The Management of Decompensated Heart Failure Resulting in Hospitalization: Proceedings from an Expert Meeting To Review Current Concepts and To Define Future DirectionsSurrogate end points in heart failure trials☆,☆☆,★
Section snippets
Neurohormonal markers
Neurohormonal markers became intriguing targets to evaluate in terms of their potential as surrogate markers once it was established that heart failure progression is related to the activation of neurohormonal systems, and not solely to hemodynamic abnormalities. The strategy of using neurohormonal markers as surrogate end points appeared promising on the basis of data from the first and second Vasodilator in Heart Failure Trials (V-HeFT I and V-HeFT II), which demonstrated a direct correlation
Ventricular function and remodeling
Measures of ventricular function, specifically ventricular dimensions and measures of remodeling, are also of interest as surrogate markers. Ejection fraction (EF) has consistently been shown in clinical trials to predict the risk for mortality; patients with lower EFs have a higher risk for clinical events. However, the change in EF based on therapy has not consistently correlated with clinical outcomes. For example, in trials of chronically administered inotropic agents such as milrinone or
Hemodynamics
As is true with respect to changes in EF, changes in hemodynamic measures have not reliably correlated with an improvement in outcomes. For example, inotropic agents improve cardiac index and reduce wedge pressure, but have consistently failed to improve clinical outcomes in large clinical trials. Several historical examples illustrate this issue. Oral milrinone and oral vesnarinone were shown to improve hemodynamic measurements in small, early trials. When these drugs were tested in large
Exercise tolerance
Exercise and functional characteristics have also been explored as end points in clinical trials for heart failure, and have been shown to predict outcomes when evaluated by use of multivariate modeling techniques. Factors such as peak oxygen consumption, 6- minute walk distance, and change in New York Heart Association (NYHA) class have all been evaluated as potential surrogate markers or end points. Although a patient's baseline exercise tolerance or peak oxygen utilization may predict
Arrhythmias
Arrhythmic death has been well described as the major mode of death for patients with NYHA class II and III heart failure. Thus, evaluating electrophysiology parameters to serve as surrogate markers for clinical outcomes is an intriguing concept. Electrophysiologic characteristics, such as history of sudden death, intraventricular conduction delays, atrial fibrillation, and history of ventricular tachycardia, have predicted mortality in multivariate models. However, in the setting of heart
Conclusions
The most reliable and important end points in heart failure trials have been mortality and morbidity outcomes, which include worsening heart failure, rehospitalization, and recurrent cardiovascular events such as myocardial infarction or stroke. In addition, signs and symptoms of heart failure, as well as quality of life measures, are valuable to assess. It is also important to evaluate the surrogate markers discussed earlier because these markers provide insight into the mechanism both of the
References (22)
Heart failure 99—the MOXCON story
Int J Cardiol
(1999)- et al.
A randomized controlled trial of epoprostenol therapy for severe congestive heart failure: the Flolan International Randomized Survival Trial (FIRST)
Am Heart J
(1997) - et al.
Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure. Principal investigators of the Randomized Evaluation of Flosequinan on Exercise Tolerance (REFLECT) study
J Am Coll Cardiol
(1993) - et al.
Surrogate end points in heart failure
J Am Coll Cardial
(2002) A regulatory authority's opinion about surrogate end points
- et al.
Effect of vasodilator therapy on mortality in chronic congestive heart failure
N Engl J Med
(1986) - et al.
A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure
N Engl J Med
(1991) Effects of enalapril on mortality in severe congestive heart failure
N Engl J Med
(1987)Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions
N Engl J Med
(1992)Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure
N Engl J Med
(1991)
Effect of metoprolol CR/XL in chronic heart failure
Lancet
Cited by (0)
- ☆
Reprint requests: Mihai Gheorghiade, MD, Division of Cardiology, Northwestern University, Feinberg School of Medicine, Galter 10-240, 201 E Huron St, Chicago, IL 60611.
- ☆☆
E-mail: [email protected]
- ★
0002-8703/2003/$30.00 + 0