The control of heart rate in patients with chronic atrial fibrillation : efficacy and safety of digoxin alone and in combination with low dose diltiazem or betaxolol

Abstract

Chronic atrial fibrillation is a common cardiac arrhythmia. It is characterized by a rapid increase in the ventricular rate during exercise. Digitalis has been used traditionally as a drug of choice far control of ventricular rate in patients with chronic aerial fibrillation. Although digitalis is valuable at rest, it is less effective in the control of exercise heart rate. Relatively high dose of beta-adrenergic blockade and calcium channel blockers have been shown to be more effective than placebo and digoxin in controlling exercise induced increase in the ventricular response rate in patients with chronic atrial fibrillation. However, side effects frequently made patients discontinue those drugs and are known to be dose dependent. The objectives of this study were three-fold : 1) to reevaluate the role of digitalis in maintaining adequate heart races in patient with chronic atrial fibrillation 2) to oupare the effects and safety between digoxin in combination with low dose diltiazem and betaxolol in controlling heart rate at rest and during exercise in patients with chronic atrial fibrillation 3) to study the frequency of side effects in using low dose diltiazem and betaxolol when added to digoxin. A prospective study was performed using a combination of low dose dilitiazem or betaxolol with digoxin in 42 patients with chronic atrial fibrillation including two patients with mild left ventricular dysfunction. Patients were gurouped as follows : Group Ⅰ - 14 patients without medication lf digoxin, diltiaem of betaxolol , Group Ⅱ - 11 patients treated with digoxin alone(0.125-0.5㎎ daily); Group Ⅲ -8 patients treated with digoxin(0.125-0.5,㎎ daily) and diltiazem (90㎎ two times daily); Group Ⅳ -9 patients teated with digoxin(0.125-0.5㎎ daily) and betaxolol (20㎎ daily). All patients were evaluated before medication, at 2 weeks and 4 weeks after medication. At each time, heart rate and blood pressure were measured at rest and during a symptom-limited treadmill exercise test. 1) Resting ventricular rates were significantly reduced in group Ⅱ,Ⅲ, and Ⅳ compared with group I [p<0.01]. During exercise, ventricular rates in group Ⅲ and Ⅳ were significantly reduced in comparison with group Ⅰ and Ⅱ [p<0.01]. Meanwhile, there was no significant difference between group Ⅲ and Ⅳ in controlling ventricular rate both at rest and during exercise. 2) Rate pressure products, at rest and during exercise, were significantly reduced in group Ⅲ and Ⅳ compared with group Ⅰ and Ⅱ[p<0.01]. But there was no significant difference between group Ⅲ and Ⅳ in reducing rate pressure products both at rest and during exercise. 3) Exercise capacity - There were no significant differences in maximal tolerated exertion between group Ⅰ, Ⅱ, Ⅲ, and Ⅳ. 4) Side effects - There were minimal side effects. In conclusions, the combination therapy of low dose diltiazem or betaxolol with digoxin provided optimal resting and exertional control of heart rate while minimizing side effects. But, there was no significant difference between the efficacy and safety low dose diltiazem and betaxolol when added to digoxin.;본연구의 목적은 1) 만성 심방세동 관자의 심박동수 조절에 대한 digoxin의 역할을 재평가하고, 2) 안정시와 운동시 심박동수 조절을 위한, digoxin과 저용량의 diltiazem 또는 betaxolol과의 병합요법 사이의 효과를 비교하고, 3) 이틀 병합요법에 따른 부작용의 빈도에 관하여 알아보고자 하였다. 저자는 1992년 8월부터 1993년 8월까지 약 1년간에 걸쳐서, 만성 심방세동을 가진 42명의 환자를 대상으로 전향적 연구들 시행하였으며, 다음과 같은 네군으로 나누었다. 제 1군 - Digoxin, diltiazem또는 betaxolol을 투여하지 않은 대조군 14명, 제 2군 - Digoxin 단독 투여군 11명 (1일 1회 0.125 - 0.5㎎ 경구투여), 제 3군 - Digoxin과 diltiazem (1일 2회 90㎎씩 경구투여) 복합 투여군 8명, 제 4군 -Digoxin과 betaxolol (1일 1회 20㎎경구투여) 복합투여군 9명. 그 결과는 각각 다음과 같다. 1) 혈청 digoxin 농도는 제 2군에서 1.24±0.1nmo1/1iter, 제 3군에서 1.151±0.1nmol/liter, 제 4군에서 1.181±0. 1nmo1/1iter로 모두 혈중 유효농도 범위를 유지하였다. 2) 안정시 심박동수는 제 1군에 비하여 2,3,4군에서 의의있게 감소하였다. 운동시 심박동수는 제 3군과 4군에서 1,2군에 비하여 의미있게 감소하였다 ( p<0.01 ). 반면에 제 3군과 4군 사이에 안정시와 운동시의 심박동수 조절은 두군간의 통계학적인 차이가 없었다. 3) 안정시와 운동시 rate-pressure products는 제 1군과 2군에 비하여 3군과 4군에서 의미있게 감소 ( p<0.01 )하였으나, 제 3군과 4군사이에는 차이가 없었다. 4) 운동량 - 각 군 사이에 최대 운동량 사이에 의미있는 차이는 없었으며, 제 4군에서 운동량 감소는 관찰되지 않았다. 5) 부작용 - 매우 적은 예에서 부작용을 나타내었다. 결론적으로, digoxin과 저용량의 diltiazem 또는 betaxolol과의 병합 요법은, 만성 심방세동 환자에서 안정시와 운동시의 심박동수를 적절히 조절하면서 부작용을 극소화 하였다. 그러나 digoxin과 복합 투여만 diltiazem과 betaxolol 사이에는 효과 및 안전성에 있어 의미있는 차이가 없었다.