Pharmacological conversion of recent-onset atrial fibrillation: A systematic review

Abstract

Objectives. Recent-onset (duration ≤ 1 week) atrial fibrillation (AF) has a high rate of spontaneous conversion to sinus rhythm (SR); still anti-arrhythmic drugs (AAD) are given for conversion purposes. We assessed the effect of AADs by reviewing the literature regarding conversion rates of available drugs in a systematic manner. Design. PubMed searches were performed using the terms “drug name”, “atrial fibrillation”, and “clinical study/RCT”, and a list of 1302 titles was generated. These titles, including abstracts or complete papers when needed, were reviewed for recent-onset of AF, the use of a control group, and the endpoint of SR within 24 hours. Postoperative and intensive care settings were excluded. Results. Five AADs were demonstrated to have an effect, and these were Amiodarone, Ibutilide (only one study and risk of torsade de pointes), Flecainide and Propafenone (only to be used in patients without structural heart disease) and Vernakalant. The time taken for conversion differed markedly; Vernakalant converted after 10 minutes, while Amiodarone converted only after 24 hours; Propafenone and Flecainide had conversion times in-between. Conclusions. For a rapid response in a broad group of patients, Vernakalant appears to be a reasonable first choice, while Flecainide and Propafenone can be used in patients without structural heart disease.

Key words::

• atrial
• fibrillation
• arrhythmia conversion
• pharmacological

Introduction

Patients may seek medical attention for symptomatic new-onset, established paroxysmal or relapsing persistent atrial fibrillation (AF). The number of patients not seeking medical attention for these conditions is not known; however, as many patients are diagnosed with AF when complaining of other symptoms and several patients who are accustomed to their bouts of this arrhythmia just wait for spontaneous conversion to sinus rhythm (SR), one might assume that the patients presenting at the emergency departments with AF are only a small proportion of the patients with recent-onset AF. In patients with severe symptoms and/or in hemodynamic distress, immediate conversion to sinus rhythm may be indicated and electrical (DC) conversion most often is the preferred method, both for its high success rate, the immediate onset of effect and the low rate of side effects. On the other hand, this approach requires a fasting patient and the need for general anaesthesia, which may not always be readily available. Furthermore, patients with established paroxysmal AF have a high rate of spontaneous conversion to sinus rhythm, even those with sufficient symptoms to warrant a visit to the emergency department. Thus, a small subset of patients characterised by (1) enough symptoms to seek immediate medical attention, (2) without symptoms or clinical findings making immediate DC conversion necessary or (3) unwillingness to accept the waiting hours for assumed spontaneous conversion to sinus rhythm may be eligible for a trial of pharmacological conversion. In this rather narrow setting of conditions, where the aim of the treatment often is only to spare the patients a few more hours in AF before spontaneous conversion most probably will occur, it is crucial to select a drug that will not put the patient at any unacceptable risk, depending on the general clinical state and the cardiac status of the patient. Often, the cardiac status of the patient is not known; accordingly, it may sometimes be wise to withhold drugs in patients when their previous history is unavailable. Acute rate control drugs and other symptomatic measures may be given as an alternative or in addition to a conversion trial; however, the combination of rate control and rhythm control drugs may have additive negative effects and should be considered carefully. The emphasis of this review is solely on documented effects of the conversion efficacies of the respective anti-arrhythmic drugs, and to discuss the side effects and precautions of those. Methodological transparency was of utmost importance when critically reviewing the existing literature.

Materials and methods

We performed Pub Med searches using “drug name” and “atrial fibrillation”, and with the limits “English language”, “Human” and “Clinical study/randomized controlled trial (RCT)”. Drugs that to our knowledge have been used for conversion trials were included in the searches. The following 23 drugs were chosen for the review, Table I. The list of titles/abstracts/papers which was generated was then evaluated with regard to the use of a control group, either placebo or another comparator. Only studies including a control group were included. By definition of recent-onset AF, only studies including patients with AF duration of ≤ 7 days were included (one study with a limit of eight and one with 10 days duration of AF were nevertheless included). If studies included patients with longer AF duration, subgroups of patients with duration equal to or less than one week were searched for and included when clearly stated results for this subgroup. An endpoint of conversion to SR within 24 hours was the longest accepted for this review. Furthermore, studies dealing with rate control, chronic or persistent AF, postoperative patients, intensive care patients and other populations not including recent-onset AF were not considered.

Table I. Drugs that were included in the PubMed searches.

a)	Ajmaline
b)	Amiodarone
c)	Atenolol
d)	Azimilide
e)	Bisoprolol
f)	Carvedilol
g)	Digoxin
h)	Diltiazem
i)	Disopyramide
j)	Dofetilide
k)	Esmolol
l)	Flecainide
m)	Ibutilide
n)	Metoprolol
o)	Pilsicainide
p)	Procainamide
q)	Propafenone
r)	Propranolol
s)	Quinidine
t)	Sotalol
u)	Timolol
v)	Verapamil
w)	Vernakalant

In case the title clearly demonstrated that the paper was dealing with other populations, the paper was directly excluded from analysis; when in doubt, the abstract or paper was carefully read and evaluated for appropriateness of this review. For 11 out of the 23 drugs, no relevant papers appeared during these searches, Table II.

Table II. Drugs for which no relevant papers emerged and number of studies generated for each drug, according to the search criteria.

Ajmaline	2
Atenolol	37
Azimilide	12
Bisoprolol	9
Carvedilol	23
Disopyramide	29
Dofetilide	23
Esmolol	15
Metoprolol	46
Propranolol	23
Timolol	5

Drugs that clearly demonstrated lack of effect were used for comparison with others drugs, in addition to placebo-controlled studies.

Results

Table III demonstrates drugs where studies appeared with relevant information according to the study criteria, as well as number of studies and number of patients given drugs or controls.

Table III. Drugs with one or more relevant papers, A number of studies found according to search criteria, B number of relevant studies with placebo (or ineffective drug) control and C number of patients given drug or placebo according to column B.

	A	B	C
Amiodarone	272	13	1286
Digoxin	179	4	397
Diltiazem	61	0	0
Flecainide	92	5	472
Ibutilide	46	1	74*
Pilsicainide	12	1	75
Procainamide	32	2	263
Propafenone	117	13	1615
Quinidine	52	1	61
Sotalol	115	2	136
Verapamil	93	0	0
Vernakalant	7	4	700

*Assuming equal numbers given placebo in this subgroup.

Results for specific drugs

All differences between the specific drugs and controls depicted in the Tables are statistically significant, unless specified by not significant “ns”.

Amiodarone

Table IV depicts studies regarding amiodarone. At the short term, three hours or shorter observation time, no benefit of amiodarone compared to control was observed. At the medium term, eight to 12 hours, the results were diverging. After 20–24 hours, all studies except one, demonstrated better conversion rates of amiodarone. Thus, only after 20–24 hours did amiodarone demonstrate a better conversion rate than that of control, either placebo or ineffective drug.

Table IV. Studies comparing amiodarone to control, placebo or other drugs with proven lack of efficacy.

	Patients (Relevant)	Duration AF	Control	Other Drug	Time to Endpoint	SR Amio	SR Control	References
1	24	≤ 2 d	Verapamil		3 hours	77%	0%	(1)
2	62 (40)	≤ 7 d	Placebo	Flecain.	3 hours	16%	29%	(2)
					8 hours	37%	48% ns
3	50 (39)	≤ 10 d	Digoxin		24 hours	95%	74%	(3)
4	98 (64)	≤ 3 d	Placebo	Flecain.	2 hours	34%	22% ns	(4)
					8 hours	59%	56% ns
5	100	≤ 7 d	Placebo		24 hours	68%	60% ns	(5)
6	417 (172)	≤ 7 d	Placebo	Flecain. Propafen.	1 hour	6%	9% ns	(6)
					3 hours	25%	18% ns
					8 hours	57%	37%
7	143 (97)	≤ 2 d	Placebo	Propafen.	24 hours	83%	55%	(7)
8	100	≤ 2 d	Placebo		24 hours	92%	64%	(8)
9	62	≤ 2 d	Placebo		8 hours	50%	20%	(9)
					24 hours	87%	35%
10	208 (106)	≤ 1 d	Placebo		1 hour	61%	45% ns	(10)
11	160	≤ 1 d	Placebo		8 hours	50%	26%	(11)
					20 hours	83%	44%
12	140	≤ 2 d (80%)	Digoxin Sotalol		12 hours	51%	50/44% ns	(12)
13	362 (182)	≤ 2 d	Placebo		24 hours	89%	61%	(13)

Several studies comprised more than one active drug, mentioned in column “other drug”; accordingly both total numbers of patients as well as number of relevant patients for the drug in question are given in the first column.

Digoxin

Table V shows studies investigating digoxin. The larger DAAF study (16) clearly demonstrates lack of effect of digoxin in converting recent-onset AF to SR, and this conclusion is supported by the other three studies.

Table V. Studies comparing digoxin to placebo.

	No patients	AF duration	SR within	SR dig IV	SR dig PO	SR placebo	References
1	36	≤ 7 d	18 hours		50%	44% ns	(14)
2	40	≤ 7 d	12 hours	47%		40% ns	(15)
3	239	≤ 7 d	16 hours	51%		46% ns	(16)
4	123 (82)	≤ 3 d	1 hour	32%	(Propafenone)	14% ns	(17)

Diltiazem

No placebo-controlled studies are available. Compared to magnesium sulphate, diltiazem was less effective after 6 hours, SR in 22% vs. 57% in one study (18), and no patient who was given diltiazem converted in another comparison (19). The evidence is not very solid, but there is a clear indication that there is no effect of diltiazem in this respect.

Flecainide

Table VI demonstrates studies regarding flecainide. Studies 1–4 comprise patients who were given flecainide compared to placebo (20), and flecainide compared to placebo and one other drug, in all studies amiodarone (2,4,6). Study 5 (21) comprises patients who were given flecainide compared to sotalol, a drug with proven lack of effect. At 1–3 hours after start of drug injection, there is a clear beneficial effect of IV flecainide, 50–82% compared to 14–22% in placebo-treated patients. For PO treatment, the amount of evidence is less. After 6–8 hours, the difference between flecainide and placebo is smaller. Accordingly, at the short term, IV flecainide is superior to placebo in converting recent-onset AF to SR, and the effect on the longer term is less. PO treatment may have a longer duration of onset of effect.

Table VI. Studies comparing flecainide to placebo (1–4) or drugs with proven lack of effect (5).

	Patients (Relevant)	AF duration	SR within	SR IV	SR PO	SR placebo	SR other	References
1	102	≤ 3 d	1 hour	57%		14%		(20)
			6 hours	67%		35%
							Amio
2	98 (66)	≤ 3 dh	2 hours	59%		22%	34%	(4)
			8 hours	68%		56% ns	59%
							Amio
3	62 (43)	≤ 7 d	3 hours		68%	16%	29%	(2)
			8 hours		91%	48%	37%
							Amio
4	417 (190)	≤ 7 d	1 hour		13%	9%	6%	(6)
			3 hours		57%	18%	25%
			8 hours		75%	37%	57%
						Sotalol
5	71	≤ 1 d	2 hours	69%		31%		(21)

Several studies comprised more than one active drug, mentioned in column “other drug”; accordingly both total numbers of patients as well as number of relevant patients for the drug in question are given in the first column.

Ibutilide

Several studies have investigated the effect of Ibutilide vs. placebo in AF patients; however, most of these have included patients with AF duration up to three months. In only one study (22) is it possible to extract the effect in a subgroup with AF duration of ≤ 7 days. When AF (133) and flutter (133) patients with an arrhythmia duration from 3 hours to 45 days were given IV Ibutilide (180 patients) or placebo (86 patients), the endpoint was SR within 90 minutes after the start of the infusion. The total conversion rate was 47% after Ibutilide and 2% after placebo. More flutter patients than AF patients converted, 63% vs. 31%, but in patients with AF duration of less than seven days, 46% (17/37) converted. One study (23) has compared Ibutilide to a drug with documented efficacy, in 207 patients with AF duration of ≤ 48 hours; Ibutilide converted 50% after 1 ½ hours, and flecainide 56%, difference ns. Thus, in patients with recent onset AF, only one relevant study was found demonstrating an effect, and this was supported by an effect similar to flecainide in another study. The data are not overwhelming, but clearly point to an effect.

Pilsicainide

One placebo-controlled study has been published (24) in 75 recent onset AF patients; SR was achieved within 90 minutes in 45% of patients who were given PO treatment, and in 9% of those who were given placebo. The evidence base is too limited to draw any conclusions.

Procainamide

One study (25) has compared procainamide to placebo, in patients with recent onset AF (84/total of 114 patients). Procainamide converted 29/42 patients (69%) compared to 16/42 (38%) placebo patients, within one hour after start of treatment. In patients with AF duration of ≥ 48 hours, no patient in either group converted. One other study (13) compared procainamide to placebo, in addition to propafenone and amiodarone, in patients with AF duration ≤ 48 hours. The endpoint was SR within 24 hours, reached in quite similar numbers: 69% (61/89) of procainamide patients and 61% (55/90) of placebo patients; however, the time to conversion was significantly shorter in procainamide patients, median time 3 hours vs. 17 hours. In patients with AF duration of ≤ 24 hours, the conversion rates after one hour were 37/40 (92%) in patients who were given flecainide compared to 25/40 (65%) in those who were given procainamide (26). Thus, compared to placebo, procainamide seems to convert more patients than placebo and to shorten the time to SR in two placebo-controlled studies, however, flecainide is more effective.

Propafenone

Eight studies have compared propafenone (PO or IV or both) to placebo (Table VI), and five other studies have compared propafenone to another drug, as well as placebo (Table VII). These 13 studies are fairly similar in design, including patients with AF duration of 2–7 days, and reporting conversion to SR within 1–24 hours, the ones with the longest observation period have also reported mean time to conversion. For IV drug, the expected conversion rate is between 41 and 70% after 2–3 hours, compared to 10 and 17% on placebo. For oral medication, the expected conversion rate is 55–71% after 3–4 hours, compared to 10–33% on placebo. After 24 hours, the difference diminishes, and it is not present in all studies. In summary, there is an overwhelming evidence for the effect of propafenone in converting recent-onset AF to SR, both for IV and PO application; after 24 hours, however, the difference is much smaller.

Table VII. Studies comparing propafenone to placebo.

	No patients	AF duration	SR within	SR drug IV	SR drug PO	SR placebo	References
1	87	≤ 7 days	1 hour	28%	3%	3%	(27)
			3 hours	41%	55%	10%
			8 hours	66%	69%	24%
2	75	≤ 3 days	3 hours	59%		29%	(28)
3	182	≤ 7 days	4 hours	79%		0%	(29)
			24 hours	91%		32%
4	105	≤ 3 days	2 hours		43%	11%	(30)
			4 hours		57%	17%
			24 hours		80%	69%-ns
5	240	≤ 7 days	3 hours		45%	18%	(31)
			8 hours		76%	37%
6	55	≤ 7 days	2 hours		41%	8%	(32)
			6 hours		65%	31%
			12 hours		69%	42%
			24 hours		79%	73%-ns
7	156	≤ 3 days	2 hours	70%		17%	(33)
8	123	≤ 3 days	1 hour	48%	15%	17%	(34)
			8 hours	53%	78%	48%

Quinidine

One study (37) has compared oral quinidine to oral sotalol, in 61 patients with AF duration of <= 48 hours, showing a better conversion effect of quinidine, with conversion rates after 3 and 8 hours respectively of 36 and 71% vs. 12 and 24%. The evidence base is too limited to draw any conclusions.

Sotalol

Only one study (38) has compared the effect of Sotalol (two different dosages) vs. placebo. The conversion rates after 30 minutes were 11% (2/18 patients), 13% (2/16 patients), and 14% (2/14 patients) respectively ns. Sotalol converted 44% compared to 50% of patients who were given digoxin after 12 hours, in a study (12) of 140 patients also including an amiodarone group (n-52), where 51% converted to SR, none of the differences were significant. Another study (21) randomized 106 patients to flecainide (52% conversion rate) and sotalol (23% conversion rate) within two hours after start of treatment. From these studies, it is unlikely that sotalol is able to convert AF to SR.

Verapamil

No RCT comparing Verapamil to placebo has been published. Three studies (39–41) have compared Verapamil to other drugs, in which only 6, 14 and 12% of patients given verapamil converted to SR. Although no placebo-controlled studies are available for verapamil, the evidence from these RCTs, comparing verapamil to other drugs, clearly points to no effect.

Vernakalant

Studies regarding vernakalant are shown in Table IX. These four studies have a quite similar design, and the results are extremely consistent, demonstrating an effect of approximately 50% of vernakalant above that of placebo/control. The reported median times to conversion across these studies were 8–11 minutes.

Table IX. Studies comparing vernakalant to control.

	No patients	AF duration	SR within	SR drug IV	SR amio	SR placebo	References
1	56	≤ 3 days	0.5 hour	61%		5%	(42)
2	220	≤ 7 days	1.5 hours	52%		4%	(43)
3	170	≤ 7 days	1.5 hours	51%		4%	(44)
4	254	≤ 2 days	1.5 hours	52%	5%		(45)

Serious adverse events are reported at similar rates for vernakalant and placebo, approximately 4% in both groups. Transient hypotension occurs in about 5%–7% of patients treated with vernakalant. Hypotension is more common in patients with heart failure after the infusion of vernakalant, as are ventricular arrhythmias. The QTc interval will be prolonged by 20–25 ms and the QRS complex will increase by 8 ms after the infusion of vernakalant.

Discussion

When assessing whether a trial of pharmacological conversion is indicated, at first it must be assured beyond any doubt that the duration of the episode is less than 48 hours in patients without adequate anticoagulation (this goes for any conversion attempts, unless the clinical condition is life-threatening). Furthermore, the physician and/or the patient must be unwilling to accept a waiting period for some more hours until spontaneous conversion to sinus rhythm may occur. In patients in severe hemodynamic distress, and with a strong indication for immediate sinus rhythm, DC conversion is the method of choice.

When there is an indication for a conversion trial with a drug, there is little evidence of large differences in conversion rates between approved drugs. Although head-to-head comparisons are scarce, all evidence point to an effect of approximately 50% conversion rate above that of placebo. For propafenone, flecainide, amiodarone, and vernakalant, the evidence for an effect is strong and consistent. Ibutilide has limited documentation in the setting of recent-onset AF, only one RCT with placebo control and one other compared to flecainide, without differences in conversion rates. Procainamide may have a slight effect, as may quinidine, but the effect is at best limited. The lack of effect of digoxin is well demonstrated; although the evidence is more limited for verapamil, diltiazem and sotalol, the available studies clearly suggest lack of effect. Interestingly, none of the pure beta blocking agents has any documented effect in this respect.

Drugs that act mainly on A-V conduction, beta-blockers, calcium channel blockers, and digitalis cannot be expected to have an effect on arrhythmia conversion; the reasons why these drugs are studied in this respect may be the clinical experience that symptoms improve, which can be attributed to the lower ventricular rate. The negative inotropic effects of drugs that block Na⁺ channels, like flecainide and propafenone, are most pronounced in patients with reduced left ventricular function and must accordingly only be used in patients with known normal hearts. Drugs that prolong both atrial and ventricular refractoriness, such as amiodarone, sotalol and ibutilide, may cause torsade de pointes ventricular arrhythmias, especially in patients with baseline long QT periods or electrolyte disturbances, and must not be used in such settings.

The conversion rates in placebo groups vary according to time to follow-up. At short follow-up times, up to 1 ½ hours, the conversion rates are between 2 and 14%, in the more recent studies typically approximately 5%. At longer follow-up times, up to 24 hours, the rates are between 32 and 77%, typically between 60 and 70%. Studies without control groups are therefore of little use in this setting, and furthermore, as the goal of pharmacological conversion trials is to shorten the symptomatic period, drugs that do not have an effect on the short term are of little value.

Most drugs used for this purpose are short acting; accordingly one cannot expect any effect after weeks or months. There is also little information in the literature regarding long-term effects of one oral or intravenous drug ingestion. Furthermore, the mechanisms for converting AF and maintaining SR may differ.

For flecainide, propafenone and amiodarone, oral formulations are available, giving the possibility to immediate continuation with the same drug to prevent relapses. For ibutilide, no oral formulation exists, and the development of an oral vernakalant formulation was recently abandoned (Merck March 19, 2012).

Regarding the “Pill in the pocket” approach: For flecainide (Table VI) and propafenone (Tables VII and VIII), oral ingestion of drugs has proven effective in hospital settings. A feasibility study (46) has demonstrated the efficacy of this approach, but only 12% of the screened patients were eligible for this approach. A more recent study from the same group (47), however, aimed at assessing whether intravenous treatment was able to predict adverse effect of oral treatment, was terminated prematurely because of high incidence of major adverse effects during the first out-of-hospital oral treatment. Accordingly, self-medication with oral drugs is indicated only in a small subset of patients and may give serious side effects if not screened properly with oral in-hospital treatment.

Table VIII. Studies comparing propafenone to another drug and placebo.

	No patients (Relevant)	AF duration	SR within	SR drug IV	SR drug PO	SR placebo	Other -	drugs	References
9	87	≤ 8 days					Dig		(35)
			6 hours		62%	17%	38%
			12 hours		83%	34%
			24 hours		86%	55%
							Dig
10	123	≤ 3 days	1 hour	49%		14%	32%		(17)
							Amio
11	143 (95)	≤ 2 days	24 hours	78%		55%	83%		(7)
							Dig/Quin	Prop/dig
12	246 (106)	≤ 2 days	3 hours		48%	27%	20%	50%	(36)
			24 hours		70%	77%(ns)	85%	88%
							Amio iv	Proc iv
13	362 (181)	≤ 2 days	24 hours	80%		61%	89%	69%	(13)

There are two important differences between the five effective drugs; firstly, contraindications, precautions and side effects, the other one the average time to conversion, Tables IV and VI–IX.

Vernakalant is very fast acting, amiodarone is very slow acting, and the three other drugs have mean conversion times in between. The contraindications and precautions also differ, limiting flecainide and propafenone only for use in patients without structural heart disease. Ibutilide may give life-threatening ventricular arrhythmias, needing immediate defibrillation. Vernakalant is contra-indicated in patients with hypotension, NYHA class III and IV heart failure, severe aortic stenosis, and QT interval prolongation (QTc > 500 ms), and should also be used with caution in patients with less severe heart failure because of the increased risk of hypotension. Propafenone has the largest number of patients studied, followed by amiodarone. On the other hand, vernakalant has larger studies. The present cost of newer drugs may in some circumstances limit their use, however.

AF in specific setting such as intensive care medicine, post-operative situations and in the setting of cardiac surgery is not discussed in this review, neither is the treatment of AF of longer duration.

It is also beyond the scope of this review to discuss dosages of drugs, as well as details in side effects or precautions.

Conclusions

Balancing precautions, side effects and time to conversion, vernakalant seems to be an attractive drug as a first choice in a broad range of patients, except in those with severe heart failure or hypotension. In patients with previously documented structural normal hearts, both flecainide and propafenone can be recommended. Because of the slow onset of action, amiodarone is not suitable in this setting. Ibutilide must only be used under extreme surveillance because of the not negligible risk of life-threatening ventricular arrhythmias.

Declaration of interest: Modest honoraria for lectures and expert group panels, paid by Merck for both MH and DA. The authors alone are responsible for the content and writing of the paper.