Relationship Between the Long-Term Preventive Effect of Combined Treatment With Antiarrhythmic Drugs Plus Angiotensin-Converting Enzyme Inhibitors and Circadian Variation in the Onset of Paroxysmal Atrial Fibrillation

Abstract

SummaryWe examined the relationship between the efficacy of combined treatment with antiarrhythmic drugs (AAD) plus enalapril for maintaining sinus rhythm and circadian variation in the onset of paroxysmal AF.Three hundred and forty-four patients with paroxysmal AF (239 men, mean age, 69 ± 11 years) who could be followed up ≥ 12 months were divided into 3 groups on the basis of circadian variation in the onset of AF: a diurnal group (7:00 AM-5:00 PM, n = 57), a nocturnal group (5:00 PM-7:00 AM, n = 108), and a mixed group (onset during both periods, n = 169). The maintenance rate of sinus rhythm during the follow-up period was compared between combined therapy (AAD plus enalapril) and AAD alone.In the diurnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 100%, 100%, 100%, and 100%, respectively, for patients treated with AAD plus enalapril (n = 22) versus 97%, 91%, 89%, and 80% for patients treated with AAD alone (n = 35, P < 0.05). In the nocturnal group, the maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 96%, 96%, 96%, and 92%, respectively, in patients treated with AAD plus enalapril (n = 24) versus 100%, 100%, 100%, and 100% in patients treated with AAD alone (n = 84, P = NS). In the mixed group, maintenance rates of sinus rhythm at 12, 36, 60, and 90 months were 90%, 71%, 61%, and 57%, respectively, in patients treated with AAD plus enalapril (n = 49) versus 88%, 78%, 68%, and 61% in patients treated with AAD alone (n = 120, P = NS).Our findings suggest that the preventive efficacy of combined therapy with AAD plus enalapril is dependent on the timing of onset of paroxysmal AF, and this regimen seems to be most beneficial for the diurnal type of paroxysmal AF. The number of patients with AF in the United States exceeded 5 million in 2000 and is expected to increase two to threefold over the next 50 years.2) In Japan, the population is aging rapidly and the prevalence of AF among elderly persons aged 70 years or older is already around 3%. This is expected to increase to about 4.5% over the next 20 years.3) Antiarrhythmic drug (AAD) therapy for the maintenance of sinus rhythm in patients with AF has limitations. 4) Accordingly, attention has recently been paid to upstream treatment, in which AAD therapy is combined with renin-angiotensin-aldosterone system (RAAS) inhibitors 5,6) or statins 7) to modify the arrhythmic substrate of the atrial myocardium which is the underlying cause of AF. In a recent large clinical trial, however, additional treatment with angiotensin II-receptor blockers (ARB) to AAD was not associated with a reduction in the incidence of recurrent atrial fibrillation.8) It is still not clear which clinical profile of paroxysmal AF benefits from the addition of RAAS inhibitor therapy as an upstream treatment.We report on the results of our investigation into the longterm preventive effect of combined treatment with enalapril, an angiotensin-converting enzyme inhibitor (ACEI), plus AAD therapy in relation to circadian variation in the onse...