we compared differences in baseline characteristics, in-hospital management and outcomes among congestion/perfusion profiles using this classification. Methods and results: We included 7865 AHF patients classified at admission as: ‘dry-warm’ (9.9%), ‘wet-warm’ (69.9%), ‘wet-cold’ (19.8%) and ‘dry-cold’ (0.4%). These groups differed significantly in terms of baseline characteristics, in-hospital management and outcomes. In-hospital mortality was 2.0% in ‘dry-warm’, 3.8% in ‘wet-warm’, 9.1% in ‘dry-cold’ and 12.1% in ‘wet-cold’ patients. Based on clinical classification at admission, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.78 (1.43–2.21) and ‘wet-cold’ vs. ‘wet-warm’ 1.33 (1.19–1.48). For profiles resulting from discharge classification, the adjusted hazard ratios (95% confidence interval) for 1-year mortality were: ‘wet-warm’ vs. ‘dry-warm’ 1.46 (1.31–1.63) and ‘wet-cold’ vs. ‘wet-warm’ 2.20 (1.89–2.56). Among patients discharged alive, 30.9% had residual congestion, and these patients had higher 1-year mortality compared to patients discharged without congestion (28.0 vs. 18.5%). Tricuspid regurgitation, diabetes, anaemia and high New York Heart Association class were independently associated with higher risk of congestion at discharge, while beta-blockers at admission, de novo heart failure, or any cardiovascular procedure during hospitalization were associated with lower risk of residual congestion. Conclusion: Classification based on congestion/perfusion status provides clinically relevant information at hospital admission and discharge. A better understanding of the clinical course of the two entities could play an important role towards the implementation of targeted strategies that may improve outcomes.noneChioncel O.; Mebazaa A.; Maggioni A.P.; Harjola V.-P.; Rosano G.; Laroche C.; Piepoli M.F.; Crespo-Leiro M.G.; Lainscak M.; Ponikowski P.; Filippatos G.; Ruschitzka F.; Seferovic P.; Coats A.J.S.; Lund L.H.; Auer J.; Ablasser K.; Fruhwald F.; Dolze T.; Brandner K.; Gstrein S.; Poelzl G.; Moertl D.; Reiter S.; Podczeck-Schweighofer A.; Muslibegovic A.; Vasilj M.; Fazlibegovic E.; Cesko M.; Zelenika D.; Palic B.; Pravdic D.; Cuk D.; Vitlianova K.; Katova T.; Velikov T.; Kurteva T.; Gatzov P.; Kamenova D.; Antova M.; Sirakova V.; Krejci J.; Mikolaskova M.; Spinar J.; Krupicka J.; Malek F.; Hegarova M.; Lazarova M.; Monhart Z.; Hassanein M.; Sobhy M.; El Messiry F.; El Shazly A.H.; Elrakshy Y.; Youssef A.; Moneim A.A.; Noamany M.; Reda A.; Dayem T.K.A.; Farag N.; Halawa S.I.; Hamid M.A.; Said K.; Saleh A.; Ebeid H.; Hanna R.; Aziz R.; Louis O.; Enen M.A.; Ibrahim B.S.; Nasr G.; Elbahry A.; Sobhy H.; Ashmawy M.; Gouda M.; Aboleineen W.; Bernard Y.; Luporsi P.; Meneveau N.; Pillot M.; Morel M.; Seronde M.-F.; Schiele F.; Briand F.; Delahaye F.; Damy T.; Eicher J.-C.; de Groote P.; Fertin M.; Lamblin N.; Isnard R.; Lefol C.; Thevenin S.; Hagege A.; Jondeau G.; Logeart D.; Le Marcis V.; Ly J.-F.; Coisne D.; Lequeux B.; Le Moal V.; Mascle S.; Lotton P.; Behar N.; Donal E.; Thebault C.; Ridard C.; Reynaud A.; Basquin A.; Bauer F.; Codjia R.; Galinier M.; Tourikis P.; Stavroula M.; Tousoulis D.; Stefanadis C.; Chrysohoou C.; Kotrogiannis I.; Matzaraki V.; Dimitroula T.; Karavidas A.; Tsitsinakis G.; Kapelios C.; Nanas J.; Kampouri H.; Nana E.; Kaldara E.; Eugenidou A.; Vardas P.; Saloustros I.; Patrianakos A.; Tsaknakis T.; Evangelou S.; Nikoloulis N.; Tziourganou H.; Tsaroucha A.; Papadopoulou A.; Douras A.; Polgar L.; Merkely B.; Kosztin A.; Nyolczas N.; Nagy A.C.; Halmosi R.; Elber J.; Alony I.; Shotan A.; Fuhrmann A.V.; Amir O.; Romano S.; Marcon S.; Penco M.; Di Mauro M.; Lemme E.; Carubelli V.; Rovetta R.; Metra M.; Bulgari M.; Quinzani F.; Lombardi C.; Bosi S.; Schiavina G.; Squeri A.; Barbieri A.; Di Tano G.; Pirelli S.; Ferrari R.; Fucili A.; Passero T.; Musio S.; Di Biase M.; Correale M.; Salvemini G.; Brognoli S.; Zanelli E.; Giordano A.; Agostoni P.; Italiano G.; Salvioni E.; Copelli S.; Modena M.G.; Reggianini L.; Valenti C.; Olaru A.; Bandino S.; Deidda M.; Mercuro G.; Dessalvi C.C.; Marino P.N.; Di Ruocco M.V.; Sartori C.; Piccinino C.; Parrinello G.; Licata G.; Torres D.; Giambanco S.; Busalacchi S.; Arrotti S.; Novo S.; Inciardi R.M.; Pieri P.; Chirco P.R.; Galifi M.A.; Teresi G.; Buccheri D.; Minacapelli A.; Veniani M.; Frisinghelli A.; Priori S.G.; Cattaneo S.; Opasich C.; Gualco A.; Pagliaro M.; Mancone M.; Fedele F.; Cinque A.; Vellini M.; Scarfo I.; Romeo F.; Ferraiuolo F.; Sergi D.; Anselmi M.; Melandri F.; Leci E.; Iori E.; Bovolo V.; Pidello S.; Frea S.; Bergerone S.; Botta M.; Canavosio F.G.; Gaita F.; Merlo M.; Cinquetti M.; Sinagra G.; Ramani F.; Fabris E.; Stolfo D.; Artico J.; Miani D.; Fresco C.; Daneluzzi C.; Proclemer A.; Cicoira M.; Zanolla L.; Marchese G.; Torelli F.; Vassanelli C.; Voronina N.; Erglis A.; Tamakauskas V.; Smalinskas V.; Karaliute R.; Petraskiene I.; Kazakauskaite E.; Rumbinaite E.; Kavoliuniene A.; Vysniauskas V.; Brazyte-Ramanauskiene R.; Petraskiene D.; Stankala S.; Switala P.; Juszczyk Z.; Sinkiewicz W.; Gilewski W.; Pietrzak J.; Orzel T.; Kasztelowicz P.; Kardaszewicz P.; Lazorko-Piega M.; Gabryel J.; Mosakowska K.; Bellwon J.; Rynkiewicz A.; Raczak G.; Lewicka E.; Dabrowska-Kugacka A.; Bartkowiak R.; Sosnowska-Pasiarska B.; Wozakowska-Kaplon B.; Krzeminski A.; Zabojszcz M.; Mirek-Bryniarska E.; Grzegorzko A.; Bury K.; Nessler J.; Zalewski J.; Furman A.; Broncel M.; Poliwczak A.; Bala A.; Zycinski P.; Rudzinska M.; Jankowski L.; Kasprzak J.D.; Michalak L.; Soska K.W.; Drozdz J.; Huziuk I.; Retwinski A.; Flis P.; Weglarz J.; Bodys A.; Grajek S.; 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Kleinrok A.; Aguiar C.T.; Ventosa A.; Pereira S.; Faria R.; Chin J.; De Jesus I.; Santos R.; Silva P.; Moreno N.; Queiros C.; Lourenco C.; Pereira A.; Castro A.; Andrade A.; Guimaraes T.O.; Martins S.; Placido R.; Lima G.; Brito D.; Francisco A.R.; Cardiga R.; Proenca M.; Araujo I.; Marques F.; Fonseca C.; Moura B.; Leite S.; Campelo M.; Silva-Cardoso J.; Rodrigues J.; Rangel I.; Martins E.; Correia A.S.; Peres M.; Marta L.; da Silva G.F.; Severino D.; Durao D.; Leao S.; Magalhaes P.; Moreira I.; Cordeiro A.F.; Ferreira C.; Araujo C.; Ferreira A.; Baptista A.; Radoi M.; Bicescu G.; Vinereanu D.; Sinescu C.-J.; Macarie C.; Popescu R.; Daha I.; Dan G.-A.; Stanescu C.; Dan A.; Craiu E.; Nechita E.; Aursulesei V.; Christodorescu R.; Otasevic P.; Seferovic P.M.; Simeunovic D.; Ristic A.D.; Celic V.; Pavlovic-Kleut M.; Lazic J.S.; Stojcevski B.; Pencic B.; Stevanovic A.; Andric A.; Iric-Cupic V.; Jovic M.; Davidovic G.; Milanov S.; Mitic V.; Atanaskovic V.; Antic S.; Pavlovic M.; Stanojevic D.; Stoickov V.; Ilic S.; Ilic M.D.; Petrovic D.; Stojsic S.; Kecojevic S.; Dodic S.; Adic N.C.; Cankovic M.; Stojiljkovic J.; Mihajlovic B.; Radin A.; Radovanovic S.; Krotin M.; Klabnik A.; Goncalvesova E.; Pernicky M.; Murin J.; Kovar F.; Kmec J.; Semjanova H.; Strasek M.; Iskra M.S.; Ravnikar T.; Suligoj N.C.; Komel J.; Fras Z.; Jug B.; Glavic T.; Losic R.; Bombek M.; Krajnc I.; Krunic B.; Horvat S.; Kovac D.; Rajtman D.; Cencic V.; Letonja M.; Winkler R.; Valentincic M.; Melihen-Bartolic C.; Bartolic A.; Vrckovnik M.P.; Kladnik M.; Pusnik C.S.; Marolt A.; Klen J.; Drnovsek B.; Leskovar B.; Anguita M.J.F.; Page J.C.G.; Martinez F.M.S.; Andres J.; Bayes-Genis A.; Mirabet S.; Mendez A.; Garcia-Cosio L.; Roig E.; Leon V.; Gonzalez-Costello J.; Muntane G.; Garay A.; Alcade-Martinez V.; Fernandez S.L.; Rivera-Lopez R.; Puga-Martinez M.; Fernandez-Alvarez M.; Serrano-Martinez J.L.; Crespo-Leiro M.; Grille-Cancela Z.; Marzoa-Rivas R.; Blanco-Canosa P.; Paniagua-Martin M.J.; Barge-Caballero E.; Cerdena I.L.; Baldomero I.F.H.; Padron A.L.; Rosillo S.O.; Gonzalez-Gallarza R.D.; Montanes O.S.; Manjavacas A.M.I.; Conde A.C.; Araujo A.; Soria T.; Garcia-Pavia P.; Gomez-Bueno M.; Cobo-Marcos M.; Alonso-Pulpon L.; Cubero J.S.; Sayago I.; Gonzalez-Segovia A.; Briceno A.; Subias P.E.; Hernandez M.V.; Cano M.J.R.; Sanchez M.A.G.; Jimenez J.F.D.; Garrido-Lestache E.B.; Pinilla J.M.G.; de la Villa B.G.; Sahuquillo A.; Marques R.B.; Calvo F.T.; Perez-Martinez M.T.; Gracia-Rodenas M.R.; Garrido-Bravo I.P.; Pastor-Perez F.; Pascual-Figal D.A.; Molina B.D.; Orus J.; Gonzalo F.E.; Bertomeu V.; Valero R.; Martinez-Abellan R.; Quiles J.; Rodrigez-Ortega J.A.; Mateo I.; ElAmrani A.; Fernandez-Vivancos C.; Valero D.B.; Almenar-Bonet L.; Sanchez-Lazaro I.J.; Marques-Sule E.; Facila-Rubio L.; Perez-Silvestre J.; Garcia-Gonzalez P.; Ridocci-Soriano F.; Garcia-Escriva D.; Pellicer-Cabo A.; de la Fuente Galan L.; Diaz J.L.; Platero A.R.; Arias J.C.; Blasco-Peiro T.; Julve M.S.; Sanchez-Insa E.; Aured-Guallar C.; Portoles-Ocampo A.; Melin M.; Hagglund E.; Stenberg A.; Lindahl I.-M.; Asserlund B.; Olsson L.; Dahlstrom U.; Afzelius M.; Karlstrom P.; Tengvall L.; Wiklund P.-A.; Olsson B.; Kalayci S.; Temizhan A.; Cavusoglu Y.; Gencer E.; Yilmaz M.B.; Gunes H.Chioncel, O.; Mebazaa, A.; Maggioni, A. P.; Harjola, V. -P.; Rosano, G.; Laroche, C.; Piepoli, M. F.; Crespo-Leiro, M. G.; Lainscak, M.; Ponikowski, P.; Filippatos, G.; Ruschitzka, F.; Seferovic, P.; Coats, A. J. S.; Lund, L. H.; Auer, J.; Ablasser, K.; Fruhwald, F.; Dolze, T.; Brandner, K.; Gstrein, S.; Poelzl, G.; Moertl, D.; Reiter, S.; Podczeck-Schweighofer, A.; Muslibegovic, A.; Vasilj, M.; Fazlibegovic, E.; Cesko, M.; Zelenika, D.; Palic, B.; Pravdic, D.; Cuk, D.; Vitlianova, K.; Katova, T.; Velikov, T.; Kurteva, T.; Gatzov, P.; Kamenova, D.; Antova, M.; Sirakova, V.; Krejci, J.; Mikolaskova, M.; Spinar, J.; Krupicka, J.; Malek, F.; Hegarova, M.; Lazarova, M.; Monhart, Z.; Hassanein, M.; Sobhy, M.; El Messiry, F.; El Shazly, A. H.; Elrakshy, Y.; Youssef, A.; Moneim, A. A.; Noamany, M.; Reda, A.; Dayem, T. K. A.; Farag, N.; Halawa, S. I.; Hamid, M. A.; Said, K.; Saleh, A.; Ebeid, H.; Hanna, R.; Aziz, R.; Louis, O.; Enen, M. A.; Ibrahim, B. S.; Nasr, G.; Elbahry, A.; Sobhy, H.; Ashmawy, M.; Gouda, M.; Aboleineen, W.; Bernard, Y.; Luporsi, P.; Meneveau, N.; Pillot, M.; Morel, M.; Seronde, M. -F.; Schiele, F.; Briand, F.; Delahaye, F.; Damy, T.; Eicher, J. -C.; de Groote, P.; Fertin, M.; Lamblin, N.; Isnard, R.; Lefol, C.; Thevenin, S.; Hagege, A.; Jondeau, G.; Logeart, D.; Le Marcis, V.; Ly, J. -F.; Coisne, D.; Lequeux, B.; Le Moal, V.; Mascle, S.; Lotton, P.; Behar, N.; Donal, E.; Thebault, C.; Ridard, C.; Reynaud, A.; Basquin, A.; Bauer, F.; Codjia, R.; Galinier, M.; Tourikis, P.; Stavroula, M.; Tousoulis, D.; Stefanadis, C.; Chrysohoou, C.; Kotrogiannis, I.; Matzaraki, V.; Dimitroula, T.; Karavidas, A.; Tsitsinakis, G.; Kapelios, C.; Nanas, J.; Kampouri, H.; Nana, E.; Kaldara, E.; Eugenidou, A.; Vardas, P.; Saloustros, I.; Patrianakos, A.; Tsaknakis, T.; Evangelou, S.; Nikoloulis, N.; Tziourganou, H.; Tsaroucha, A.; Papadopoulou, A.; Douras, A.; Polgar, L.; Merkely, B.; Kosztin, A.; Nyolczas, N.; Nagy, A. C.; Halmosi, R.; Elber, J.; Alony, I.; Shotan, A.; Fuhrmann, A. V.; Amir, O.; Romano, S.; Marcon, S.; Penco, M.; Di Mauro, M.; Lemme, E.; Carubelli, V.; Rovetta, R.; Metra, M.; Bulgari, M.; Quinzani, F.; Lombardi, C.; Bosi, S.; Schiavina, G.; Squeri, A.; Barbieri, A.; Di Tano, G.; Pirelli, S.; Ferrari, R.; Fucili, A.; Passero, T.; Musio, S.; Di Biase, M.; Correale, M.; Salvemini, G.; Brognoli, S.; Zanelli, E.; Giordano, A.; Agostoni, P.; Italiano, G.; Salvioni, E.; Copelli, S.; Modena, M. G.; Reggianini, L.; Valenti, C.; Olaru, A.; Bandino, S.; Deidda, M.; Mercuro, G.; Dessalvi, C. C.; Marino, P. N.; Di Ruocco, M. V.; Sartori, C.; Piccinino, C.; Parrinello, G.; Licata, G.; Torres, D.; Giambanco, S.; Busalacchi, S.; Arrotti, S.; Novo, S.; Inciardi, R. M.; Pieri, P.; Chirco, P. R.; Galifi, M. A.; Teresi, G.; Buccheri, D.; Minacapelli, A.; Veniani, M.; Frisinghelli, A.; Priori, S. G.; Cattaneo, S.; Opasich, C.; Gualco, A.; Pagliaro, M.; Mancone, M.; Fedele, F.; Cinque, A.; Vellini, M.; Scarfo, I.; Romeo, F.; Ferraiuolo, F.; Sergi, D.; Anselmi, M.; Melandri, F.; Leci, E.; Iori, E.; Bovolo, V.; Pidello, S.; Frea, S.; Bergerone, S.; Botta, M.; Canavosio, F. 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Sacubitril/valsartan eligibility and outcomes in the ESC-EORP-HFA Heart Failure Long-Term Registry: bridging between European Medicines Agency/Food and Drug Administration label, the PARADIGM-HF trial, ESC guidelines, and real world

Aims: To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM-HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes. Methods and results: Outpatients with HFrEF in the ESC-EORP-HFA Long-Term Heart Failure (HF-LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM-HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM-HF and guideline criteria, respectively. Absent PARADIGM-HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub-optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%). and sub-optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM-HF and guidelines. One-year heart failure hospitalization was higher (12% and 17% vs. 12%) and all-cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM-HF. Conclusions: Among outpatients with HFrEF in the ESC-EORP-HFA HF-LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM-HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM-HF enalapril group