Carvedilol Does Not Improve Exercise Performance in Fontan Patients: Results of a Crossover Trial.
Butts R, Atz AM, BaezHernandez N, Sutcliffe D, Reisch J, Mahony L.
Pediatr Cardiol. 2021 Feb 14. doi: 10.1007/s00246-021-02565-6. Online ahead of print.
Take Home Points:
- Carvedilol does not improve exercise performance of patients with “good” Fontan.
- There is a decrease in heart rate at peak exercise accompanied by an increase in oxygen level post Carvedilol treatment.
Commentary from Dr. M.C. Leong (Kuala Lumpur, Malaysia), section editor of ACHD Journal Watch: Patients with heart failure have chronically elevated levels of neurohormones e.g., norepinephrine and epinephrine, which compensates for the reduced heart function and maintains cardiac output. However, chronic high levels of norepinephrine lead to overstimulation of the heart, hastening the process of heart failure (1). Beta-blocker has been shown to reduce cardiac remodeling caused by elevated circulating catecholamines. Patients with Fontan circuits were associated with elevated circulating neurohormones as a compensatory mechanism to chronic low cardiac output syndrome (2). Meanwhile, in the absence of a subpulmonic pump, it is unknown whether increasing the filling time of the systemic ventricle will potentially increase the cardiac output of Fontan circuit.
In this study, the authors aimed to investigate the role of adding a selective beta-blocker, Carvedilol on the cardiac output of patients with Fontan circulation by using exercise capacity as the endpoint. The study also aimed to assess the carvedilol adverse event profile and effect on chronotropic incompetence in Fontan patients.
This study is a randomized, double-blind, placebo-controlled crossover trial of oral Carvedilol in young adults and children with Fontan circulation. 23 beta-blocker naïve patients with good Fontan i.e., able to achieve an RER > 1.0 during exercise testing, low NT-proBNP of < 300 pg./mL, serum albumin > 2.0 g/dL, serum creatinine < 2.0 mg/dL, AST or ALT < 3 times upper limit of normal, hemoglobin < 18 g/dL or > 7 g/dL were recruited. The patients were prescribed Carvedilol or placebo over 12 weeks as described in Figure 1, followed by a 6-week washout, before the crossover. Cardiopulmonary exercise tests were performed at the end of the 12-week treatment before and after the crossover. A 10% change in peak VO2 was defined as a desired detectable difference in the change in peak VO2. Baseline characteristics of the patients were as shown in table 2.
The study showed that oxygen consumption at rest did not differ between treatment groups. There was a statistically significant decrease in diastolic blood pressure with Carvedilol and heart rate. The rest of the exercise parameters were not significantly different between the treatment groups (Table 3). The change in oxygen consumption at peak exercise did not differ between subjects taking carvedilol vs. placebo (Figure 2). Understandably, treatment with Carvedilol was associated with a decrease in heart rate at peak exercise accompanied by an increase in oxygen.
level (Figures 3 and 4). The blood parameters demonstrated a similar non-remarkable difference; sans the clinically non-meaningful NT-proBNP change.
This study showed that Carvedilol failed to improve the exercise capacity of patients with Fontan circulation. There is, however, a blunted chronotropic response with Carvedilol, a condition which although expected, was a worrying feature given the association of Fontan circulation with chronotropic incompetence. This along with the potential of side effects from the beta-blocker has cast concerns over its routine use in the absence of cardiac arrhythmia in this group of patients.
While this study was very well planned and executed, I find the selection of patients concerning. Beta-blocker works well in patients with biventricular physiology and heart failure. The study population was patients with good Fontan and minimal heart failure, and hence potentially reduced the response observed. Perhaps studying its effect on patients with failed Fontan circuits would be more meaningful.
- Lymperopoulos A, Rengo G, Koch WJ. Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 2013 Aug 30;113(6):739-53.
- Ohuchi H, Negishi J, Ono S, Miyake A, Toyota N, Tamaki W, Miyazaki A, Yamada O. Hyponatremia and its association with the neurohormonal activity and adverse clinical events in children and young adult patients after the Fontan operation. Congenit Heart Dis. 2011 Jul-Aug;6(4):304-12.