Climbing the mountain of acute decompensated heart failure: the EVEREST Trials.

IN THIS ISSUE OF JAMA, 2 ARTICLES REPORT FINDINGS FROM the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) clinical trials program. Konstam et al report the overall longterm effects of tolvaptan in terms of safety and clinical outcomes for patients with worsening heart failure (HF) requiring hospitalization. Gheorghiade et al report shortterm effects of tolvaptan for acute symptom relief in these same patients, but presented as 2 trials that were based on study center assignment following completion of patient enrollment and randomization in the long-term trial. The aggregate findings demonstrate that tolvaptan relieves some symptoms associated with acute decompensated heart failure (ADHF) and has no demonstrable evidence of harm such as worsening of renal failure, but importantly, does not reduce mortality or HF-related morbidity at 1 year. In the context of ADHF, these are noteworthy findings. To date, no other therapeutic intervention has been demonstrated in large-scale randomized, placebo-controlled studies to positively influence symptoms in ADHF without generating a question of harm. Inotropes have been associated with increased mortality risk, and calcium sensitizers have been associated with increased cardiovascular mortality. Nesiritide was shown to relieve dyspnea and to reduce pulmonary congestion over the short term, but also was associated with increased intermediate-term mortality risks. Traditional vasodilator therapy relieves HF symptoms, but neither nitroglycerin nor nitroprusside has been subjected to prospective randomized controlled study, and effects on mortality are unknown. Even diuretics, which clearly relieve congestion, have uncertain effects on outcomes. Addressing the challenge of ADHF has been daunting. Acute decompensated HF accounts for more than 1 million acute hospitalizations per year in the United States at an annual cost of more than $30 billion and is associated with significant mortality. The risk of inpatient death is approximately 4% (but ranges from 2%-22%), and the risk of death/rehospitalization at 60 to 90 days after an episode of ADHF is 36%. At the core of this challenge, however, is the limited understanding of the pathophysiology of ADHF. While hemodynamic disturbances are clearly responsible for the observed signs and symptoms, plausible causative mechanisms that trigger acute decompensation, eg, ventricular injury and augmented neurohormonal activation, remain uncertain. Thus, therapy for ADHF is relegated to correcting perturbed hemodynamics. Comparison is made with the evolution of therapy for chronic HF—targeting hemodynamic abnormalities did not yield meaningful clinical benefits, but elucidation of relevant pathophysiological mechanisms followed by appropriately focused interventions in largescale trials resulted in salutary improvements. A similar approach is needed for ADHF. Another challenge of ADHF involves clinical trial design and construct. The studies to date have been small to moderate short-term hemodynamic or symptom-focused designs, constructed primarily to meet regulatory requirements. Important questions, including mechanistic hypotheses and the effect of interventions on rehospitalizations/mortality, have been inadequately studied. Trials in ADHF have also been confounded by considerable heterogeneity of the patient phenotype. Patients with ADHF are older, represent a mix of new-onset HF and decompensated chronic HF, have both reduced and preserved ejection fraction HF, have equal gender representation, and frequently have a number of important comorbidities, especially renal insufficiency. Moreover, “standard therapy” does not truly exist, as there are no evidence-based interventions proven to reduce morbidity and mortality associated with ADHF. Guidelines for ADHF have recently been put forward, but the treatment algorithms are sparse and focus on hemodynamic targets. The strategy is to relieve symptoms preferentially with diuretic use, including high-dose loop diuretics and continuous diuretic infusions (the safety of which is not known in HF), and to add vasodilator therapy (nitroglycerin or nitroprusside) if adjunctive approaches are needed. Inotropes are reserved for impending or frank shock but are otherwise dissuaded. Ultrafiltration represents at best an emerging technology with intriguing preliminary data but limited applications.