Effect of beta‐adrenergic blockade with carvedilol on cachexia in severe chronic heart failure: results from the COPERNICUS trial

Abstract

BackgroundCardiac cachexia frequently accompanies the progression of heart failure despite the use of effective therapies for left ventricular dysfunction. Activation of the sympathetic nervous system has been implicated in the pathogenesis of weight loss, but the effects of sympathetic antagonism on cachexia are not well defined.MethodsWe prospectively evaluated changes in body weight in 2289 patients with heart failure who had dyspnoea at rest or on minimal exertion and a left ventricular ejection fraction <25%. Patients were randomly assigned (double‐blind) to receive either placebo (n = 1133) or carvedilol (n = 1156) and were followed for the occurrence of major clinical events for up to 29 months (COPERNICUS trial). Patients were not enrolled if they had signs of clinically significant fluid retention due to heart failure.ResultsPatients in the carvedilol group were 33% less likely than patients in the placebo group to experience a further significant loss of weight (>6%) (95% confidence interval: 14–48%, P = 0.002) and were 37% more likely to experience a significant gain in weight (≥5%) (95% confidence interval: 12–66%, P = 0.002). Carvedilol's ability to prevent weight loss was most marked in patients with increased body mass index at baseline, whereas its ability to promote weight gain was most marked in patients with decreased body mass index at baseline. Increases in weight were not accompanied by evidence of fluid retention. Baseline values for body mass index and change in body weight were significant predictors of survival regardless of treatment.ConclusionsCarvedilol attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss.

The use of diuretics in heart failure with congestion — a position statement from the Heart Failure Association of the European Society of Cardiology

“…Furthermore, heart failure is often associated with cachexia which makes the interpretation of weight changes difficult. Additionally, cachexia might result in a loss of plasma proteins, reducing plasma oncotic pressure, hampering plasma refilling from the interstitium . Additionally, weight loss during hospitalization is not necessarily associated with improved in‐hospital or post‐discharge morbidity or mortality, however weight gain has been associated with poor outcome .…”

“…Additionally, cachexia might result in a loss of plasma proteins, reducing plasma oncotic pressure, hampering plasma refilling from the interstitium. 18,19 Additionally, weight loss during hospitalization is not necessarily associated with improved in-hospital or post-discharge morbidity or mortality, however weight gain has been associated with poor outcome. 20,21 Therefore, the European Society of Cardiology (ESC) guidelines for the diagnosis and treatment of acute and chronic heart failure recommend to distinguish acute fluid redistribution from true volume overload in patients presenting with congestion (no class recommendation).…”

Muscle wasting and sarcopenia in heart failure and beyond: update 2017

“…Subjects with cardiac cachexia show higher rates of atrial fibrillation, possibly contributing to the higher mortality. In patients with severe CHF, the non‐specific beta‐blocker carvedilol has been shown to reduce the development and lead to a partial reversal of cachexia . Overall, standard heart failure medication seems to reduce not only cardiac cachexia but also has the potential to attenuate cachexia progression in cancer .…”

“…In patients with severe CHF, the non-specific beta-blocker carvedilol has been shown to reduce the development and lead to a partial reversal of cachexia. 111 Overall, standard heart failure medication seems to reduce not only 494 cardiac cachexia but also has the potential to attenuate cachexia progression in cancer. 112 However, while the numbers of patients with cardiac cachexia have been lowered by heart failure medication, there is still a great medical need to find novel strategies for the sub-group of patients that seems to have no protection from developing cardiac cachexia by standard medication.…”

Do we need an individual approach to atrial fibrillation and adrenergic overload in the critically ill?

“…Clinical studies have confirmed the metabolic ef-fects of non-selective blockers, such as propranolol, on reduced hypermetabolism in burns, which could be prolonged up to 2 years, and carvedilol, which attenuated the development and promoted a partial reversal of cachexia in patients with severe chronic heart failure, supporting a role for prolonged sympathetic activation in the genesis of weight loss. (62,63) CONCLUSIONS Catecholamine administration is useful and even life-saving for short-term restoration of tissue perfusion or correction of life threatening hypotension. However, catecholamines are poisonous when given in excess, causing regional ischemia, triggering arrhythmia and promoting systemic inflammation.…”