Both acute and advanced heart failure are an increasing threat in term of survival, quality of life and socio-economical burdens. Paradoxically, the use of successful treatments for chronic heart failure can prolong life but-per definition-causes the rise in age of patients experiencing acute decompensations, since nothing at the moment helps avoiding an acute or final stage in the elderly population. To complicate the picture, acute heart failure syndromes are a collection of symptoms, signs and markers, with different aetiologies and different courses, also due to overlapping morbidities and to the plethora of chronic medications. The palette of cardio- and vasoactive drugs used in the hospitalization phase to stabilize the patient's hemodynamic is scarce and even scarcer is the evidence for the agents commonly used in the practice (e.g. catecholamines). The pipeline in this field is poor and the clinical development chronically unsuccessful. Recent set backs in expected clinical trials for new agents in acute heart failure (AHF) (omecamtiv, serelaxine, ularitide) left a field desolately empty, where only few drugs have been approved for clinical use, for example, levosimendan and nesiritide. In this consensus opinion paper, experts from 26 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Israel, Italy, The Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, Turkey, U.K. and Ukraine) analyse the situation in details also by help of artificial intelligence applied to bibliographic searches, try to distil some lesson-learned to avoid that future projects would make the same mistakes as in the past and recommend how to lead a successful development project in this field in dire need of new agents.

Advanced Heart Failure and Transplantation Center Department of Cardiology Ljubljana University Medical Center SI 1000 Ljubljana Slovenia

Critical Care Orion Pharma 02101 Espoo Finland

Department of Anaesthesiology and Critical Care Medicine AP HP Saint Louis and Lariboisière University Hospitals Université de Paris and INSERM UMR S 942 MASCOT 75010 Paris France

Department of Anesthesiology and Intensive Care Medicine University of Lübeck 23562 Lübeck Germany

Department of Anesthesiology Perioperative Medicine and Intensive Care Masaryk Hospital J E Purkinje University 400 96 Usti nad Labem Czech Republic

Department of Anesthesiology Reanimatology and Intensive Care University Hospital Centre 10000 Zagreb Croatia

Department of Cardiac Intensive Care Petrovskii National Research Centre of Surgery Sechenov University 119146 Moscow Russia

Department of Cardiology and Internal Medicine Nicolaus Copernicus University 87 100 Torun Poland

Department of Cardiology Århus University Hospital 8200 Århus Denmark

Department of Cardiology Dokuz Eylul University Faculty of Medicine 35340 Izmir Turkey

Department of Cardiology Medical School University of Cyprus 1678 Nicosia Cyprus

Department of Cardiology North Estonia Medical Center 13419 Tallinn Estonia

Department of Cardiology Oslo University Hospital Ullevaal 0372 Oslo Norway

Department of Cardiovascular Respiratory Nephrology Anesthesiology and Geriatric Sciences 'La Sapienza' University of Rome 00185 Rome Italy

Department of Intensive Care Experimental Laboratory of Intensive Care Erasme Hospital Université Libre de Bruxelles 1050 Bruxelles Belgium

Department of Intensive Care Medicine Amsterdam UMC location VUmc 081 HV The Netherlands

Department of Internal Medicine 3 Cardiology and Angiology Medical University of Innsbruck 6020 Innsbruck Austria

Division of Clinical Physiology Department of Cardiology Faculty of Medicine University of Debrecen H 4032 Debrecen Hungary

Emergency Cardiology Department National Scientific Center M D Strazhesko Institute of Cardiology 02000 Kiev Ukraine

Emergency Department Attikon University Hospital National and Kapodistrian University of Athens 157 72 Athens Greece

Emergency Medicine Department of Emergency Medicine and Services Helsinki University Hospital University of Helsinki 00014 Helsinki Finland

HAS UD Vascular Biology and Myocardial Pathophysiology Research Group Hungarian Academy of Sciences 4001 Debrecen Hungary

Heart Diseases Institute Hospital Universitari de Bellvitge 08015 Barcelona Spain

Heart Failure Clinic of S Francisco Xavier Hospital CHLO 1449 005 Lisbon Portugal

Heart Failure Unit Rabin Medical Center Tel Aviv University Petah Tikva 4941492d Israel

Institute of Anaesthesiology University Hospital of Zurich University of Zurich 8091 Zurich Switzerland

Intensive Care Unit National Health Service Leeds LS2 9JT UK

Transplant Institute Sahlgrenska University Hospital 413 45 Gothenburg Sweden

Zobrazit více v PubMed

Machaj F., Dembowska E., Rosik J., Szostak B., Mazurek-Mochol M., Pawlik A. New therapies for the treatment of heart failure: A summary of recent accomplishments. Clin. Risk Manag. 2019;15:147–155. doi: 10.2147/TCRM.S179302. PubMed DOI PMC

Hamo C.E., Butler J., Gheorghiade M., Chioncel O. The bumpy road to drug development for acute heart failure. Eur. Heart J. Suppl. 2016;18:G19–G32. doi: 10.1093/eurheartj/suw045. DOI

Tamargo J., Caballero R., Delpón E. New drugs in preclinical and early stage clinical development in the treatment of heart failure. Expert Opin. Investig. Drugs. 2019;28:51–71. doi: 10.1080/13543784.2019.1551357. PubMed DOI

Rame J.E. Introduction to topical collection on updates in advanced heart failure. Curr. Heart Fail. Rep. 2019 doi: 10.1007/s11897-019-00439-w. PubMed DOI

Pollesello P. Drug discovery and development for acute heart failure drugs: Are expectations too high? Int. J. Cardiol. 2014;172:11–13. doi: 10.1016/j.ijcard.2013.12.136. PubMed DOI

Farmakis D., Simitsis P., Bistola V., Triposkiadis F., Ikonomidis I., Katsanos S., Bakosis G., Hatziagelaki E., Lekakis J., Mebazaa A., et al. Acute heart failure with mid-range left ventricular ejection fraction: Clinical profile, in-hospital management, and short-term outcome. Clin. Res. Cardiol. 2017;106:359–368. doi: 10.1007/s00392-016-1063-0. PubMed DOI

Packer M., Colucci W., Fisher L., Massie B.M., Teerlink J.R., Young J., Padley R.J., Thakkar R., Delgado-Herrera L., Salon J., et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail. 2013;1:103–111. doi: 10.1016/j.jchf.2012.12.004. PubMed DOI

Metra M., Teerlink J.R., Felker G.M., Greenberg B.H., Filippatos G., Ponikowski P., Teichman S.L., Unemori E., Voors A.A., Weatherley B.D., et al. Dyspnoea and worsening heart failure in patients with acute heart failure: results from the Pre-RELAX-AHF study. Eur. J. Heart Fail. 2010;12:1130–1139. doi: 10.1093/eurjhf/hfq132. PubMed DOI PMC

Haikala H., Pollesello P. Calcium sensitivity enhancers. IDrugs. 2000;3:1199–1205. PubMed

Malik F.I., Hartman J.J., Elias K.A., Morgan B.P., Rodriguez H., Brejc K., Anderson R.L., Sueoka S.H., Lee K.H., Finer J.T., et al. Cardiac myosin activation: A potential therapeutic approach for systolic heart failure. Science. 2011;331:1439–1443. doi: 10.1126/science.1200113. PubMed DOI PMC

Teerlink J.R., Felker G.M., McMurray J.J.V., Ponikowski P., Metra M., Filippatos G.S., Ezekowitz J.A., Dickstein K., Cleland J.G.F., Kim J.B., et al. Acute treatment with omecamtiv mecarbil to increase contractility in acute heart failure. J. Am. Coll. Cardiol. 2016;67:1444–1455. doi: 10.1016/j.jacc.2016.01.031. PubMed DOI

Cleland J.G., Teerlink J.R., Senior R., Nifontov E.M., Mc Murray J.J., Lang C.C., Tsyrlin V.A., Greenberg B.H., Mayet J., Francis D.P., et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet. 2011;378:676–683. doi: 10.1016/S0140-6736(11)61126-4. PubMed DOI

Gouda P., Ezekowitz J.A. Update on the diagnosis and management of acute heart failure. Curr. Opin. Cardiol. 2019;34:202–206. doi: 10.1097/HCO.0000000000000594. PubMed DOI

Teerlink J.R., Cotter G., Davison B.A., Felker G.M., Filippatos G., Greenberg B.H., Ponikowski P., Unemori E., Voors A.A., Adams K.F., et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised, placebo-controlled trial. Lancet. 2013;381:29–39. doi: 10.1016/S0140-6736(12)61855-8. PubMed DOI

Metra M., Teerlink J.R., Cotter G., Davison B.A., Felker G.M., Filippatos G., Greenberg B.H., Pang P.S., Ponikowski P., Voors A.A., et al. Effects of serelaxin in patients with acute heart failure. N. Engl. J. Med. 2019;381:716–726. doi: 10.1056/NEJMoa1801291. PubMed DOI

Wang T.S., Hellkamp A.S., Patel C.B., Ezekowitz J.A., Fonarow G.C., Hernandez A.F. Representativeness of RELAX-AHF clinical trial population in acute heart failure. Circ. Cardiovasc. Qual. Outcomes. 2014;7:259–268. doi: 10.1161/CIRCOUTCOMES.113.000418. PubMed DOI

Maggioni A.P., López-Sendón J., Nielsen O.W., Hallén J., Aalamian-Mattheis M., Wang Y., Ertl G. Efficacy and safety of serelaxin when added to standard of care in patients with acute heart failure: Results from a PROBE study, RELAX-AHF-EU. Eur. J. Heart Fail. 2019;21:322–333. doi: 10.1002/ejhf.1368. PubMed DOI

Packer M., O’Connor C., McMurray J.J.V., Wittes J., Abraham W.T., Anker S.D., Dickstein K., Filippatos G., Holcomb R., Krum H., et al. Effect of ularitide on cardiovascular mortality in acute heart failure. N. Engl. J. Med. 2017;376:1956–1964. doi: 10.1056/NEJMoa1601895. PubMed DOI

Khan H., Metra M., Blair J.E.A., Vogel M., Harinstein M.E., Filippatos G.S., Sabbah H.N., Porchet H., Valentini G., Gheorghiade M. Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na–K-ATPase inhibition: A new promising treatment for acute heart failure syndromes? Heart Fail. Rev. 2009;14:277–287. doi: 10.1007/s10741-009-9136-z. PubMed DOI

Gheorghiade M., Blair J.E.A., Filippatos G.S., Macarie C., Ruzyllo W., Korewicki J., Bubenek-Turconi S.I., Ceracchi M., Bianchetti M., Carminati P., et al. Hemodynamic, echocardiographic, and neurohormonal effects of istaroxime, a novel intravenous inotropic and lusitropic agent. J. Am. Coll. Cardiol. 2008;51:2276–2285. doi: 10.1016/j.jacc.2008.03.015. PubMed DOI

NCT00616161, U.S. National Library of Medicine. [(accessed on 6 September 2019)]; Available online: https://clinicaltrials.gov/ct2/show/NCT00616161.

Greenberg B., Butler J., Felker G.M., Ponikowski P., Voors A.A., Desai A.S., Barnard D., Bouchard A., Jaski B., Lyon A.R., et al. Calcium upregulation by percutaneous administration of gene therapy in patients with cardiac disease (CUPID 2): A randomised, multinational, double-blind, placebo-controlled, phase 2b trial. Lancet. 2016;387:1178–1186. doi: 10.1016/S0140-6736(16)00082-9. PubMed DOI

U.S. National Library of Medicine. [(accessed on 1 September 2019)]; Available online: https://clinicaltrials.gov.

Papp Z., Édes I., Fruhwald S., De Hert SG., Salmenperä M., Leppikangas H., Mebazaa A., Landoni G., Grossini E., Caimmi P., et al. Levosimendan: Molecular mechanisms and clinical implications: Consensus of experts on the mechanisms of action of levosimendan. Int. J. Cardiol. 2012;159:82–87. doi: 10.1016/j.ijcard.2011.07.022. PubMed DOI

Farmakis D., Alvarez J., Gal T.B., Brito D., Fedele F., Fonseca C., Gordon A.C., Gotsman I., Grossini E., Guarracino F., et al. Levosimendan beyond inotropy and acute heart failure: Evidence of pleiotropic effects on the heart and other organs: An expert panel position paper. Int. J. Cardiol. 2016;222:303–312. doi: 10.1016/j.ijcard.2016.07.202. PubMed DOI

Mebazaa A., Parissis J., Porcher R., Gayat E., Nikolaou M., Boas F.V., Delgado J.F., Follath F. Short-term survival by treatment among patients hospitalized with acute heart failure: The global ALARM-HF registry using propensity scoring methods. Intensive Care Med. 2011;37:290–301. doi: 10.1007/s00134-010-2073-4. PubMed DOI

Pollesello P., Parissis J., Kivikko M., Harjola V.-P. Levosimendan meta-analyses: Is there a pattern in the effect on mortality? Int. J. Cardiol. 2016;209:77–83. doi: 10.1016/j.ijcard.2016.02.014. PubMed DOI

Hasenfuss G., Pieske B., Castell M., Kretschmann B., Maier L.S., Just H. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation. 1998;98:2141–2147. doi: 10.1161/01.CIR.98.20.2141. PubMed DOI

Nagy L., Pollesello P., Papp Z. Inotropes and inodilators for acute heart failure: Sarcomere active drugs in focus. J. Cardiovasc. Pharmacol. 2014;64:199–208. doi: 10.1097/FJC.0000000000000113. PubMed DOI PMC

Pollesello P., Papp Z., Papp J.G. Calcium sensitizers: What have we learned over the last 25 years? Int. J. Cardiol. 2016;203:543–548. doi: 10.1016/j.ijcard.2015.10.240. PubMed DOI

Mebazaa A., Nieminen M.S., Filippatos G.S., Cleland J.G., Salon J.E., Thakkar R., Padley R.J., Huang B., Cohen-Solal A. Levosimendan vs. dobutamine: Outcomes for acute heart failure patients on β-blockers in SURVIVE. Eur. J. Heart Fail. 2009;11:304–311. doi: 10.1093/eurjhf/hfn045. PubMed DOI PMC

Bergh C.-H., Andersson B., Dahlström U., Forfang K., Kivikko M., Sarapohja T., Ullman B., Wikström G. Intravenous levosimendan vs. dobutamine in acute decompensated heart failure patients on beta-blockers. Eur. J. Heart Fail. 2010;12:404–410. doi: 10.1093/eurjhf/hfq032. PubMed DOI PMC

Ponikowski P., Voors A.A., Anker S.D., Bueno H., Cleland J.G.F., Coats A.J.S., Falk V., González-Juanatey J.R., Harjola V.-P., Jankowska E.A., et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 2016;37:2129–2200. PubMed

Altenberger J., Parissis J.T., Ulmer H., Poelzl G., LevoRep Investigators Rationale and design of the multicentre randomized trial investigating the efficacy and safety of pulsed infusions of levosimendan in outpatients with advanced heart failure (LevoRep study) Eur. J. Heart Fail. 2010;12:186–192. doi: 10.1093/eurjhf/hfp189. PubMed DOI

Comín-Colet J., Manito N., Segovia-Cubero J., Delgado J., García Pinilla J.M., Almenar L., Crespo-Leiro M.G., Sionis A., Blasco T., Pascual-Figal D., et al. Efficacy and safety of intermittent intravenous outpatient administration of levosimendan in patients with advanced heart failure: The LION-HEART multicentre randomised trial: Levosimendan in advanced HF: The LION-HEART trial. Eur. J. Heart Fail. 2018;20:1128–1136. doi: 10.1002/ejhf.1145. PubMed DOI

García-González M.J., LAICA Study Investigators Efficacy and security of intermittent repeated levosimendan administration in patients with advanced heart failure: A randomized, double-blind, placebo controlled multicenter trial: LAICA study; Proceedings of the European Society of Cardiology—Heart Failure Association Congress; Florence, Italy. 21 May 2016.

Silvetti S., Nieminen M.S. Repeated or intermittent levosimendan treatment in advanced heart failure: An updated meta-analysis. Int. J. Cardiol. 2016;202:138–143. doi: 10.1016/j.ijcard.2015.08.188. PubMed DOI

Silvetti S., Belletti A., Fontana A., Pollesello P. Rehospitalization after intermittent levosimendan treatment in advanced heart failure patients: A meta-analysis of randomized trials: Repeated levosimendan in AdHF and rehospitalization. ESC Heart Fail. 2017;4:595–604. doi: 10.1002/ehf2.12177. PubMed DOI PMC

Oliva F., Perna E., Marini M., Nassiacos D., Cirò A., Malfatto G., Morandi F., Caico I., Perna G., Meloni S., et al. Scheduled intermittent inotropes for ambulatory advanced heart failure. The RELEVANT-HF multicentre collaboration. Int. J. Cardiol. 2018;272:255–259. doi: 10.1016/j.ijcard.2018.08.048. PubMed DOI

Müller C.E. GALACTIC—Goal-Directed AfterLoad Reduction in Acute Congestive Cardiac Decompensation. ESC Congress 2019, Paris, France. Hot Line Session 3. [(accessed on 3 October 2019)]; Available online: https://esc365.escardio.org/Congress/ESC-CONGRESS-2019/Hot-Line-Session-3/202174-galactic-goal-directed-afterload-reduction-in-acute-congestive-cardiac-decompensation-a-randomized-controlled-trial#video.

McCullough P.A. How trialists and pharmaceutical sponsors have failed us by thinking that acute heart failure Is a 48-hour illness. Am. J. Cardiol. 2017;120:505–508. doi: 10.1016/j.amjcard.2017.04.056. PubMed DOI

Triposkiadis F., Butler J., Abboud F.M., Armstrong P.W., Adamopoulos S., Atherton J.J., Backs J., Bauersachs J., Burkhoff D., Bonow R.O., et al. The continuous heart failure spectrum: Moving beyond an ejection fraction classification. Eur. Heart. J. 2019;40:2155–2163. doi: 10.1093/eurheartj/ehz158. PubMed DOI PMC

Severino P., Mariani M.V., Fedele F. Futility in cardiology: The need for a change in perspectives. Eur. J. Heart Fail. 2019 doi: 10.1002/ejhf.1576. PubMed DOI

Fedele F., Mancone M., Adamo F., Severino P. Heart failure with preserved, mid-range, and reduced ejection fraction: The misleading definition of the new guidelines. Cardiol. Rev. 2017;25:4–5. doi: 10.1097/CRD.0000000000000131. PubMed DOI PMC

Fedele F., Severino P., Calcagno S., Mancone M. Heart failure: TNM-like classification. J. Am. Coll. Cardiol. 2014;63:1959–1960. doi: 10.1016/j.jacc.2014.02.552. PubMed DOI

De Backer D., Bakker J., Cecconi M., Hajjar L., Liu D.W., Lobo S., Monnet X., Morelli A., Myatra S.N., Perel A., et al. Alternatives to the Swan–Ganz catheter. Intensive Care Med. 2018;44:730–741. doi: 10.1007/s00134-018-5187-8. PubMed DOI

Shameer K., Johnson K.W., Glicksberg B.S., Dudley J.T., Sengupta P.P. Machine learning in cardiovascular medicine: Are we there yet? Heart. 2018;104:1156–1164. doi: 10.1136/heartjnl-2017-311198. PubMed DOI

Johnson K.W., Torres Soto J., Glicksberg B.S., Shameer K., Miotto R., Ali M., Ashley E., Dudley J.T. Artificial Intelligence in Cardiology. J. Am. Coll. Cardiol. 2018;71:2668–2679. doi: 10.1016/j.jacc.2018.03.521. PubMed DOI

Sim I. Mobile Devices and Health. N. Engl. J. Med. 2019;381:956–968. doi: 10.1056/NEJMra1806949. PubMed DOI

Eurlings C.G.M.J., Boyne J.J., de Boer R.A., Brunner-La Rocca H.P. Telemedicine in heart failure—more than nice to have? Neth. Heart J. 2019;27:5–15. doi: 10.1007/s12471-018-1202-5. PubMed DOI PMC

Bondar G., Togashi R., Cadeiras M., Schaenman J., Cheng R.K., Masukawa L., Hai J., Bao T.-M., Chu D., Chang E., et al. Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support. PLoS ONE. 2017;12:e0189420. doi: 10.1371/journal.pone.0189420. PubMed DOI PMC

Deng M.C. A peripheral blood transcriptome biomarker test to diagnose functional recovery potential in advanced heart failure. Biomark. Med. 2018;12:619–635. doi: 10.2217/bmm-2018-0097. PubMed DOI PMC

Krittanawong C., Namath A., Lanfear D.E., Tang W.H.W. Practical pharmacogenomic approaches to heart failure therapeutics. Curr. Treat. Options Cardiovasc. Med. 2016;18:60. doi: 10.1007/s11936-016-0483-5. PubMed DOI

Gensini G.F., Alderighi C., Rasoini R., Mazzanti M., Casolo G. Value of telemonitoring and telemedicine in heart failure management. Card. Fail. Rev. 2017;3:116–121. doi: 10.15420/cfr.2017:6:2. PubMed DOI PMC

Hemingway H., Asselbergs F.W., Danesh J., Dobson R., Maniadakis N., Maggioni A., van Thiel G.J.M., Cronin M., Brobert G., Vardas P., et al. Big data from electronic health records for early and late translational cardiovascular research: Challenges and potential. Eur. Heart J. 2018;39:1481–1495. doi: 10.1093/eurheartj/ehx487. PubMed DOI PMC

Narula S., Shameer K., Salem Omar A.M., Dudley J.T., Sengupta P.P. Machine-learning algorithms to automate morphological and functional assessments in 2D echocardiography. J. Am. Coll. Cardiol. 2016;68:2287–2295. doi: 10.1016/j.jacc.2016.08.062. PubMed DOI

Maragatham G., Devi S. LSTM model for prediction of heart failure in big data. J. Med. Syst. 2019;43:111. doi: 10.1007/s10916-019-1243-3. PubMed DOI

Safety and Efficacy of Tafamidis in Patients with Transthyretin Cardimyopathy (ATTR-ACT) [(accessed on 11 September 2019)]; Available online: https://clinicaltrials.gov/ct2/show/results/NCT01994889?term=NCT01994889.&rank=1.

Pölzl G., Allipour Birgani S., Comín-Colet J., Delgado J.F., Fedele F., García-Gonzáles M.J., Gustafsson F., Masip J., Papp Z., Störk S., et al. Repetitive levosimendan infusions for patients with advanced Chronic heart failure in the vulnerable post-discharge period: Rationale and design of the LeoDOR Trial. Esc. Heart Fail. 2019;6:174–181. doi: 10.1002/ehf2.12366. PubMed DOI PMC

Pölzl G., Altenberger J., Baholli L., Beltrán P., Borbély A., Comin-Colet J., Delgado J.F., Fedele F., Fontana A., Fruhwald F., et al. Repetitive use of levosimendan in advanced heart failure: Need for stronger evidence in a field in dire need of a useful therapy. Int. J. Cardiol. 2017;243:389–395. doi: 10.1016/j.ijcard.2017.05.081. PubMed DOI

Collins S.P., Lindsell C.J., Pang P.S., Storrow A.B., Peacock W.F., Levy P., Rahbar M.H., Del Junco D., Gheorghiade M., Berry D.A. Bayesian adaptive trial design in acute heart failure syndromes: Moving beyond the mega trial. Am. Heart J. 2012;164:138–145. doi: 10.1016/j.ahj.2011.11.023. PubMed DOI PMC

Lin J., Bunn V. Comparison of multi-arm multi-stage design and adaptive randomization in platform clinical trials. Contemp. Clin. Trials. 2017;54:48–59. doi: 10.1016/j.cct.2017.01.003. PubMed DOI

Wason J.M.S., Trippa L. A comparison of Bayesian adaptive randomization and multi-stage designs for multi-arm clinical trials. Stat. Med. 2014;33:2206–2221. doi: 10.1002/sim.6086. PubMed DOI

Saville B.R., Berry S.M. Efficiencies of platform clinical trials: A vision of the future. Clin. Trials. 2016;13:358–366. doi: 10.1177/1740774515626362. PubMed DOI

Morrell L., Hordern J., Brown L., Sydes M.R., Amos C.L., Kaplan R.S., Parmar M.K.B., Maughan T.S. Mind the gap? The platform trial as a working environment. Trials. 2019;20:297. doi: 10.1186/s13063-019-3377-5. PubMed DOI PMC

Hague D., Townsend S., Masters L., Rauchenberger M., Van Looy N., Diaz-Montana C., Gannon M., James N., Maughan T., Parmar M.K.B., et al. Changing platforms without stopping the train: Experiences of data management and data management systems when adapting platform protocols by adding and closing comparisons. Trials. 2019;20:294. doi: 10.1186/s13063-019-3322-7. PubMed DOI PMC

Schiavone F., Bathia R., Letchemanan K., Masters L., Amos C., Bara A., Brown L., Gilson C., Pugh C., Atako N., et al. This is a platform alteration: A trial management perspective on the operational aspects of adaptive and platform and umbrella protocols. Trials. 2019;20:264. doi: 10.1186/s13063-019-3216-8. PubMed DOI PMC

Packer M. Why are physicians so confused about acute heart failure? N. Engl. J. Med. 2019;381:776–777. doi: 10.1056/NEJMe1904713. PubMed DOI

Blecker S., Sontag D., Horwitz L.I., Kuperman G., Park H., Reyentovich A., Katz S.D. Early identification of patients with acute decompensated heart failure. J. Card. Fail. 2018;24:357–362. doi: 10.1016/j.cardfail.2017.08.458. PubMed DOI PMC

Blecker S., Katz S.D., Horwitz L.I., Kuperman G., Park H., Gold A., Sontag D. Comparison of approaches for heart failure case identification from electronic health record data. JAMA Cardiol. 2016;1:1014. doi: 10.1001/jamacardio.2016.3236. PubMed DOI PMC

Golas S.B., Shibahara T., Agboola S., Otaki H., Sato J., Nakae T., Hisamitsu T., Kojima G., Felsted J., Kakarmath S., et al. A machine learning model to predict the risk of 30-day readmissions in patients with heart failure: A retrospective analysis of electronic medical records data. BMC Med. Inf. Decis. Mak. 2018;18:44. doi: 10.1186/s12911-018-0620-z. PubMed DOI PMC

Karanasiou G.S., Tripoliti E.E., Papadopoulos T.G., Kalatzis F.G., Goletsis Y., Naka K.K., Bechlioulis A., Errachid A., Fotiadis D.I. Predicting adherence of patients with HF through machine learning techniques. Healthc. Technol. Lett. 2016;3:165–170. doi: 10.1049/htl.2016.0041. PubMed DOI PMC

Kreusser M.M., Tschierschke R., Beckendorf J., Baxmann T., Frankenstein L., Dösch A.O., Schultz J.-H., Giannitsis E., Pleger S.T., Ruhparwar A., et al. The need for dedicated advanced heart failure units to optimize heart failure care: Impact of optimized advanced heart failure unit care on heart transplant outcome in high-risk patients: The need for dedicated AHFUs to optimize HF care. ESC Heart Fail. 2018;5:1108–1117. doi: 10.1002/ehf2.12314. PubMed DOI PMC

Koehler F., Koehler K., Deckwart O., Prescher S., Wegscheider K., Kirwan B.-A., Winkler S., Vettorazzi E., Bruch L., Oeff M., et al. Efficacy of telemedical interventional management in patients with heart failure (TIM-HF2): A randomised, controlled, parallel-group, unmasked trial. Lancet. 2018;392:1047–1057. doi: 10.1016/S0140-6736(18)31880-4. PubMed DOI

Möckel M., Koehler K., Anker S.D., Vollert J., Moeller V., Koehler M., Gehrig S., Wiemer J.C., Haehling S., Koehler F. Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: Results from the TIM-HF2 trial. Eur. J. Heart Fail. 2019 doi: 10.1002/ejhf.1530. PubMed DOI

Matsumura T., Matsui M., Iwata Y., Asakura M., Saito T., Fujimura H., Sakoda S. A Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy. Intern. Med. 2018;57:311–318. doi: 10.2169/internalmedicine.8651-16. PubMed DOI PMC

Andrès E., Talha S., Zulfiqar A.-A., Hajjam M., Ervé S., Hajjam J., Gény B., Hajjam El Hassani A. Current research and new perspectives of telemedicine in chronic heart failure: Narrative review and points of interest for the clinician. J. Clin. Med. 2018;7:544. doi: 10.3390/jcm7120544. PubMed DOI PMC

Maack C., Eschenhagen T., Hamdani N., Heinzel F.R., Lyon A.R., Manstein D.J., Metzger J., Papp Z., Tocchetti C.G., Yilmaz M.B., et al. Treatments targeting inotropy. Eur. Heart J. 2018 doi: 10.1093/eurheartj/ehy600. PubMed DOI PMC

Nagy L., Pollesello P., Haikala H., Végh Á., Sorsa T., Levijoki J., Szilágyi S., Édes I., Tóth A., Papp Z., et al. ORM-3819 promotes cardiac contractility through Ca2+ sensitization in combination with selective PDE III inhibition, a novel approach to inotropy. Eur. J. Pharm. 2016;775:120–129. doi: 10.1016/j.ejphar.2016.02.028. PubMed DOI

Márton Z., Pataricza J., Pollesello P., Varró A., Papp J.G. The Novel inodilator ORM-3819 relaxes isolated porcine coronary arteries: Role of voltage-gated potassium channel activation. J. Cardiovasc. Pharm. 2019;74:218–224. doi: 10.1097/FJC.0000000000000700. PubMed DOI

Nielsen T.B., Brass E.P., Gilbert D.N., Bartlett J.G., Spellberg B. Sustainable discovery and development of antibiotics—Is a nonprofit approach the future? N. Engl. J. Med. 2019;381:503–505. doi: 10.1056/NEJMp1905589. PubMed DOI PMC

Dungen H.-D., Petroni R., Correale M., Coiro S., Monitillo F., Triggiani M., Leone M., Antohi E.-L., Ishihara S., Sarwar C.M.S., et al. A new educational program in heart failure drug development: The Brescia international master program. J. Cardiovasc. Med. 2018;19:411–421. doi: 10.2459/JCM.0000000000000669. PubMed DOI

Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use

Levosimendan Efficacy and Safety: 20 years of SIMDAX in Clinical Use