Past, Present, and Future of Acute Heart Failure Clinical Trials—A High-Risk Population in Search of a Strategy (2017)

Acute heart failure (AHF) resulting in hospitalizations is associated with a 25–30% 1-year post-discharge mortality and 50% 6-month readmission risk, despite minimal symptoms, stable vital signs, and minimal or no signs of congestion at discharge.1-4 This high event rate has not changed substantially in the last two decades. AHF accounts for the majority of the over $30 billion spent for the care of heart failure (HF) in the United States. Many novel therapies were tested, including those with vasodilating properties (e.g. nesiritide, TRV027, and tezosantan), inotropic properties (e.g. milrinone, istaroxime and levosimendan), or targeting congestion and/or renal function (e.g. rolofylline, low-dose nesiritide or dopamine, and tolvaptan) and failed to improve outcomes.5, 6 The relatively low in-hospital mortality rate and short length of stay in the United States for AHF are not amenable for further meaningful improvement. Short-term improvement in dyspnoea continues to be a focus in AHF and led to the approval of nesiritide. While there was a statistically significant proportion of patients who improved dyspnoea with nesiritide at 3-hour endpoint, the vast majority of those in the standard of care arm also improved with intravenous diuretics.5 This modest benefit further narrowed during hospitalization. Questions were raised if this benefit was worth the cost. Relationship between in-hospital dyspnoea improvement and post-discharge outcomes is inconsistent. Long-term safety concern subsequently led to the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF), which failed to show any post-discharge outcomes benefit.5 Many other trials also attempted to improve dyspnoea in AHF and failed, including two recent trials with tolvaptan, bringing to light that dyspnoea is not an unmet need and standard diuretic therapy is an adequate option for AHF symptoms. These experiences guided a discussion about the goals of AHF therapy. With dyspnoea largely being a met need with standard therapy, post-discharge readmission and mortality improvements were felt to be the most important goals. But there was scepticism whether it is possible to improve post-discharge outcomes with short-term in-hospital therapy. Two smaller trials with serelaxin, however, signalled 6-month post-discharge mortality improvement.5 Secondary analysis of the Efficacy and Safety of Relaxin for the Treatment of Acute Heart Failure (RELAX-AHF) trial showed that early short-term administration of serelaxin was associated with favourable trends in serum troponin, cystatin C, and liver enzymes,7 and there was also less risk of in-hospital worsening HF. These observations gave credence to the ‘injury hypothesis’,8 proposing that AHF leads to cardiac and kidney injury, and short-term therapy given during hospitalization may prevent or limit this, in turn improving post-discharge outcomes. To test this hypothesis, two large trials were conducted, including Efficacy and Safety of Ularitide for the Treatment of Acute Decompensated Heart Failure (TRUE-AHF) with ularitide,9 and RELAX-AHF-2 with serelaxin. TRUE-HF showed no benefit in composite clinical score and post-discharge mortality or readmissions. While the details of the RELAX-AHF-2 trials have not been presented, the sponsors announced recently that the trial failed to achieve either of its two composite primary endpoints including in-hospital worsening HF or post-discharge 6-month mortality. With over two decades and billions of dollars of investment, not a single trial has been shown to improve post-discharge outcomes. Drugs were evaluated for targets that were either poorly defined or were not crucial. Dyspnoea assessment remains imprecise and, regardless of how it is measured, represents a met need. Worsening serum creatinine may represent better decongestion and improved, not worsened outcomes. In-hospital worsening HF is infrequent and may be simply related to conservative initial management requiring escalation of standard therapy. Early therapy with decongestion may not alter serum troponin levels, indicating that cardiac injury may not be acute and likely present chronically pre-admission. What lessons should be learned from these experiences and how should we proceed forward? Should we continue to do trials with short-term interventions in AHF? While we do not know if this approach will or will not work in the future, until we understand the pathophysiology of AHF better, the wisdom to continue further investigations with this approach should be questioned. This patient population is too common, too heterogeneous, too costly, and too important to ignore. Further research should be encouraged to understand the pathophysiology, taxonomy, and the phenotypes of this syndrome based on both clinical and biological characteristics, before trying to attempt an all-comer approach with non-specific therapies given short-term but hoping for longer-term benefit. It is important to acknowledge the possibility that there is no specific pathophysiology of AHF and that it represents either worsening chronic HF or have other triggers including patient non-compliance or exacerbation of co-morbidities. Most of these patients do not have end-stage disease with scarred myocardium, but represent high-risk patients with viable dysfunctional myocardium that is amenable to therapy and improvement. In that sense, effectively the ‘vulnerable phase’ may not be as important post-discharge but likely pre-admission when patients are experiencing worsening of their disease, underscoring the importance of optimization of known HF therapies. We should consider dividing these patients into three groups. Patients with new-onset HF (∼10–15%) should be evaluated for aetiology and treated with evidence-based therapies. Until they are on standard therapy, these patients should not be enrolled in AHF trials. Those with end-stage diseases (∼5%) should be targeted for either palliative care or advanced therapies. The rest of the patients that do not fit either of the two categories should be targeted for mechanistic research to understand the pathophysiological features that differentiate them from their chronic counterparts beyond congestion, to discover targets for novel therapy. Until such insights are gained, these patients should be considered high-risk chronic HF patients who should be encouraged to enroll in clinical trials with agents given long term that target deranged cardiovascular biology. It is important to realize that the vast majority of these patients actually do not have AHF but either worsening of chronic HF, and even if the presentation was acute, in most cases it is related to another precipitating factor like ischaemia or rapid atrial fibrillation. Hence, consideration should be given whether the terminology AHF per se truly represent the clinical reality. While attempts are made to discover novel agents, we should not forget that many therapies are already known to improve outcomes in chronic HF but are underutilized or under-dosed, including newer agents like sacubitril/valsartan and ivabradine. Similarly, effective device therapy is sub-optimally managed in many patients, as is treatment for coronary artery disease. Aggressive guideline-recommended therapy for chronic HF remains the best treatment option for these patients. While the search for novel agents improving outcomes is critical, equally important is to optimize therapies known to improve HF outcomes. This is also true for both the cardiac and non-cardiac co-morbidities that these patients may present with, and these need to be adequately addressed as well. Concomitant co-morbidities lead to significant heterogeneity in the profile of these patients. Similarly, other features like blood pressure and renal function can be seen across a spectrum in patients with AHF, also contributing to the heterogeneity in this group. This heterogeneity should be taken into account for both targeting specific novel therapies to the most suitable sub-population in clinical trials, as well as the impact of this heterogeneity in how these patients are approached for clinical care. It should be acknowledged that the time period for highest risk for these patients is soon post-discharge and this risk slowly decreases over time. Thus, especial attention should be paid to adequate discharge planning (including not only optimization of therapy but also patient education and the logistics of post-discharge care) and care subsequent to hospitalization. Finally, worsening HF is associated with poor prognosis even in the absence of hospitalization, and data would suggest that the outcomes of patients with worsening HF regardless if they are hospitalized, treated in the emergency department and discharged, or treated with intravenous diuretics in the outpatient setting, carry equally grim prognosis.10 Thus, the definition of acute or worsening HF should expand to beyond the venue of care, i.e. hospitalization. Patients with AHF represent a high-risk group in need for better care and treatment. In the past, we have failed to discover effective therapies. Presently, we have plenty of opportunities to improve quality of care and optimize known therapies, manage co-morbidities better, and improve systems of healthcare delivery. For the future, we should realize that a one-size-fits-all and a short-term therapy approach for a chronic syndrome is unlikely to improve outcomes. Better understanding of the disease process and treatment targets should be the immediate research priority for AHF. Conflict of interest: J.B. reports receiving research support from the National Institutes of Health, European Union, and Patient Centered Outcomes Research Institute; and serves as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiocell, CVRx Medtronic, Merck, Novartis, Relypsa, and ZS Pharma. M.G. reports consulting relationships with Abbott, Astellas, AstraZeneca, Bayer, Cardiorentis, CorThera, Cytokinetics, CytoPherx, DebioPharm SA, Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection Medical, Johnson & Johnson, Medtronic, Merck, Novartis, Ono Parmaceuticals, Otsuka Pharmaceuticals, Palatin Technologies, Pericor Therapeutics, Protein Design Laboratories, Sanofi-aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT, Takeda, and Trevena Therapeutics. N.S. reports no disclosures.