Heart rate variability in patients with mild to moderate heart failure: Effects of neurohormonal modulation by digoxin and ibopamine
Key result
Digoxin reduces plasma norepinephrine and improves HRV versus placebo in HF, whereas ibopamine fails.
- P<0.01
- n=59
Why the study?
Heart rate variability reflects autonomic dysfunction in chronic heart failure, but the effects of digoxin and ibopamine on heart rate variability in relation to neurohormonal activation remained to be assessed.
Does digoxin or ibopamine improve heart rate variability and neurohormonal activation in patients with mild to moderate heart failure?
Key Points
- To evaluate the effects of digoxin and ibopamine on heart rate variability parameters in relation to neurohormonal activation in patients with mild to moderate heart failure.
- Randomized, double-blind trial of 59 patients with mild to moderate heart failure (mean age 60 ± 1 years, mean ejection fraction 0.30 ± 0.01) receiving background furosemide therapy.
- Patients received 3 months of treatment with digoxin (0.25 mg daily, n=22), ibopamine (100 mg three times daily, n=19), or placebo (n=18).
- Plasma norepinephrine decreased in the digoxin group (-60 pg/ml) compared with an increase in the placebo group (+31 pg/ml, p < 0.01), whereas ibopamine showed a nonsignificant reduction (-27 pg/ml, p = 0.10).
- Digoxin significantly increased daytime pNN50 (+1.7 ± 0.9%, p < 0.01), absolute high frequency power (+40 ± 33 ms², p < 0.05), and normalized high frequency power (+2.4 ± 1.7%, p < 0.01), with the largest changes seen in patients with worse baseline variability.
- Heart rate variability parameters worsened in the placebo group, while ibopamine produced nonsignificant trends similar to digoxin.
Study Design
Type
RCT (n=59)
Blinding
double-blind
Randomization
randomized
Multicenter
Yes
Structured PICO
Does digoxin or ibopamine improve heart rate variability and neurohormonal activation in patients with mild to moderate heart failure?
P
Population
59 patients with mild to moderate heart failure (mean age 60 years, mean ejection fraction 0.30) followed for 3 months.
I
Intervention
Digoxin 0.25 mg (n=22) or ibopamine 100 mg three times a day (n=19), with background therapy of furosemide (up to 80 mg).
C
Comparator
Placebo (n=18), with background therapy of furosemide (up to 80 mg).
O
Outcome
Variables of heart rate variability and plasma norepinephrine levels at 3 months.surrogate
Main Result
Absolute Event Rate: -60% vs 31%
p-value: p=<0.01
In patients with mild to moderate heart failure, digoxin prevents deterioration in heart rate variability and decreases neurohormonal activation, whereas ibopamine does not have statistically significant effects.
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“In low doses, digitalis glycosides primarily work as a neurohormonal modulator, and low-dose digoxin was shown to lower plasma norepinephrine (and also aldosterone and renin) compared to placebo. Further, digoxin also improved heart rate variability, including a pronounced increase”
Implication
Supports autonomic modulation in mild-moderate HF; extends RCT evidence for digoxin and ibopamine effects on HRV.
Abstract
OBJECTIVES This study assessed the effects of digoxin and ibopamine on variables of heart rate variability in relation to neurohormonal activation. BACKGROUND Analysis of heart rate variability can be used to study the autonomic dysfunction that characterizes chronic heart failure. In the Dutch Ibopamine Multicenter Trial, patients with heart failure were found to have increased neurohormonal activation with placebo therapy but not with digoxin and ibopamine therapy. METHODS We studied 59 patients with mild to moderate heart failure (mean [+/- SEM] age 60 +/- 1 years, mean ejection fraction 0.30 +/- 0.01). Patients were randomized to double-blind treatment with digoxin (0.25 mg [n = 22]), ibopamine (100 mg three times a day [n = 19]) or placebo (n = 18); background therapy consisted of furosemide (up to 80 mg). RESULTS After 3 months, plasma norepinephrine levels had increased with placebo, whereas they decreased with digoxin (+31 vs. -60 pg/ml, respectively, p < 0.01). With ibopamine, nonsignificant decrease was observed (-27 pg/ml, p = 0.10). All variables of heart rate variability showed a deterioration in the placebo group. With digoxin, the percent differences between successive RR intervals > 50 ms (pNN50) increased (+ 1.7 +/- 0.9%, p < 0.01), along with absolute and normalized high frequency power (+ 40 +/- 33 ms2, p < 0.05 and + 2.4 +/- 1.7%, p < 0.01, respectively). These changes were observed during daytime hours only and were most pronounced in patients with the most impaired baseline heart rate variability. With ibopamine, nonsignificant trends similar to the changes with digoxin were observed. CONCLUSIONS In patients with early stages of heart failure, digoxin may prevent a progressive deterioration in heart rate variability, whereas ibopamine does not show statistically significant effects. The changes in heart rate variability with digoxin parallel an observed decrease in neurohormonal activation. Digoxin apparently enhances cardiac vagal tone in the setting of neuroendocrine activation.
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Cite This Study
Brouwer et al. (1995) conducted an RCT in mild to moderate heart failure (n=59). Digoxin and ibopamine vs. Placebo was evaluated on change in plasma norepinephrine levels (p=<0.01). Digoxin decreased plasma norepinephrine levels compared to placebo and improved heart rate variability in mild to moderate heart failure, whereas ibopamine did not.