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Three Part Question

In a patient with [atrial fibrillation requiring rate limitation] is [verapamil better than diltiazem] at 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 with a calcium channel blocker and wonder whether you should use diltiazem or verapamil.

Search Strategy

Medline 1966 to 09/2004 using Ovid Interface
[(exp atrial fibrillation OR atrial fibrillation.mp OR AF.mp) AND (exp diltiazem OR diltiazem.mp) AND (exp verapamil OR verapamil.mp)].
Embase 1974 to 06/2005 using Dialog DataStar interface.
[(atrial ADJ fibrillation) AND (verapamil) AND (diltiazem)].
The Cochrane library was also searched (accessed 09/2005).
References of the relevant articles were scrutinised.

Search Outcome

The Medline search produced 84 papers, Embase 419 papers, and Cochrane 11. A total of 3 papers were relevant to the 3-part question and of sufficient quality. The reference review discovered no further studies.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Phillips 1997	17 patients (>18 years) with stable AF/ flutter (>120/min) of unspecified duration randomised to receive either iv verapamil (5mg) or diltiazem (20mg) bolus. A second bolus (double strength) was given if there was no response (defined as HR <100/min or reduced by 20%) after 15mins. If there was still no response then the patient was withdrawn from the study. If there was a response then the patient was given an 8 hour infusion of drug followed by washout period without drug which lasted until the HR returned to the pre-study level. Following this they were crossed over to the other drug.	Prospective, randomised, double-blind, cross-over trial.	1. Heart rate	1. there was no difference in heart rate between verapamil and diltiazem after both bolus 2. There was no further reduction in rate during either infusion.3. More patients responded to diltiazem (78%) than verapamil (20%); however the study was too small for this to achieve statistical significance.	1. Very small study with a high drop out rate (47%). 2. Insufficient data was given to differentiate patients with AF from those with flutter. 3. It was difficult to compare non-responder rates because those who failed to respond to one drug were not given the other. 4. The study compared iv route of administration and iv diltiazem is not available in the UK.
			2. BP	3 patients (37.5%) given verapamil had to be withdrawn from the study due to symptomatic hypotension compared with none given diltiazem.
			These were measured 2, 5, 10, and 15 mins after each bolus and hourly during the infusions.
Tezcan 1996	24 patients with stable AF, rate >120/min (unspecified duration) given either diltiazem 0.35mg/kg iv (n=12) or verapamil 0.15mg/kg iv (n=12)	Randomised trial	1. Therapeutic effect: 20% decrease in HR from baseline; HR<10/min; Cardioversion	1. There was no significant difference between diltiazem (92%) and verapamil (100%).	1. Small study 2. The study compared iv route of administration and iv diltiazem is not available in the UK.
			2. Time to effect	2. No significant difference in time to effect:V. 3.9+/- 5 mins; D. 2.7 +/- 1 min.
			3. Rate of hypotension	3. Symptomatic hypotension occurred significantly more with verapamil (33% vs 0% with diltiazem). Mean blood pressure reductions in each group
Botto 1998	18 patients with chronic stable AF (>6/12). They were randomly given 1 week courses of gallapomil SR (100mg bd), diltiazem SR (120mg bd), verapamil SR (120mg bd), or digoxin (od, dose given determined by serum concentration).	Non-blinded, randomised, cross-over trial.	Patients had 24 hour Holter monitoring and a 6 minute exercise test on the last day of each treatment period.		1. Small study. 2. Not blinded. 3. No washout period between treatments.
			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 three studies identified were remarkably concordant in their findings; there was no significant difference in terms of heart rate limitation, but verapamil therapy was associated with more symptomatic hypotension. This hypotensive effect of verapamil makes biological sense because Bohm and colleagues4, using human papillary muscle, found that it had nearly three times the negative inotropic effects of diltiazem. In addition, intravenous diltiazem is not available in the UK. Further theoretical concerns were highlighted by Shenasa and colleagues5 who studied patients undergoing electrophysiological studies for the investigation of both AF and ventricular arrhythmias. Programmed electrical stimulation was used to induce AF in these subjects and duration of the AF was measured before and after administration of verapamil or diltiazem, and it was found that both drugs were associated with a prolongation of arrhythmia. Although it is difficult to translate these results directly to clinical practice, it may be that calcium channel blockers should be avoided in patients who present to Emergency Departments with paroxysmal AF (a group that would be expected to revert to sinus rhythm). Overall, it must be concluded that further, larger studies are needed to assess the effectiveness of diltiazem as a rate-controlling agent in acute AF; in particular, research into oral loading and its safety in patients with heart failure need to be undertaken.

Clinical Bottom Line

Intravenous diltiazem is at least as effective as verapamil at slowing heart rate in stable atrial fibrillation & flutter, and seems to have less negative inotropic effects. Both drugs should possibly be avoided in patients with paroxysmal AF, and verapamil should be used with caution in patients with heart failure, however, further research is needed.

References

1. Phillips BG, Ghandi AJ, Sanoski CA, Just VL, and Bauman JL. Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and atrial flutter. Pharmacotherapy. 1997; 17; 1238-1245
2. Tezcan H, Okucu M, Fak AS and Oktay A. Efficacy and safety of intravenous diltiazem versus verapamil in the acute treatment of atrial fibrillation. Turk Kardiyol Dernegi Ars 1996; 24; 36-42.
3. Botto GL, Bonini W and Broffoni T. Modulation of ventricular rate in atrial fibrillation: randomized, crossover study of the effects of slow-release formulations of gallopamil, diltiazem, or verapamil. Clinical Cardiol. 1998; 21; 837-840.