Author + information
- Received September 13, 2017
- Accepted September 13, 2017
- Published online December 25, 2017.
- aUniversity Paris Diderot, Paris, France
- bPôle de Recherche et D'enseignement Supérieur Sorbonne Paris Cité, Paris, France
- cINSERM U942, Paris, France
- dDepartment of Anesthesiology, Burn and Critical Care Medicine, Hôpitaux Universitaires Saint-Louis-Lariboisière, Assistance Publique-Hôpitaux de Paris, Paris, France
- ↵∗Address for correspondence:
Dr. Alexandre Mebazaa, University Paris Diderot, PRES Sorbonne Paris Cité, Inserm U942, Department of Anesthesiology and Critical Care Medicine, Hôpitaux Universitaires Saint-Louis-Lariboisière, Assistance Publique-Hôpitaux de Paris (AP-HP), 2 Rue A. Pare, Paris 75475 Cedex 10, France.
- acute heart failure
- chronic obstructive pulmonary disease
- left ventricle ejection fraction
- oral heart failure therapies
With 2 recent neutral trials (1), many physicians caring daily all around the world for acute heart failure (AHF) patients were disappointed. Are we going to manage those patients like we did in past years and keep facing high mortality and a high rate of readmission?
In fact, those neutral trials are clear indications that we still do not understand AHF and that we should join forces and support our understanding of what mechanisms lead to acute heart failure before performing new large phase III trials.
We Still Do Not Understand: What Is Acute Heart Failure?
We likely performed trials in AHF without a clear understanding of AHF. Patients were included based on circulating natriuretic peptides and subjective symptoms. Misunderstanding AHF likely translated into the bad outcome associated with AHF. Indeed, many national surveys showed in-hospital and mid-term mortality remained high and unchanged in the last years. This is confirmed in the very recent AHF trials.
Furthermore, the term “acute heart failure” is not ideal, although no other term has achieved consensus. It is not ideal because the word “heart” does not represent the disease (2). AHF starts with an alteration in heart properties followed by alterations in many other extracardiac, including neuro-endocrine, systems that lead to congestion and AHF. In addition, most drugs administered in AHF (except in cardiogenic shock) have little influence on the heart. By contrast, in the term acute heart failure, “acute” is correct as emergency and critical medicine define “patient admitted for unscheduled visit with a high risk of death” as “acute” (3). As pointed out by recent Heart Failure Association of the European Society of Cardiology guidelines, the precipitating factors of AHF were overlooked and often not treated. Patients admitted with a combination of cardiogenic pulmonary edema and acute coronary syndrome or infection are admitted in critical condition and at high risk of death (Figure 1A) (4). Similarly acute decompensated COPD (chronic obstructive pulmonary disease represent) patients have been admitted for pneumonia that lasted several days before admission and for whom antibiotic therapy improved outcome.
Oral heart failure therapies (OHFT) are necessary to prevent worsening conditions and sometime even partially restore heart function. However, those therapies will not reduce the rate of AHF in the short term. Indeed one should keep in mind that: 1) the first episode of AHF (also named de novo HF) represents up to 40% of AHF patients; 2) OHFT have proven to be active only in heart failure with reduced left ventricle ejection fraction (LVEF) that are the minority of AHF patients, dominated by patients with preserved LVEF; 3) many patients with optimal OHFT are still admitted with AHF; and 4) optimization of OHFT is still an unresolved challenge as only 30% of HF patients receive optimal doses and even much <30% in the oldest old patients who are becoming the majority of AHF. Indeed, failure in implementation of OHFT contributes to the excessively high rate of short-term readmission, a phenomenon that is unique in medicine. Management of AHF after discharge raises other issues. For example, should we and how can we generalize about HF nurses? Should we have other health care providers in the loop? Those questions and many others are now included in the “post-discharge vulnerable phase,” although no clear indications are given to the physicians in charge, who are largely noncardiologists, throughout the world.
What Have We Learned From the Last 30 Years of Acute Heart Failure Trials?
No trial to date assessing effects of drug therapy on AHF has been positive, although we were eager to find new therapies for AHF patients. To do so, various intravenous agents, mostly with either vasodilator or positive inotropic properties, or both, were tested using similar trial designs: short-term administration to achieve improvement in mid-term outcome. All drugs tested showed benefits in hemodynamics in phase II but neutral effects in large phase III randomized clinical trials. Mid-term mortality in AHF, the coprimary of TRUE-AHF (Efficacy and safety of Ularitide for the treatment of acute decompensated heart failure) and RELAX-AHF (Effect of serelaxin versus standard of core in acute heart failure patients), was neutral. Benefits for mortality may not be achievable because mid-term mortality is influenced by many factors, some of them not actionable (comorbidities). Improvement in short-term symptoms, however, seems achievable, although transient. In the 2 recent trials, benefits for symptoms were minimal, knowing that many patients were included with mild decompensation of severe chronic heart failure.
The 2 very recent trials have focused on “time to start” the administration of active therapies. Time to start the administration of an active drug in AHF trial is an unresolved issue, although emergency department (ED) physicians think it matters. The 2 trials failed to demonstrate that ularitide or serelaxin were effective for AHF, although both drugs were administered earlier than in former AHF trials. It is also possible that 6 h after presentation was not early enough. Indeed, today, in most EDs, AHF patients receive intravenous drugs often within 90 min after presentation. Furthermore, studies showed that noninvasive ventilation and very recently intravenous diuretics given within <30 min of presentation were associated with the best outcome (5). Keeping the parallel between AHF and other diseases that appear several days before presentation, for example, sepsis, several recent studies showed that administration of antibiotics at presentation saves lives, whereas early administration of volume, another recommended tool, was not associated with additional benefits. In summary, it is likely a general rule that we better administer active agents as early as possible, any active agent in critically ill patients, in order to prevent worsening. However, which drug(s) may be considered as active agent(s) in AHF?
Although it would be ideal to better understand AHF before moving forward with large clinical trials, some agents are already in the pipeline. As advised by many famous people: “If you always do what you’ve always done, you always get what you’ve always gotten.”
Five recommendations may be applied immediately to those ongoing AHF research programs to optimize chances of success (and avoid repeating failure): 1) together with safety, phase II trial(s) should aim at assessing efficacy endpoint(s) that are applicable to the phase III trial; 2) select 1 phenotype of AHF patients that may be the best target for the active drug, rather than including the whole heterogeneous spectrum of AHF; 3) the shorter the delay between hospital presentation and time of primary endpoint, the better are the chance of trial success (between 30 and 90 days, deaths rather related to comorbidities and not improved by an active drug); 4) if possible, the active drug for AHF should be administered for a period longer than the hospital stay, in order to overlap the period of administration of active therapy and the period to count the events for the primary endpoint; and 5) trials should be preferably performed in countries in which hospital and outpatient infrastructure and research facilities are in line with international requirements.
We Need Tremendous Financial Support to Join Forces
A rapid PubMed search showed that the amount of research published for AHF in the last 40 years was consistently lower than that for acute myocardial infarction and a log-scale lower than that for stroke (Figure 1B). However, those 3 cardiovascular diseases have similar rates of unscheduled hospitalization and bad outcome. Furthermore, in heart failure, grants and research money are quasi-exclusively dedicated to stable chronic heart failure as reflected by a much greater rate of publications compared to AHF.
Knowledge of AHF should be improved in many areas. In pre-clinical studies, several animal models of stable heart failure exist, although almost none in AHF, especially for acute heart failure with preserved ejection fraction (HFpEF). Animal models that can reproduce heart dysfunction and congestion of the lung, kidney, and liver are urgently needed. Furthermore, in vitro models that may reproduce heart, vessels (including coronary artery), or any organ, tissue, or cellular dysfunction seen in AHF patients are missing. To do so, close collaboration between the clinicians in charge of AHF patients (ED, intensive care units [ICU], and cardiologists) and basic researchers should be largely promoted and financially supported. Tools used in basic science to investigate chronic heart failure may already be used in AHF. This includes imaging, biomarkers, organ function tests, and cell-cell interactions, among others.
Human nonpharmacological and pharmacological studies of AHF should also be financially supported. How does stable heart dysfunction decompensate? Are all precipitating factors equal? What is the role of the neuroendocrine system in the days preceding unscheduled admission? Is acute heart failure with reduced ejection fraction (HFrEF) different from acute HFpEF? Does contemporary treatment, combining diuretics and nitrate, neutralize benefits of any new therapy?
Human studies in AHF should also be horizontal. An increasing number of countries collect AHF data through national societies of cardiology, or emergency medicine, or heart failure working groups. In Europe, Heart Failure Association of the European Society of Cardiology and European Society of Emergency Medicine collected transnational data for AHF. Similarly, large cohorts are also collected in Asia-Pacific, Latin America, and the Middle East. In addition to data from large AHF randomized trials, the United States may benefit from a contemporary, large observational cohort including all specialties involved in AHF management. Multidisciplinary efforts remain the exception and should be promoted. Recently, the transcontinental GREAT (Global research on acute conditions team) network, including cardiologists, ED, intensivists, statisticians, basic scientists, and epidemiologists showed benefits of merging databases to assess the role of comorbidities, sex, continent, precipitating factors, and preserved LVEF on AHF outcome. All those efforts should aim to at least achieve a “universal definition of AHF” that may help our daily practice and, as importantly, select the phenotype that best matches potential new agents.
The 2 most recent AHF trials were as neutral as many others performed in the last years. Altogether, we need to face the fact that, in the ED, coronary care unit, and ICU, AHF is here to stay, with the high mortality rate and high rate of hospital readmission (6). It is, therefore, urgent to radically change the course of AHF research programs and to markedly increase the surface of the wing. Two actions may be applicable immediately by national and international funding agencies, as follows: first, dedicate specific funds to AHF research, whether pre-clinical, clinical, or ideally, both, and promote multidisciplinary projects; and second, each research program in chronic heart failure should include at least 20% of the resources to investigate AHF as part of the program.
The author thanks Gadi Cotter for editing the manuscript and Tahar Chouihed for his help in Figure 1B.
Dr. Mebazaa is a compensated speaker for Abbott, Novartis, Orion, and Roche et Servier; and a compensated member of advisory boards for Bristol-Myers Squibb, Cardiorentis, Adrenomed, MyCartis, Neurotronik, Sanofi, and Sphyngotec.
- Received September 13, 2017.
- Accepted September 13, 2017.
- 2018 American College of Cardiology Foundation
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