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Three Part Question

In a patient with [atrial fibrillation requiring rate limitation], are [calcium channel blocker superior to digoxin] in achieving [control of ventricular rate]?

Clinical Scenario

A 57 year old woman attends the Emergency Department with newly diagnosed atrial fibrillation of uncertain duration. You decide to treat her by ventricular rate limitation and wonder whether you should use digoxin or a calcium channel blocker.

Search Strategy

Medline 1966 to 07/2004 using Ovid Interface
Embase 1964-04/2005 using Dialog DataStar interface
The Cochrane library was also searched (accessed 09/2005).
Articles obtained had their references scrutinised for further relevant papers.
Medline:[(exp atrial fibrillation OR atrial fibrillation.mp OR AF.mp) AND (exp calcium channel blocker OR calcium channel blocker.mp) AND (exp digoxin OR digoxin.mp OR exp digitalis OR exp digitalis glycosides OR digitalis.mp)]
Embase:[(atrial ADJ fibrillation) AND (calcium ADJ channel ADJ blockers) AND (digoxin OR digitalis OR glycoside$)].

Search Outcome

The Medline search produced 146 papers, Embase 771 papers, and Cochrane 65, of which 6 were found to be of sufficient quality and relevant to the three-part question.
The reference review identified no further studies.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Lang 1983	52 patients (30-82 years) with stable, chronic AF (>1 year duration) treated in cardiology outpatients. They were give five 2/52 trial periods (random order) of no treatment, digoxin 0.25mg and 0.5mg, verapamil 240mg/day, and digoxin 0.25mg + verapamil 240mg/day.	Unblinded, randomised, controlled crossover trial	Resting HR, Post exercise HR, Exercise tolerance	Significant reduction in both resting and post exercise HR with verapamil compared with digoxin	Small unblinded study Not an ED population
Lewis 1987	12 patients with chronic stable AF (> 1 year) undergoing 2 treatment periods, each of 6/52 (random order): 1. digoxin (given at a predetermined dose to give plasma levels of 1.3-2.6 nmol/l); 2. verapamil started at 40mg tds and increased at 2/52 intervals to 80mg then 120mg tds.	Randomised, double-blind, crossover trial.	Resting HR, post exercise HR, and exercise tolerance	Verapamil significantly reduced post exercise HR compared to digoxin, but there was no significant difference in resting HR and exercise tolerance.	Small study High drop out rate (3 [25%] – 1 patient spontaneously reverted to SR, while 2 suffered unacceptable side-effects [both on verapamil]) No note of baseline HR, before study Not an ED population
Lewis 1988	14 patients with chronic stable AF (> 1 year) undergoing 3 treatment periods, each of 4/52 (random order): 1. digoxin (given at a predetermined dose to give plasma levels of 1.3-2.6 nmol/l); 2. diltiazem 60mg tds or 120mg tds after 2/52; 3. digoxin + diltiazem 60mg tds.	Randomised, double-blind, crossover trial.	Resting HR, post exercise HR, exercise tolerance	Diltiazem produced a small reduction in resting and post exercise HR compared with digoxin, but there was no difference in exercise tolerance.	Small study High drop out rate (4 [29%] – 1 patient spontaneously reverted to SR, while 3 suffered unacceptable side-effects [both on diltiazem]) No note of baseline HR, before study Not an ED population
Moragno 1988	19 patients (29-73 years) with chronic stable AF (>3/12) undergoing 3 treatment periods: 1. digoxin (given at a predetermined dose to give plasma levels of 0.7-2.0 ng/l for 2/52); 2. digoxin + diltiazem 60mg tds (10) or qds (9) for 1/52; 3. diltiazem alone.	Non-randomised, crossover trial.	Resting and post exercise HR	There was no significant difference in resting HR between diltiazem (either dose) and digoxin. However diltiazem significantly reduced post exercise HR compared to digoxin.	Small unblinded study Not an ED population Short study periods.
Schreck 1997	33 patients presenting to an ED with acute onset atrial fibrillation or flutter receiving either iv digoxin, iv diltiazem, or both to control VR	Unblinded randomised controlled trial	Patients had 24 hour Holter monitoring and a 6 minute exercise test on the last day of each treatment period.		Small unblinded study Low dose of iv digoxin given as two boluses Exclusions include those patients with acute MI and pulmonary congestion and those with severe heart failure. Not adequately powered to study complications
			1. Mean HR over 24 hours.	1. No significant difference between any of the drugs.
			2. Minimum HR at night.	2. No significant difference between any of the drugs.
			3. Maximum HR during exercise.	3. There was no significant difference between any of the calcium channel blockers. However, they were all significantly better than digoxin (gallapomil p=0.01, others p<0.001): • Digoxin 167/min (149-185). • Gallapomil 149/min (105-176). • Diltiazem 142/min (114-173). • Verapamil 137/min (90-182).

Comment(s)

The four studies of patients with chronic stable AF1-4 seem to indicate that oral verapamil and diltiazem are more effective at controlling heart rate than digoxin in this group of patients. Interestingly, this does not seem to have been translated into improved exercise tolerance, possibly due to the negative inotropic effects of the calcium channel blockers (in contrast to digoxin which is a positive inotrope). These studies were small, of short duration, and involved cardiology outpatients so care must be exercised in drawing direct conclusions with ED patients, particularly those with acute AF. In contrast, covariate analysis of the AFFIRM Study6 (Reference 6. The AFFIRM Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004; 109; 1509-1513.) indicated that long-term digoxin use (mean follow up in this study was more than 3 years) was associated with a higher mortality (for further discussion, see Rate vs Rhythm BET). Although such a study cannot entirely exclude the influence of confounding variables, it raises significant concerns about the safety of long term digoxin for patients with otherwise stable AF. In Schreck's study5, iv diltiazem produced more rapid control of heart rate than iv digoxin. Although not directly addressed, blood pressure is lower with iv diltiazem, but this was thought not to be clinically significant. Unfortunately, iv diltiazem is not licensed in the UK. Further research is needed to ascertain the effect of alternative treatment strategies such as oral administration of calcium channel blockers or iv verapamil. In particular, studies should not measure only reduction in heart rate, but also clinical effects such as exercise tolerance, cardiac output, morbidity and mortality.

Clinical Bottom Line

The evidence suggests that calcium channel blockers are superior to digoxin in terms of reducing heart rate, however, this may not be translated into better clinical effect and further research is needed to clarify this.

References

1. 1. Lang R, Klein HO, Weiss E, David D, Sareli P, Levy A, Guerrero J, Di Segni E, and Kaplinsky E. Superiority of oral verapamil therapy to digoxin in treatment of chronic atrial fibrillation. Chest. 1983; 83; 491-499.
2. Lewis R, Lakhani M, Moreland TA and McDevitt DG. A comparison of verapamil and digoxin in the treatment of atrial fibrillation. Eur Heart J. 1987; 8; 148-153.
3. Lewis RV, Laing E, Moreland TA, Service E, and McDevitt DG. A comparison of digoxin, diltiazem and their combination in the treatment of chronic atrial fibrillation. Eur Heart J. 1988; 9; 279-283.
4. Maragno I, Santostasi G, Gaion RM, Trento M, Grion AM, Miraglia G, and Volta SD. Low- and medium-dose diltiazem in chronic atrial fibrillation: comparison with digoxin and correlation with drug plasma levels. Am Heart J. 1988; 116; 385-392.
5. Schreck DM, Rivera AR, Tricarico VJ. Emergency Management of Atrial Fibrillation and Flutter: Intravenous Diltiazem Versus Intravenous Digoxin. Annals of Emergency Medicine 1997:29;135-140