Spironolactone helps prevent AF recurrence

Background
In March 2003 I published a report “Aldosterone: Villain of the Peace?” in which I suggested that elevated aldosterone levels could be a trigger for AF episodes and that the aldosterone antagonist spironolactone might be helpful in lengthening the interval between paroxysmal atrial fibrillation episodes. To quote from the March 2003 issue of "The AFIB Report":

“Spironolactone, a potassium-sparing diuretic, is highly effective in blocking MC-receptors. By doing so, it rebalances the ANS (increase parasympathetic activity and decreases sympathetic activity), decreases the risk of stroke, prevents hypokalemia, reduces fibrosis, improves endothelial function, and helps prevent hypertension (by blocking MC-receptors in the brain)[1,2]. Could spironolactone help extend the period between LAF episodes or prevent them altogether? Clearly it is a possibility, but one that only a clinical trial can confirm or deny.

Spironolactone, unfortunately, has several nasty side effects, especially breast enlargement and impotence. It is therefore not likely to be a viable long-term solution for LAF prevention. However, a "cousin" of spironolactone, eplerenone, has recently been developed and shows great promise in initial trials. Eplerenone is significantly more effective than spironolactone and animal experiments have shown that it protects the heart, brain and kidneys, especially against stroke and vascular injury[1,2]. Eplerenone does not cause breast enlargement or impotence. Could this new drug help prevent episodes? If the hypothesis is correct, it is certainly a very real possibility, but of course only a clinical trial will tell.

That long wished for clinical trial has now been completed.

[1] Kolb, C, et al. Modes of initiation of paroxysmal atrial fibrillation from analysis of spontaneously occurring episodes using a 12-lead Holter monitoring system. American Journal of Cardiology, Vol. 88, No. 8, October 15, 2001, pp. 853-57
[2] Pitt, B, et al. New insights into the role of aldosterone in cardiorenal disease and the clinical implications. Reference

Abstract
WARSAW, POLAND. Angiotensin II and aldosterone are key factors in the structural and neuro-hormonal remodeling of the atria and ventricles in patients with AF. A group of Polish researchers now report that the aldosterone antagonist (blocker) spironolactone is effective in lengthening the interval between episodes among paroxysmal afibbers with no underlying heart disease. Their prospective, randomized clinical trial involved 164 consecutive symptomatic, paroxysmal AF patients of which 53% were male. Average age of all patients was 66 years, 73% had hypertension, 41% had metabolic syndrome, 27% had coronary artery disease, and 59% were on statin drugs – so not exactly a healthy group.

The patients were randomized into receiving for different combinations of spironolactone, enalapril (an angiotensin II receptor blocker) and beta-blocker (propranolol, metoprolol or bisoprolol) as follows:

  • Group A – spironolactone + enalapril + beta-blocker
  • Group B – spironolactone + beta-blocker
  • Group C – enalapril + beta-blocker
  • Group D – beta-blocker (control group)

The daily spironolactone dose was 25 mg, the mean dose of enalapril was 12.5 mg/day, and the beta-blocker dosage was adjusted to achieve a resting heart rate (in sinus rhythm) between 60 and 70 bpm. In patients with hypertension, blood pressure was controlled to achieve a level below 130/80 mm Hg. The number of AF episodes (documented with ECG) over four separate 3-month periods was compared as shown below:

-
Group A
Group B
Group C
Group D
Baseline
4.0
3.5
2.9
3.6
0 to 3 months
1.0
1.5
1.1
2.5
4 to 6 months
0.7
0.7
1.5
3.1
7 to 9 months
0.6
0.7
1.7
3.3
9 to 12 months
0.6
0.5
1.5
2.6

The total cumulative incidence of AF episodes in the one-year follow-up period was 2.9 for group A (13 episodes less than baseline), 3.4 for group B (11 episodes less than baseline), 5.8 for group C (5.8 episodes less than baseline), and 11.5 for group D (2.9 episodes less than baseline). Only the improvement noted for groups A and B were statistically significant indicating that only spironolactone, but not enalapril or beta-blocker, is effective in AF prevention.

The researchers conclude that spironolactone + beta-blocker (group B) treatment might be a simple and valuable option in preventing paroxysmal AF episodes. They also comment that eplerenone might be a good alternative since it does not have the side effects of spironolactone, especially gynecomastia.

Dabrowski, R, et al. Effect of combined spironolactone-beta-blocker with or without enalapril treatment on occurrence of symptomatic atrial fibrillation. American Journal of Cardiology, Vol. 106, 2010, pp. 1609-14

Editor’s comment: It is indeed gratifying to see my 8-year-old hypothesis regarding the role of aldosterone and spironolactone confirmed in a clinical trial. The following sentence in the Polish report is also of particular interest:

Goette et al. demonstrated that AF occurrence results in an increase in aldosterone concentrations and that 2 days after cardioversion, its level has decreased, with a reduction of the aldosterone-renin index and mean heart rate.

In February 2003 I had my aldosterone and renin levels measured 2 days after an episode and 1 day before the next episode. Aldosterone levels were 34 nmol/day (24-hour urine test) 2 days after the episode and 51 nmol/day just before the next episode, while renin levels were 0.04 ng per liter per second after the episode and an undetectable 0.00 prior to the next episode. These results clearly confirm Goette’s observations and again demonstrate the desirability of afibbers having their aldosterone:renin ratio determined, particularly if episodes are of a cyclical nature.