Rate control in permanent atrial fibrillation

Abstract

Guidelines on the use of digoxin are inconsistent with evidence from randomised trials

Atrial fibrillation is the most common cardiac arrhythmia and it causes substantial morbidity, especially in elderly people. In June 2006, the UK National Institute for Health and Clinical Excellence (NICE) published new guidelines for control of heart rate in people with chronic atrial fibrillation.¹ The guidelines depart from historical practice by recommending that instead of digoxin, β adrenoceptor blockers or rate limiting calcium antagonists should be the preferred initial monotherapy, except in predominantly sedentary people. Similarly, the revised 2006 joint American College of Cardiology/American Heart Association/European Society of Cardiology (ACC/AHA/ESC) guidelines recommend the use of β blockers or calcium antagonists alone to control heart rate.² We have reviewed the evidence to support this fundamental change in practice and challenge its safety.

No single definition of ideal control of heart rate in chronic atrial fibrillation exists.³ Rate control drugs aim to reduce heart rate at rest and during exercise, without causing excessive nocturnal bradycardia. The ultimate aim of treatment is to improve symptoms and exercise tolerance, and to prevent cardiomyopathy induced by tachycardia. To reduce morbidity, the benefits of treatment need to be weighed against the harms. A substudy of the atrial fibrillation follow-up investigation of rhythm management (AFFIRM) study found no association between achieved ventricular rate and overall survival or quality of life.⁴

Epidemiological studies in the United Kingdom and the United States have reported an overall decline in the use of digoxin, perhaps as a result of recent recommendations. People with atrial fibrillation sometimes take β blockers or calcium antagonists for indications other than arrhythmia. In a descriptive study of the management of rate control in 2027 people, the AFFIRM investigators reported no significant difference in adequate control of heart rate at rest and exercise in people treated with β blockers alone or digoxin alone, which suggests that digoxin is still one of the first line drugs for the management of heart rate.⁵

Of previously published systematic reviews,^{6 7} one highlighted the lack of evidence on optimal control of heart rate in people with atrial fibrillation and the importance of symptom control. In the other, the comparisons of β blockers and calcium antagonists with placebo were confounded by most patients on either treatment arm also being on digoxin.⁶ Clearly, larger randomised trials are needed to inform prescribing decisions. However, the current evidence on which recommendations have been made is summarised below.

We searched the literature using the Medline, PubMed, and Cochrane databases for studies published in English. By reviewing bibliographies of relevant articles we identified additional studies. We reviewed 57 studies, including 25 randomised double blind controlled trials, assessing digoxin, β blockers, calcium antagonists, and combinations for rate control in chronic atrial fibrillation. The smallest trial recruited six participants and the largest included 136. Differences in methodology and outcomes make direct comparisons difficult. Only a minority of studies reported symptom scores and patient preferences.

Digoxin has long been used for control of heart rate in chronic atrial fibrillation. It acts primarily by exerting a vagomimetic influence on the atrioventricular node and has a positive inotropic effect. It has few side effects but has a flat dose-response curve and a narrow therapeutic index, so that subtherapeutic doses are often used. It is less effective at controlling heart rate during exercise and in states of increased sympathetic activation.

In people with atrial fibrillation, β adrenoceptor blockers have heterogeneous effects on heart rate, depending on their specificity for the β receptor and how much concomitant β agonist activity they possess. Ten studies^{8 9 10 11 12 13 14 15 16 17} evaluated β blockers alone. The β blocker was better than digoxin in controlling heart rate at rest in only one study,⁸ although it improved heart rate during exercise in four studies.^{8 9 11 15} Xamoterol (discontinued in the United Kingdom in 2000) was the only β blocker to improve exercise tolerance compared with digoxin, but at the expense of worsening control of heart rate.¹³ In six other studies, exercise capacity did not improve when β blockers were used alone. In comparison, several studies have shown that better heart rate control at rest and during exercise is achieved with combined digoxin and a β blocker than with digoxin alone.^{8 14 18 19 20 21 22 23 24 25 26 27 28} However, the effect of this combination on exercise tolerance is not consistent—some studies reported deterioration in exercise capacity,^{18 19 21 23 28} some reported improvement,^{13 22 24} and others reported no change.^{14 15 18 20 25 27 29} Other side effects were reported with the use of β blockers in the above studies and, importantly, two studies reported worsening symptoms of heart failure on withdrawal of digoxin in people with heart failure.^{13 14}

The calcium channel blocker diltiazem has been evaluated in five studies.^{15 30 31 32 33} They found that diltiazem was better than digoxin at controlling heart rate during exercise, but not during rest, and no improvement was seen in exercise capacity. Eleven studies^{15 21 22 30 32 33 34 35 36 37 38} assessed the combination of diltiazem and digoxin; most of these reported improved heart rate control at rest and exercise when compared with digoxin alone. Two also found improved exercise tolerance with the combination.^{22 36} One person developed worsening heart failure after discontinuation of digoxin while receiving diltiazem 360 mg daily.³³ In another study, two people with previous episodes of heart failure deteriorated when digoxin was discontinued.³⁰

Results were similar when monotherapy with verapamil was compared with digoxin. Verapamil improved heart rate during exercise compared with digoxin in three studies.^{31 39 40} Exercise tolerance with verapamil alone improved in two of the three studies that tested it.^{17 40} The combination of digoxin with verapamil provided better heart rate control at rest and during exercise than digoxin alone.^{20 18 36 41 42 43 44 45 46} However, bradycardic episodes or pauses were sometimes seen with the combination. Exercise tolerance was not consistently improved despite better heart rate control, with some studies reporting improvement^{36 40 41} and others no change.^{18 20 44 47} Concomitant use of both drugs increases digoxin concentrations.

Limitations to the use of verapamil and diltiazem include their negative inotropic effects and considerable dose related side effects.

In patients with chronic atrial fibrillation, digoxin has been the mainstay of treatment for many years, so new recommendations relegating digoxin should be evidence based and safe. We believe that little evidence exists that monotherapy with β blockers or calcium channel blockers improves exercise tolerance compared with digoxin. On the contrary, there is clear evidence that when β blockers are used alone, exercise capacity may worsen, especially in people with a history of heart failure.

Similarly, little evidence exists that monotherapy with these drugs improves heart rate control at rest and during exercise compared with digoxin alone. Beneficial effects on heart rate variability, together with improved exercise tolerance, have only been shown with the combination of digoxin and a β blocker or calcium channel blocker. We believe that the combination of digoxin and a β blocker or calcium antagonist should be recommended as first line management. We would emphasise that it is safest to start treatment with digoxin first.