Short-Term Therapies for Treatment of Acute and Advanced Heart Failure-Why so Few Drugs Available in Clinical Use, Why Even Fewer in the Pipeline?

Abstract

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.

Keywords: acute heart failure; advanced heart failure; clinical development; levosimendan; regulatory clinical trials; short-term hemodynamic therapy.

Figure 1

Regulatory clinical trials of Phase III for drugs meant for short-term treatment of acute heart failure (AHF) and/or advanced heart failure (AdHF), published in the past 20 years. For each study, the year of publication of the main report, the first author and the PMID are the following—VMAC, 2002, VMAC investigators, 11911755; OPTIME-CHF, 2002, Cuffe MS, 11911756; LIDO, 2002, Follath F, 12133653; RUSSLAN 2002 Moiseyev VS 12208222; PRECEDENT, 2002, Burger AJ, 12486437; RITZ-4, 2003, O’Connor CM, 12742280; ACTIV-CHF, 2004, M. Gheorghiade, 15113814; FUSION I, 2004, Yancy CW, 15342289; PROACTION, 2005, Peacock WF, 15915407; EVEREST, 2007, Konstam MA, 17384437; ECLIPSE, 2007, Udelison JE, published as abstract; SURVIVE, 2007, Mabazaa A, 17473298; EMOTE, 2007, Feldman AM, 17967591; VERITAS, 2007, McMurray JJ, 17986694; HORIZON-HF, 2008, Gheorghiade M, 18534276; PROTECT-1, 2008, Cotter G, 18926433; ESSENTIAL, 2009, Metra M, 19700774; FUSION II, 2008, Yancy CW, 19808265; REACH UP, 2010, Gottlieb SS, 20797594; PROTECT-2, 2010, Massie BM, 20925544; ASCEND-HF, 2011, O’Connor, 21732835; STARBRITE, 2011, Sha MR, 21807321; COMPOSE, 2012, Gheorghiade M, 22713287; RELAX-AHF, 2013, Teerlink JR, 23141816; REVIVE I-II, 2013, Packer M, 24621834; PRONTO, 2014, Peacock WF, 24655702; ATOMIC-AHF, 2016, Teerlink JR, 27012405; ROSE, 2016, Wan SH, 27512103; ROSE, 2016, Wan SH, 27512103; TACTICS-HF, 2016, Felker GM, 27654854; RELAX-AHF-ASIA, 2017, Sato N, 27825893; SECRET OF HF, 2017, Konstam MA, 28302292; TRUE-AHF, 2017, Packer M, 28402745; ATHENA-HF, 2017, Butler J, 28700781; FIGHT, 2018, Sharma A, 30120812; RELAX-AHF-EU, 2019, Maggioni AP, 30604559; RELAX-AHF-2, 2019, Metra M, 31433919.

Figure 2

Amount of regulatory clinical trials of Phase III for drugs meant for short-term treatment of AHF and/or AdHF per year of publication in the period 2000–2019.

Figure 3

Advances in information and data-processing technology have created a base from which heart failure research can be re-configured towards highly defied phenotypes in ways that will facilitate both the optimal use of current therapies and the identification of new agents specifically tailored to a particular pathophysiology. See text for further discussion. Freely from Triposkiadis et al [42].