Results of Expert Meetings

Phase III clinical trial end points in acute heart failure syndromes: A virtual roundtable with the acute heart failure syndromes international working group

Dyspnea is the most common presenting symptom in patients with acute heart failure (AHF), but is difficult to quantify as a research measure. The URGENT Dyspnea study compared 3 scales: (1) 10 cm VAS, (2) 5-point Likert, and (3) a 7-point Likert (both VAS and 5-point Likert were recorded in the upright and supine positions). However, the minimal clinically important difference (MCID) to patients has not been well established.

We performed a secondary analysis from URGENT Dyspnea, an observational, multi-center study of AHF patients enrolled within 1 h of first physician assessment in the ED. Using the anchor-based method to determine the MCID, a one-category change in the 7-point Likert was used as the criterion standard (‘minimally improved or worse’). The main outcome measures were the change in visual analog scale (VAS) and 5-point Likert scale from baseline to 6-h assessment relative to a 1-category change response in the 7-point Likert scale (‘minimally worse’, ‘no change’, or ‘minimally better’).

Of the 776 patients enrolled, 491 had a final diagnosis of AHF with responses at both time points. A 10.5 mm (SD 1.6 mm) change in VAS was the MCID for improvement in the upright position, and 14.5 mm (SD 2.0 mm) in the supine position. However, there was no MCID for worsening, as few patients reported worse dyspnea. There was also no significant MCID for the 5-point Likert scale.

A 10.5 mm change is the MCID for improvement in dyspnea over 6 h in ED patients with AHF.

Management approaches for patients in the emergency department (ED) who present with acute heart failure (AHF) have largely focused on intravenous diuretics. Yet, the primary pathophysiologic derangement underlying AHF in many patients is not solely volume overload. Patients with hypertensive AHF (H-AHF) represent a clinical phenotype with distinct pathophysiologic mechanisms that result in elevated ventricular filling pressures. To optimize treatment response and minimize adverse events in this subgroup, we propose that clinical management be tailored to a conceptual model of disease based on these mechanisms. This consensus statement reviews the relevant pathophysiology, clinical characteristics, approach to therapy, and considerations for clinical trials in ED patients with H-AHF.

The last decade of acute heart failure (HF) research is characterized by disappointments in large phase 2 and 3 pharmacologic studies of therapeutics including calcium-sensitizing agents and antagonists of endothelin, vasopressin, and adenosine. As a result, pharmacologic management for acute HF has changed little in recent years, and adverse event rates remain higher than in chronic HF. Despite neutral results in many acute HF trials, recent studies including RELAX-AHF, ASTRONAUT, and PRONTO have highlighted the role of appropriate timing of patient enrollment, targeting the “right” patients, and selecting appropriate end points and sites. We describe lessons learned from recent trials in acute HF and outline strategies to improve the potential for success in future trials. This review is based on discussions between scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from November 30 to December 1, 2012.