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Three Part Question

In a stable patient with [acute atrial fibrillation], is [treatment superior] with [calcium channel blockers or digoxin]?

Clinical Scenario

A 57 year old woman attends the Emergency Department with palpitations of uncertain duration. A diagnosis of recent onset atrial fibrillation with a ventricular rate of 160bpm is made. 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 week 3, August 2009 using Ovid Interface. Embase 1980 to August 2009 using NHS National Library for Health Interface. The Cochrane Library was also searched (accessed August 2009) for articles on atrial fibrillation.

The articles obtained had their references scrutinised for further articles.

Studies assessing patients with chronic atrial fibrillation were excluded. One study comparing intravenous diltiazem with combined intravenous ditliazem and digoxin in acute atrial fibrillation was excluded.

Medline:[{exp atrial fibrillation OR atrial fibrillation.mp} AND ({exp calcium channel blockers OR calcium channel blockers.mp} OR {exp verapamil OR verapamil.mp OR exp diltiazem OR diltiazem.mp}) AND (exp digoxin OR digoxin.mp OR exp digitalis glycosides OR digitalis.mp)].

Embase:[(atrial fibrillation) AND (digoxin OR digitalis OR lanatoside OR oubain OR glycoside$) AND (verapamil OR diltiazem OR calcium channel blocker)}.

Search Outcome

The Medline search produced a total of 339 articles and Embase 236. Five papers were found to be directly relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Schreck et al, 1997, USA	30 consecutive patients presenting to an ED with acute onset AF or atrial flutter randomised to receive either: 9 patients allocated to IV digoxin 0.25 mg and again 30 min later; 11 patients allocated to IV diltiazem at an initial dose of 0.25 mg/kg, followed by 0.35 mg/kg at 15 min followed by an infusion of 10 mg/h to a maximum of 20 mg/h to keep VR ,100 bpm; 10 patients allocated to both IV diltiazem and digoxin. Excluded if BP,100 mm Hg systolic, drug allergy, acute MI or heart failure (NYHA Class 3 or 4), IV beta-blocker in preceding hour, WPW, SSS, cardiogenic shock, current treatment with calcium channel blockers other than diltiazem.	Unblinded randomised controlled trial	VR control measured over 3 h as defined as a HR ,100.	Rate control achieved within 15 min for IV diltiazem group and at 30 min for IV dlitiazem with digoxin group but not achieved at any time with IV digoxin alone. Reduction in HR in digoxin group reached significance at 3 h (p=0.0099). No additional benefit for HR control with the addition of digoxin to diltiazem	Unblinded but adequately powered study, only lasting 3 h. Dose of digoxin given as two boluses of 0.25 mg. Exclusions include those patients with acute MI and pulmonary congestion and those with severe heart failure. Not adequately powered to study complications
			Blood Pressure	Blood pressures lower with IV diltiazem
Innes et al, 1996, Canada	Convenience sample of 41/451 ED patients age 18–75, presenting in AF of ,48 h duration. 22 patients allocated to receive verapamil 5 mg IV, repeated at 20, 60 and 120 min if HR .100. 19 patients allocated to digoxin 0.5 mg IV and 0.25 mg at 60 and 120 min if HR .100. Placebo was given to ensure patients and clinicians were blinded. Exclusion criteria of HR ,100 or 200, allergy to study drugs, BP ,90 mm Hg with clinical evidence of hypoperfusion, heart block, SSS or prolonged QRS interval.	Randomised controlled trial	Number of patients with HR ,100.	5/22 patients receiving verapamil converted to sinus rhythm prior to rate control. 10/19 patients receiving digoxin converted to sinur rhythm prior to achieving rate control. Results difficult to extract from graph accurately, however at 20 min, average HR in verapamil group about 100 and digoxin about 130. At 40 min these results are 100 and 120, respectively. At 180 min the results are unchanged.	Small study. Study designed to compare the speed and success of cardioversion using first verapamil or digoxin (to control the rate), then quinidine (to cardiovert). Results are hard to extract.
Tisdale et al, 1998,	40 patients with acute AF within 7 days of CABG. 20 patients assigned to diltiazem 20 mg IV followed by 25 mg 15 min later. An infusion of 10 mg/h was started and increased 1 h later to 15 mg/h if ,20% decrease in ventricular rate. 20 patients assigned to digoxin 0.5 mg IV followed by 0.25 mg and 0.25 mg at 3 and 6 h. Placebo administered to enable blinding of doctors and patient. Exclusions included BP ,100 mm Hg, heart failure, renal failure, mechanical ventilation, hypokalaemia, hypomagnesaemia, heart block, WPW or administration of digoxin or calcium antagonist.	Randomised controlled trial	Ventricular rate control (.20% decrease) Time to ventricular rate control	At 2 h, 15/20 with diltiazem and 7/20 with digoxin, achieved rate control (p=0.03).At 6 h, 17/20 with diltiazem and 9/20 with digoxin achieved rate control (p=0.02). At 12 h, 17/20 with diltiazem and 13/20 with digoxin achieved rate control (p=0.27). At 24 h, 19/20 with diltiazem and 17/20 with digoxin achieved rate control (p=0.61)	All patients had undergone CABG in previous 7 days. Only 40/101 potential patients included because of wide exclusion criteria.
			Adverse events	3/20 with diltiazem developed hypotension. 1/20 with digoxin had sinus pauses on ECG.
Tan et al, 1999, China	54 patients presenting with acute AF or atrial flutter. 34 patients were randomised to IV diltiazem or 20 patients were randomised to IV cediland.	Single blind randomised trial.	Mean decrease in heart rate.	IV diltiazem group 34% and IV cediland group 23% reduction in HR from baseline.	Small study Doses uncertain. Details were difficult to extract as only the abstract available in English.
			Mean response time to bolus.	IV diltiazem 7 min and IV cediland 33 min.
			Side effects of drugs including effects on LV function, blood pressure and arrhythmias	No worsening of LVF in any patient. In the IV diltiazem group, 2/34 had asymptomatic hypotension and 1/34 had a ventricular pause.
Siu et al, 2009, Hong Kong	150 ED patients with acute symptomatic AF ,48 h duration with VR .120 bpm. 50 patients allocated to IV diltiazem 0.25 mg/kg over 2 min followed by 0.35 mg/kg if initial bolus failed, followed by infusion of 10 mg/h for 24 h. 50 patients allocated to digoxin 0.5 mg IV followed by 0.25 mg every 8 h (1.25 mg over 24 h). 50 patients allocated to amiodarone 300 mg over 1 h followed by 10 mg/kg over the next 24 h. Excluded if BP 90 mm Hg, congestive heart failure, recent ACS, VR .200 bpm, WPW, CVA or PE within 6 months, antiarrhythmic use, allergy to study drugs or other major medical condition.	Open-label randomised controlled trial.	Time to control of VR ,90.	Median time to VR control significantly shorter for diltiazem group compared with digoxin or amiodarone (3 h vs 6 h vs 7 h, respectively p,0.0001).	Initial digoxin dose low as was maintenance dose of amiodarone. Open-label study, therefore potential bias in assessment of AF symptoms. Adverse effects only defined as HR ,50 bpm for .30 min or BP,60 mm Hg systolic.
			Sustained control of VR defined as VR ,90 bpm for .4 h at 24 h.	Patients in diltiazem group significantly more likely to achieve control of VR within 24 h than those in the digoxin or amiodarone group (90% vs 74% vs 74%, respectively, p=0.047).
			Improvement of symptoms.	AF symptom score significantly lower in diltiazem group at 24 h compared with digoxin (p=0.047) and amiodarone (p=0.01).
			Length of stay in hospital.	Length of stay significantly less in diltiazem group compared with digoxin or amiodarone group (3.9 days vs 4.7 days vs 4.7 days respectively, p=0.023).
			Adverse events.	One case of phlebitis in amiodarone group, no other adverse effects.

Comment(s)

These drugs have not been compared in a population with severe left ventricular failure; in this population, diltiazem as a negative ionotrope may be disadvantageous. Although not directly addressed, the studies show that intravenous diltiazem has blood pressure-lowering effects.

Intravenous diltiazem and intravenous lanatoside (cediland) are not licensed in the UK; oral diltiazem may serve as an alternative.

Editor Comment

ACS, acute coronary syndrome; AF, atrial fibrillation; BP, blood pressure; CABG, coronary artery bypass graft; CVA, cerebrovascular accident; ED, emergency department; HR, heart rate; IV, intravenous; MI, myocardial infarction; PE, pulmonary embolism; VR, ventricular rate; WPW, Wolff-Parkinson-White syndrome.

Clinical Bottom Line

Although the evidence is limited, intravenous diltiazem produces more rapid control of heart rate than intravenous digoxin. While diltiazem undoubtedly produces more rapid control of the ventricular rate, this may not translate into a clinically significant difference for the stable patient in whom there may not be any urgency for ventricular rate control.

The search also serves as a reminder that the two databases may differ importantly in their search results (the Chinese paper was not picked up by Medline) and that drugs not available in the UK may be of use.

References

1. Schreck DM, Rivera AR, Tricarico VJ. Emergency Management of Atrial Fibrillation and Flutter: Intravenous Diltiazem Versus Intravenous Digoxin. Ann Emerg Med 1997:29;135-140.
2. Innes G, Vertesi L, Dillon E, et al. Effectiveness of verapamil-quinidine versus digoxin-quinidine in the emergency department treatment of paroxysmal atrial fibrillation. Ann Emerg Med 1997;29:126–34.
3. Tisdale J, Padhi I, Goldberg A, et al. . A randomized, double-blind comparison of intravenous diltiazem and digoxin for atrial fibrillation after coronary artery bypass surgery. Am Heart J 1998;135:739–47,
4. Tan H, Song Y, Cheng X. A comparative study on the efficacy and safety of intravenous diltiazem and cediland in rapid atrial arrhythmias. Chinese J Cardiol 1999;27:357–9.
5. Siu C, Lau C, Lee W, et al. . Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation Crit Care Med 2009;37:2174–9.