Advances in Clinical and Experimental Medicine

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Advances in Clinical and Experimental Medicine

2021, vol. 30, nr 3, March, p. 331–348

doi: 10.17219/acem/130592

Publication type: review article

Language: English

License: Creative Commons Attribution 3.0 Unported (CC BY 3.0)

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Springer J, Szmuda T, Kozłowski D. Does the choice of drug in pharmacologic cardioversion correlate with the guidelines? Systematic review. Adv Clin Exp Med. 2021;30(3):331–348. doi:10.17219/acem/130592

Does the choice of drug in pharmacologic cardioversion correlate with the guidelines? Systematic review

Janusz Springer1,A,B,C,D,E,F, Tomasz Szmuda2,B,C,D,E,F, Dariusz Kozłowski3,A,E,F

1 Department of Emergency Medicine, Medical University of Gdańsk, Poland

2 Department of Neurosurgery, Medical University of Gdańsk, Poland

3 Department of Cardiology and Electrotherapy, Medical University of Gdańsk, Poland

Abstract

Background. Atrial fibrillation (AF) is the most common sustained arrhythmia, the most common cause of supraventricular tachycardia in the global population and the most common arrhythmia requiring treatment in an emergency department.

Objectives. To systematically review recent literature and quantify the correlation between the choice of pharmacological cardioversion (PCV) drug and the national or international guidelines.

Materials and methods. A systematic review was performed in accordance with the PRISMA statement methodology. The PubMed search engine was used to search for articles regardless of type or language and published in the last 6 years (May 2014–May 2020). In addition, we searched for AF guidelines and recommendations published online by cardiology and emergency medicine societies.

Results. The search strategy returned a total of 2615 abstracts. A total of 2598 full texts were screened; 2540 full texts were excluded with reasons and 58 articles from 32 countries were included in the analysis. In 17 of the 58 articles (29%), we noted discrepancies with the AF guidelines, specifically regarding the PCV drug used, the patients’ comorbidities and the contraindications associated with the PCV drug. The most common clinical situation for the use of a contraindicated drug was when ibutilide was administered to patients with heart failure. The analysis did not reveal any statistically significant correlations, although the correlation between the sample size and guideline adherence was close to statistical significance (p < 0.06).

Conclusions. Our systematic analysis revealed substantial non-adherence to AF treatment guidelines.

Key words: atrial fibrillation, cardioversion, guideline adherence, antiarrhythmic

Background

Atrial fibrillation (AF) is the most common sustained arrhythmia and the most common cause of supraventricular tachycardia in the world.1, 2 Furthermore, acute AF is a common complaint among emergency department (ED) patients and is the most common arrhythmia requiring treatment in the ED.3 It commonly occurs because AF is often caused by common diseases (see Table 1). However, ongoing academic discussions seek to answer whether a patient with AF who does not have any cardio-pulmonary disease should be diagnosed with “lone AF”.4 According to the latest AF guidelines published by the European Society of Cardiology (ESC), the term/diagnosis of “lone AF” should not be used because AF always has an underlying cause.5

There are 2 widely accepted and separate goals of AF treatment: rate control and rhythm control. In the case of paroxysmal AF, a clinician has a choice of 2 methods to restore sinus rhythm (SR): pharmacological (chemical) cardioversion (PCV) or electric cardioversion (ECV). According to a large international emergency physician survey, PCV is the first line of treatment for recent-onset AF.6 The efficacy of PCV in restoring sinus rhythm varies among published studies and is subject to ongoing debate.

When deciding to perform PCV, clinicians have several antiarrhythmic drugs to choose from, which are listed in national and international guidelines (Table 2). Little is known about adherence to AF guidelines when it comes to PCV, particularly in the ED.

Objectives

The aim of this study was to systematically review the most recent literature in an attempt to answer the following clinical question: Do recently published articles about PCV reveal any correlation between the choice of PCV drug and national or international guidelines?

Materials and methods

A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement methodology.7 The PubMed search engine was used to find articles regardless of type or language and published in the last 6 years (May 2014–May 2020). The unusual six-year timespan was purposefully chosen because the American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Rhythm Society (HRS) and National Institute for Health and Care Excellence (NICE) guidelines were published in December and August of 2014, respectively.6, 7 The following search terms were applied: atrial fibrillation AND pharmacological cardioversion AND antazoline OR amiodarone OR dronedarone OR flecainide OR ibutilide OR procainamide OR propafenone OR vernakalant.

(((((((((“atrial fibrillation”[MeSH Terms] OR (“atrial”[All Fields] AND “fibrillation”[All Fields]) OR “atrial fibrillation”[All Fields]) AND ((“pharmacology”[MeSH Terms] OR “pharmacology”[All Fields] OR “pharmacological”[All Fields]) AND (“electric countershock”[MeSH Terms] OR (“electric”[All Fields] AND “countershock”[All Fields]) OR “electric countershock”[All Fields] OR “cardioversion”[All Fields]))) AND (“antazoline”[MeSH Terms] OR “antazoline”[All Fields])) OR (“amiodarone”[MeSH Terms] OR “amiodarone”[All Fields])) OR (“dronedarone”[MeSH Terms] OR “dronedarone”[All Fields])) OR (“flecainide”[MeSH Terms] OR “flecainide”[All Fields])) OR (“ibutilide”[Supplementary Concept] OR “ibutilide”[All Fields])) OR (“propafenone”[MeSH Terms] OR “propafenone”[All Fields])) OR (“procainamide”[MeSH Terms] OR “ procainamide”[All Fields])) OR (“vernakalant”[Supplementary Concept] OR “vernakalant”[All Fields]) AND (“2014/05/01”[PDAT] : “2020/05/01”[PDAT])

The search strategy yielded a total of 2615 abstracts. A total of 2598 (full texts) were screened, of which 2540 were excluded with reasons (Figure 1). Although they included large patient samples, meta-analyses were excluded due to an insufficient amount of detail about PCV and the patients’ comorbidities. Articles describing the use of antiarrhythmic drugs as prophylaxis of AF prior to surgery were also excluded. So-called “pre-treatment” studies with an antiarrhythmic drug immediately prior to electric cardioversion did not meet the criteria of PCV and were also excluded. The following data was extracted from the 58 eligible full-text articles: number of patients (n), patient age (or average age), patient sex, etiology of AF (or significant comorbidities), antiarrhythmic drug chosen for PCV, dose, bolus or infusion, success of PCV, time to SR, management after PCV attempt (e.g., Was the dose of PCV drug repeated? Was another antiarrhythmic drug administered? Was ECV performed instead?), and country where the patients were treated.

Data were extracted from the articles and entered into Excel spreadsheets (Microsoft Office 2007; Microsoft Corp., Redmond, USA) and subsequently exported to STATISTICA v. 12.0 (StatSoft Inc., Tulsa, USA) for analysis. The following statistical tests were performed: Mann–Whitney U test (for continuous variables) and Fisher’s two-tailed test (for categorical variables). Values of p <0.05 were considered statistically significant.

In addition, we searched for AF guidelines and recommendations published online by cardiology and emergency medicine societies. Our search returned guidelines from Australia (National Heart Foundation of Australia (NHFA)/Cardiac Society of Australia and New Zealand (CSANZ)),8 Canada (Canadian Association of Emergency Physicians (CAEP), Canadian Cardiovascular Society (CCS)),9, 10 Europe (European Resuscitation Council (ERC), ESC)5, 11 UK (NICE),12 and USA (American College of Emergency Physicians (ACEP), AHA/ACC/HRS) (Table 2).13, 14 We used these recommendations as a reference point to answer the research question described earlier.

Results

Our search returned 58 articles from 32 countries; most articles were published in 2017–2018 (Figure 2, Figure 3).15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 Unfortunately, not all relevant data was provided by the authors, thus making it impossible to perform a full meta-analysis. Detailed results of the systematic review are summarized in Table 3 (Figure 2, Figure 3).

Despite the incomplete data, the analyzed articles revealed a surprising trend of non-adherence to AF treatment guidelines. In 17 of the 58 articles (29%), we noted discrepancies with AF guidelines, specifically regarding the PCV drug used, the patients’ comorbidities and the PCV contraindications (Table 4).16, 18, 20, 21, 22, 26, 27, 28, 31, 32, 36, 39, 41, 49, 55, 60, 63 ­According to the data presented in the articles, it appeared that a total of 239 patients underwent PCV using a drug that was contraindicated given their specific comorbidities. In the described cases, the most common culprit PCV drug was ibutilide, followed by vernakalant, amiodarone, propafenone, and flecainide. The most commonly described clinical situation for the use of contraindicated drug was ibutilide when administered to a patient with HF, which is contraindicated according to the ACEP, CAEP and ESC guidelines (Table 2).10, 12, 13, 31, 39, 55, 63 In 9 of the 17 articles, using a contraindicated drug during PVC was performed in the ED (Table 4).21, 22, 26, 27, 32, 36, 39, 55, 63 Due to incomplete data, it was impossible to assess whether an additional 338 patients were administered a PCV drug that was contraindicated or not.21, 36 (Table 4).

Analysis using the Mann–Whitney U test and Fisher’s test did not reveal any statistically significant correlations between adherence to AF guidelines and demographic variables such as sample size, patient age, and male sex (Table 5). However, it is noteworthy that the correlation between the sample size and guideline adherence was close to statistical significance (p < 0.059). It appears that the larger the sample size, the less adherence was observed. The analysis using Fisher’s two-tailed tests did not reveal any statistically significant correlations between adherence to AF guidelines and the type of study/article, region/country or department where the PCV was performed (Table 5).

It is noteworthy that our search retrieved a total of 6 articles (in 1612 patients) that included PCV using antazoline mesilate.19, 32, 33, 34, 42, 66 This is an old antihistaminic drug, which, despite its proven antiarrhythmic efficacy, is not currently mentioned in any AF guidelines.72, 73, 74 According to publicly available data, it appears that the intravenous form of antazoline is registered and sold in Poland only; therefore, it is not surprising that majority of the research on antazoline was conducted and published by Polish physicians.74, 75, 76, 77, 78

Discussion

Although we found articles describing PCV performed on all of the inhabited continents of the world, we are aware that they do not necessarily reflect daily clinical practice. The articles we analyzed did not contain enough data to answer the question why the AF guidelines were not followed. We do not want to speculate about the particular authors’ intent or the circumstances during the described PCV. However, given our institutional experience with PCV, we can think of several possible reasons, most of which are rather mundane or perhaps even temporary, e.g., the availability of antiarrhythmic drugs, institutional/personal experience with particular drug(s), and interest in comparing the efficacy of a new drug (e.g., vernakalant) compared to a “tried and tested” drug.

The very same issue of non-adherence with AF guidelines was addressed in the literature, although the answers were not definitive. Authors suggested reasons such as lack of quality evidence (see Table 2 for information about the level of evidence in the analyzed AF guidelines), impossibility to establish AF onset, concerns about thromboembolic events, concerns about negative inotropic or proarrhythmic effect of PCV drugs, time constrains (excluding secondary causes of AF is time-consuming and adds more complexity to decision-making), and the fact that a significant number of ED patients with AF spontaneously revert to SR.35, 45, 49, 78, 79, 80, 81 Finally, patient preference, or perhaps the physician’s attitude, towards a given therapeutic option may influence the decisions about adopting a wait and observe approach or rhythm control or rate control, as well as electrical or pharmacological cardioversion.46

In a survey of 561 physicians, Heidbuchel et al. found 8 major barriers to AF guidelines implementation that were knowledge-related (e.g., diagnosing AF based on duration instead of etiology, uncertainty during decision-making, use and interpretation of risk assessment scores, difficulties in choosing stroke prevention treatment), skill-related (e.g., difficulties in EKG interpretation/detection of AF, difficulties in discussing with patients their treatment strategy) and systemic (e.g., poor cooperation between specialists and general practitioners, local regulations regarding the use of novel anticoagulants).82

Limitations

Our systematic review had several limitations, most notably, the high heterogeneity and incompleteness of the obtained data which did not allow us to perform a meta-analysis. Specifically, we were unable to extract enough data about the patients (e.g., patient age is provided only as an average value, comorbidities listed as totals without mention if any patients had more than 1 comorbidity). Therefore, it was not possible to assess if AF guidelines were followed during PCV of those patients. Furthermore, although reports of single cases are universally defined as weak evidence, we had little data to choose from and decided to include them in the analysis. Had there been more data from large trials available, we would have chosen them over case reports, thus making our statistical analysis and conclusions more robust. Finally, we are aware that there might be national AF guidelines which we were unable to find.

Conclusions

Our review of the published clinical literature about PCV reveals significant non-adherence to AF treatment guidelines. Specifically, the drugs used for PCV in patients with AF and comorbidities such as heart failure and thyroid disease are inconsistent with the guidelines.

Tables


Table 1. Etiology of atrial fibrillation (AF) (according to Benjamin et al. and Kirchhof et al.)

Ageing

Cardiomyopathies

Chronic obstructive pulmonary disease

Coronary artery disease

Diabetes

Heart failure

Heart valve disease

Hypertension

Obesity

Post-operative

Thyroid disease

Unknown (not yet diagnosed, formerly “lone AF”)

Table 2. Pharmacological cardioversion recommendations published in national and international guidelines

Drug

Route

Dose

Indications (class, source)

Contraindications (class, source)

ACEP

AHA/ACC/HRS 2014 + 2019 update

CAEP 2018

CCS 2018

ERC 2015

ESC 2016

NHFA/CSANZ 2018

NICE 2014

Amiodarone

iv*

not stated

150 mg over 10 min, then 1 mg/min for 6 h, then 0.5 mg/min for 18 h or change to oral dosing

not recommended

150 mg bolus, then 60 mg/h for 6 h, then 30 mg/h for 18 h

300 mg over 20–60 min followed by 900 mg over 24 h. Less effective than flecainide, ibutilide, and propafenone

5–7 mg/kg over 1–2 h; follow-up dose: 50 mg/h to a maximum of 1.0 g over 24 h

recommended

recommended for patients with structural heart disease

newly detected HF in the presence of AF with a rapid ventricular response (AHA), hypertrophic cardiomyopathy + AF (AHA Class IIa), ACS + AF associated with severe LV dysfunction and HF or hemodynamic instability (AHA Class IIb), ­severely impaired heart function (ERC), HF + AF (ESC), IHD + AF (ESC), structural heart disease (CCS)

hyperthyroidism + AF (“Antiarrhythmic drugs and cardioversion often fail to achieve sustained sinus rhythm while thyrotoxicosis persists; therefore, efforts to restore normal sinus rhythm may be deferred until the patient is euthyroid.” – AHA)

Antazoline

iv

not stated

not stated

not stated

not stated

not stated

not stated

not stated

not stated

paroxysmal atrial arrhythmias including tachycardia/AF, nor reacting to standard treatment

avoid in patients with history of seizures, concurently using MAO inhibitors, anticholinergic drugs, CNS depressants, or alcohol); use carefully in patients with HTN, DM, hyperthyroidism, and prostatic hyperplasia

Flecainide

po

300 mg PO ×1 if ≥70 kg or 200 mg PO ×1 if <70 kg

200–300 mg ×1**

not stated

300 mg (>70 kg), 200 mg (≤70 kg)

recommended; more effective than amiodarone

200–300 mg; iv: 1.5–2 mg/kg over 10 min

recommended; more effective than amiodarone

recommended for patients without ischemic or structural heart disease

no evidence of structural or ischemic heart disease + AF (ACEP, NICE)

known ischemic or structural heart disease + AF (ESC, NICE), LV systolic dysfunction, moderate LV hypertrophy or coronary artery disease (GRADE: Strong, Evidence: Moderate, NHFA)

Ibutilide

iv

1 mg iv over 10 min; may repeat same dose 10 min after first infusion if still in AF; if still in AF at 60 min after last infusion consider electrical cardioversion

1 mg over 10 min; may repeat 1 mg once if necessary (if weight <60 kg, use 0.01 mg/kg)

not stated

1 mg iv over 10 min, may repeat once

recommended; more effective than amiodarone

1 mg over 10 min; follow-up dose: 1 mg over 10 min after waiting for 10 min

not stated

not stated

post-cardiac and thoracic surgery + AF (AHA Class IIa), hemodynamically stable WPW and pre-excitation syndromes + AF (AHA Class IIa), “no need to confirm lack of structural heart disease or occlusive coronary disease” (ACEP)

long QTc, hypokalemia, HF (ACEP, CAEP, ESC), severe LVH (ESC), hypomagnesemia (CCS)

Procainamide

iv

not stated

not stated

15 mg/kg in 500 mL NS over 30–60 min

15–18 mg/kg over
30–60 min

not stated

not stated

not stated

not stated

hemodynamically stable WPW and pre-excitation syndromes + AF (AHA Class I), (CAEP)

Brugada syndrome (CCS), hypotension (SBP < 100 mm Hg) or long QT (QTc > 500 ms) (CAEP)

Propafenone

po

not stated

450–600 mg ×1**

not stated

600 mg (>70 kg), 450 mg (≤70 kg)

recommended; more effective than amiodarone

450–600 mg; iv: 1.5–2 mg/kg over 10 min

not stated

not stated

COPD + AF (“may be considered in patients with obstructive lung disease who develop AF and do not have bronchospasm” – AHA)

COPD + AF (“contraindicated in patients with bronchospasm” – AHA), known ischemic or structural heart disease + AF (ESC, NICE)

Vernakalant

iv

not stated

not stated

not stated

3 mg/kg over 10 min, followed by 2 mg/kg if no conversion

not stated

3 mg/kg over 10 min/follow-up dose: 2 mg/kg over 10 min after waiting for 15 min

not stated

not stated

mild HF (NYHA Class I–II) + AF, IHD + AF (ESC)

avoid in patients with hypotension (SBP < 100 mm Hg), recent (<30 days) ACS, HF (NYHA Class III–IV), QT long QT (uncorrected >440 ms) and severe aortic stenosis (CCS, ESC)

* Use a large peripheral vessel and change to oral amiodarone within 24 h of IV (central line) administration.** It is recommended to pre-treat with a β-blocker or nondihydropyridine calcium channel antagonist ≥30 min before administering this drug.ACEP – American College of Emergency Physicians; ACS – acute coronary syndrome; AF – atrial fibrillation; AHA/ACC/HRS – American Heart Association/American College of Cardiology/Heart Rhythm Society; AV – atrio-ventricular; CAD – coronary artery disease; CAEP – Canadian Association of Emergency Physicians; CCS – Canadian Cardiovascular Society; COPD – chronic obstructive pulmonary disease; ERC – European Resuscitation Council; ESC – European Society of Cardiology; GI – gastrointestinal; IHD – ischemic heart disease; iv – intravenous; LV – left ventricular; MAO – monoamine oxidase; NICE – National Institute for Health and Care Excellence; NHFA/CSANZ – National Heart Foundation of Australia/Cardiac Society of Australia and New Zealand; NYHA – New York Heart Association; po – per os (orally); SBP – systolic blood pressure WPW – Wolff–Parkinson–White syndrome.
Table 3. Detailed results of the systematic review

Author(s)

Date of publication

Study type

Country

Number of patients

Age of patients [years]

Sex of patients

PCV setting

PCV drug

PCV drug dose and route

PCV succesful, n

Time to SR [min]

Management after failed PCV attempt

Comorbidities

AF guideline adherence

Albakri et al.

VII 2017

case report

Germany

1

60

M

IMD

flecainide

1 mg/kg

1

30

after 25 min 2nd infusion of flecainide 0.3 mg/kg

borderline hypertension without LV hypertrophy, obstructive bronchitis, episodic

orthostatic intolerance (most probably vasovagal)

Y

Amin et al.

III 2015

prospective single-center observational

Netherlands

112

63 ±1

52 F, 60 M

CER

flecainide

2 mg/kg (maximum dose of 150 mg) iv infusion over 10 min

97

not stated

if AF 6 h after infusion ECV

CAD 11, HTN 52, DM 8, THY 5

N

Andrade et al.

I 2018

prospective single-center observational

Canada

80

53.0 ±12.6

27 F, 53 M

AF clinic

immediate release AV nodal blocker + AAD Class Ic

diltiazem 30–60 mg po, verapamil 30–60 mg po or metoprolol 25–50 mg po + if <70kg F: 200 mg po or PROP: 450 mg po; if ≥70kg F: 300 mg po or P 600 mg po

in 30/43

<6 h

if AF 6 h after infusion ECV

HVD 2, CAD 4, DM 8, HTN 16

Y

Balik et al.

X 2017

retrospective

Czech Republic

197

67.8 ±11.4 (amiodarone), 66.8 ±11.3 (propafenone)

not stated

ICU

amiodarone; propafenone

AMIO: 1.8–4.6 g iv infusion over 2–6 days; PROP: 460–700 mg/day iv infusion*

amiodarone in 114/197;

not stated

switch drugs, ECV

hyperthyroidism (5 A)

N

Balsam et al.

IX 2015

retrospective, non-randomized, no placebo-controlled observational study

Poland

141 (74 persistent AF, 67 paroxysmal AF)

57 (49–63)

38 F, 103 M

EPL

antazoline

maximum 500 mg iv 30–50 mg/min

in 79/141 (31% of persistent AF patients, 83% of paroxysmal AF patients)

≤20

not stated

HTN 69.3%, lone AF 22.7%, THY 18.4%, DM 12.1%, HVD 2.8%

Y

Beatch et al.

V 2016

RCT

Canada, Chile, Israel, Mexico, Peru, South Africa, USA

129

63.7 (SD 12.7)

53 F, 76 M

not stated

vernakalant

3 mg/kg iv infusion over 10 min

59

25% converted in ≤11; endpoint at 90

if AF 15 min after 1st infusion vernakalant 2 mg/kg iv over 10 min; if AF 2 h after 1st infusion ECV

HTN 89, HVD 27, CAD 18, DM 18

Y

Beatch et al.

II 2017

RCT

China, Hong-Kong, India, Korea, Taiwan

55

60.7 ±13.7

18 F, 37 M

not stated

vernakalant

3 mg/kg iv infusion over 10 min

29

median 17, endpoint at 90

if AF 15 min after 1st infusion 2 mg/kg iv over 10 min; if AF 2 h after 1st infusion ECV

HF 5, IHD 4, VHD 2

N

Bonora et al.

IX 2017

retrospective propensity matching

Italy

179 (amiodarone), 179 (flecainide, propafenone)

66.2 ±12.8 (amio), 66.4 ±11.6 (flec or prop)

not stated

ED

amiodarone, flecainide, propafenone

AMIO: 5 mg/kg in a 20 min infusion; FLEC or PROP: 2 mg/kg in 15 min rapid infusion

after 12 h  A 95/179 and F or P 130/179; after 48 h  A 139/179 and F or P 154/179

A 420 (331.6–508.3); F or P 55 (44.8–65.1)

a 15 mg/kg
dose in 24 h slow maintenance ­infusion)

IHD 76 (A), 18 (F or P); HTN 290 (A), 223 (F or P); VHD 48 (A), 53 (F or P); THY 23 (A), 67 (F or P)

N

Carbajosa et al.

X 2017

prospective multi-center observational

Spain

165

68 (56–77)

76 F, 89 M

ED

vernakalant

3 mg/kg iv infusion over 10 min

in 128/165

8 (6–12); after 2nd dose 34 (22–62)

if AF 15 min after 1st infusion vernakalant 2 mg/kg iv over 10 min

HTN 99, DM 16, HF 15

N

Champion et al.

VI 2018

prospective single-center observational

France

75

not stated

not stated

ICU

amiodarone

median dose of 300 mg (150–600 mg)

51

NS

ECV

not stated

Y

Chauveau et al.

VI 2019

case series

France

1

32

F

ICU

flecainide

100 mg iv

yes

NS

NA

speculation (thyroiditis? left-sided accessory pathway?)

Y

Comelli et al.

XI 2018

case report

Italy

1

56

M

ED

flecainide

100 mg iv infusion over 20 min

yes, spontaneous

~30

not stated

none

Y

Cosin-Sales et al.

VI 2016

prospective single-center observational

Spain

47

66 (24–89)

24 F, 23 M

ED

vernakalant

not stated

45

12.5 (1–115, median 8)

NS

HTN 28, DM 3, IHD 3, HF 1, CMP 1

N

Costabel et al.

II 2015

single-center, retrospective

Brazil

121

58.1 ±13.9

39 F, 82 M

ED

vernakalant

initial dose 3.0 mg/kg iv over 10 min

102

10

2nd dose 2 mg/kg iv

56 HTN, 16 structural heart disease, 6 HF (EF < 55%), 2 COPD, 2 DM

N

Dalyanoglu et al.

V 2018

single-center, retrospective

Germany

129

70.2 ±9.1

39 F, 90 M

CSD

vernakalant

3 mg/kg iv over 10 min

57

13.7 ±14.1

2nd dose 2 mg/kg iv over 10 min

124 CAD, 16 CAD + HVD, 37 DM, 70 hyperlipidemia, 109 HTN, 20 HVD, 21 LVEF < 50%

N

Dasgupta et al.

III 2020

retrospective, single-center

USA

14

15 (14–17)

not stated

PED

ibutilide

if >60 kg: 1 mg iv over 10 min, if <60 kg 0.01 mg/kg iv over 10 min

9

not stated

a 2nd dose of equal amount, at the physician’s discretion

not stated

Y

Dilber et al.

XI 2015

case report

Croatia

1

75

M

ED

amiodarone, propafenone

AMIO: 300 mg in 250 mL 5% dextrose solution iv infusion; PROP: 150 mg in 250 mL 5% dextrose solution iv infusion

0

NA

transesophageal echocardiography + ECV

HTN

Y

Dong et al.

VI 2017

prospective single-center observational

China

79

64.6 ±11.2 (40–80)

31 F, 48 M

not stated

ibutilide (39), ibutilide ± amiodarone (40)

AMIO 300 mg + I 1 mg iv; I 1 mg iv

I = 51.3% (20/39),
A + I = 71.8% (28/39)

I 75–120;
A+I 60–120

additional ibutilide 1 mg

CAD 51.31% (I), 47.11% (A+I); HTN 56.41%, 61.12%; DM 5.11%, 6.24%; HF 29.71%, 28.35%

N

Farkowski et al.

VI 2016

retrospective case-control

Poland

432

68.9 ±9.8

152 F, 280 M

ED

antazoline 334, propafenone 98

ANT: 50 mg every 3–5 min up to max 250–300 mg or SR; PROP: max 2 mg/kg iv slow bolus

A 239, P 54

not stated

other drug, ECV or discharge

CAD (A 138, P 28), DM (A 58, P 15), IHD (A 66, P 14), HTN (A 202, P 55), HVD (A 3, P 2), non-ischemic structural heart disease (A 3, P 0), THY (A 29, P 15)

N

Farkowski et al.

XII 2018

retrospective case-control

Poland

548

CAD(−) 66.9 ±9.9, CAD(+) 71.3 ±9.1

CAD(−) F 84, 112 M; CAD(+) F 27, 111 M

ED

antazoline

50 mg every 3–5 min up to max 250–300 mg or SR

CAD(−) 125, CAD(+) 114

not stated

not stated

HTN 95, 107; DM 10, 48; THY 23, 6; CAD(+): post-PCI 47, post-CABG 53, post-MI 65

Y

Farkowski et al.

V 2019

experimental prospective, control group

Poland

5

63.4 (59.9–66.8)

not stated

EPL

antazoline

257.1 (246.7–267.6) mg

5

8.4 ±6.2

not stated

not stated

Y

Gillinov et al.

IV 2016

multi-center RTC

Canada + USA

261

68.4 ±8.4

62 F, 199 M

CSD

amiodarone

3 g po before hospital discharge, with a maintenance dose of 200 mg/day or less for 60 days if direct-current cardioversion was successful

244 at hospital discharge, 227 from discharge to 60 days

not stated

ECV

all post-cardiac surgery (CABG 100, HVD 43, CABG + HVD 7), DM 79, HF 33, HTN 198, HVD 148, post-MI 48, post-stroke 15

Y

Hamilton et al.

VI 2015

retrospective

UK

564

68 (mean)

257 F, 307 M

ED

flecainide (n = 85), amiodarone (n = 32)

NS

F 69, A 26,
F + A 19

not stated

21 received PCV + ECV

COPD 40, DM 51, HF 29, HTN 249, HVD 52, IHD 162, previous congenital heart disease 5, stroke/TIA 37, THY 48

N

Kapelios

VII 2019

case report

Greece

1

55

M

not stated

amiodarone

300 mg in 60 min iv

1

not stated

NA

ibrutinib

Y

Karavelioglu et al.

I 2015

retrospective

Turkey

218

64.1 ±14.6

126 F, 92 M

ED

amiodarone

300 mg in 100 mL 5% dextrose solution (over 1 h) iv + 900 mg AMIO in 500 mL 5% dextrose (over 23 h) iv

not stated

not stated

not stated

CAD 27, DM 37, HF 20, HTN 125

Y

Kriz et al.

VIII 2016

prospective observational, single-centre

Austria

236

66.8 ±1.8

133 F, 103 M

ED

ibutilide 107, vernakalant 68, flecainide 59, amiodarone 2

I: 0.87 mg iv for 10 min; V: 3 mg/kg iv for 10 min; FLEC: 2 mg/kg (max 200 mg) iv for 10–20 min; AMIO: 150 mg iv for a 10 min

I 73, V 54, F 42, A 2

not stated

I: 2nd dose after 10 min, V: 2nd dose 2 mg/kg (max 340 mg) after 15 min

DM (I 17, V 0, F 6, A 1), HF/LV dysfunction (I 3, V 4, F 1, A 0), HTN (I 89, V 46, F 47, A 2), stroke/TIA/TE (I 7, V 7, F 1, A 0), vascular disease* (I 19, V 10, F 8, A 0)

N

Lewis et al.

XII 2015

case report

UK

1

38

M

not stated

flecainide

1.5 mg/kg (120 mg)

1

90

not stated

none

Y

Liberman et al.

VI 2018

retrospective, single-center

USA

13

16 (4.6–20.3)

not stated

PED

flecainide

<40 kg: 4–6 mg/kg, 40–70 kg: 200 mg, >70 kg: 300 mg

13

60 (30–120)

NA

CMP 6, HVD 3, post-heart transplantation 1

N

Maciag et al.

X 2017

single-center, randomized, double-blind, placebo-controlled, superiority clinical trial

Poland

36

68 ±12 (31–90)

35 F, 39 M

“ED or clinical ward”

antazoline

50 mg diluted to 10 cm3 every 5 min iv (total dose 250 mg/50 cm3)

26

16 (9–35)

not stated

HTN 52; CAD 13; THY 4

Y

Maimone et al.

IX 2015

case report

Italy

1

73

F

not stated

amiodarone

5 mg/kg (1st h), 50 mg/h (maintenance)

1

not stated

not stated

iodine contrast

Y

Manolis et al.

II 2018

retrospective single-center observational

Greece

23

63 ±12

10 F, 13 M

CD

vernakalant

3 mg/kg over 10 min, and after 15 min

15 (65%)

25 ±31 min (median ¼ 12 min)

2nd infusion of 2 mg/kg over 10 min

HTN 4, “mild CAD” 3, post-AVR normal EF 1, CMP 1, idiopathic 9

Y

Mansoor et al.

XI 2014

retrospective, single-center

South Africa

59

16–82 (mean: 51.9)

26 F, 33 M

CSD

amiodarone

300 mg in 200 mL of 5% dextrose water over 45 min iv, followed by 900 mg in 1 L of 5% dextrose water over 24 h

7 (PCV only), 35 (ECV + PCV), 9 (ECV only), 5 (ECV + other PCV drug), 2 (other PCV drug), 1 spontaneous cardioversion

not stated

PCV was performed after failed ECV

all were immediately post-cardiac surgery (CABG or HVD); 24 DM, 33 CAD, 6 CAD + HVD, 35 HTN, 20 DM + HTN

Y

Milojevic et al.

I 2019

retrospective, single-center

France

200

65.9 ±16

58 F, 142 M

MICU

amiodarone

300 mg iv for 30 min (10 mg/min), if <40 kg: consider 150 mg for 30 min iv (5 mg/min), if >90 kg: consider 450 mg for 30 min iv (15 mg/min)

66

2% @ 20,
18% @ 40,
22% @ 60,
24% @ 90

not stated

not stated

Y

Mitrić et al.

IV 2016

retrospective, single-center

Australia

177

69 (60–75)

64 F, 113 M

ICU

amiodarone

median (IQR) total dose 905 mg (488–1651) (includes boluses and infusions)

86 (91 had recurrence of AF)

not stated (median treatment with amiodarnone 24 h (16–40 h))

not stated

COPD 58, DM 25, HF 22, HTN 106, IHD 58, MI 43, HVD 9, PVD 40

Y

Mochalina et al.

III 2015

retrospective

Sweden

113

63 (23–87)

44 F, 69 M

not stated

vernakalant

3 mg/kg over 10 min

75

10 (4–90)

2nd infusion of 2 mg/kg over 10 min

HTN 57, IHD 18, DM 8, CHF 3

Y

Nemati et al.

VI 2016

RCT (2 centers)

Iran

122

A: 68.1 ±9.9, P: 66.7 ±8.7

not stated

ICU

amiodarone 67, propafenone 55

AMIO: 300 mg iv, followed by 600 mg iv over 12–24 h after the occurrence of AF; PROP: 600 mg po and 150 mg every 8 h for 10 days after the onset of AF

A 44, P 38

A 384.1 ±428.4, P 262.5 ±321.5

repeat dose, switch drugs, ECV

all after CABG, HTN P 39 A 52; hyperlipidemia P 38 A 45; DM P 28 A 33; CHF P 0 A 2; COPD P 9 A 21; right atrium enlargement P 0 A 1, intra-aortic balloon pump P 5 A 6; previously diagnosed AF P 5 A 2

N

Pluymaekers et al.

III 2019

multicenter, randomized, open-label, non-inferiority trial

Netherlands

219

65 ±11

89 F, 130 M

CD

not stated (“preferably with flecainide”)

not stated

83

not stated

not stated

HTN 133, DM 25, MI 13

Y

Pohjantahti-Maaroos et al.

III 2019

single-center non-randomized

retrospective

Finland

200

F 55.3 ±13.0; V 59.3 ±12.5

F 65, V 66

ED

flecainide 100, vernakalant 100

F: 2.0 mg/kg (max 150 mg) during 30 min; V: 3.0 mg/kg (max 339 mg) during 10 min

F 46%, V 67%

120

AF after 15 min 2nd dose of V 2.0 mg/kg (max 226 mg) during 10 min

DM F 9, V 9; HTN F 37, V 46; Prior AMI F 0, V 3

Y

Rudiger et al.

V 2014

retrospective single-center

Switzerland

32

74 (36–86)

10 F, 22 M

ICU

vernakalant

3 mg/kg over 10 min iv

17

30 (4–355)

2 mg/kg

all post-CS: 13 CABG, 18 HVD, 9 “major vascular”, LV EF 35–80%

Y

Schnaubelt et al.

IV 2020

single-center trial

Austria

10

76 (63–79)

4 F, 6 M

ICU

vernakalant

3 mg/kg in 100 mL of normal saline iv

7

8.0 (6.0–9.0)

2 mg/kg in 100 mL of normal saline iv

all after elective cardiac surgery: 7 HVD, 3 HVD + CABG

Y

Shibata et al.

IV 2016

retrospective single-center

Japan

23

68 (60, 76)*

7 F, 16 M 

ICU

amiodarone

150 mg over 30 min, followed by 
20–50 mg/h

10

150

administration of a 2nd drug (not defined which), ECV

all post-surgery: CABG 8, CABG + HVD 4, HVD 9, vascular 2

Y

Simon et al.

III 2016

RCT

Austria

100

56.5 (SD 15.00)

32 F, 68 M

ED

vernakalant 49, ibutilide 51

V: 3 mg/kg in 100 mL normal saline iv infusion over 10 min;
I: 1 mg in 100 mL normal
saline iv infusion over 10 min

vernakalant: 34/49
(29 converted
after 1st infusion); ibutilide: 22/51
(14 converted after 1
st infusion)

V 10, I 26

if AF 15 min after vernakalant infusion 2nd infusion (10 min) of vernakalant (2 mg/kg); if AF 10 min after ibutilide infusion 2nd infusion of ibutilide (10 min, 1 mg); if AF 2 h after 1st infusion ECV

HF (48 V, 51 I); HTN (30 V, 36 I); DM (5 V, 6 I); THY (7 V, 7 I); CAD (3 V, 4 I)

N

Simopoulos et al.

IX 2018

prospective, randomized, allocation-concealed, single-blind, single-site clinical trial

Greece

511

A: 65.5 ±9.6, A+R: 65.3 ±9.5

A: 31 F, 224 M; A+R: 35 F, 221 M

CSD

amiodarone 255; amiodarone + ranolazine 256

AMIO: 300 mg in 30 min + 750 mg in 24 h iv; AMIO + R: 500 mg po + 375 mg after 6 h and 375 mg twice daily thereafter

511

≤24 h: 37 A, 235 A+R > 24 h: 218 A, 21 A+R

A: 375 mg in 12 h

all after CABG surgery, DM (152 A, 146 A+R), HTN (140 in both groups), MI (139 A, 154 A+R)

Y

Stefatos et al.

VI 2018

case report

Canada

1

45

M

not stated

amiodarone

2 × 150 mg iv + 3 × 400 mg po

1

not stated (“by the next day”)

not stated

bipolar-type schizoaffective disorder, apiprazole in depot

Y

Stiell et al.

II 2020

multi-center partial factorial trial of 2 protocols (blinded, placebo-controlled RCT + nested, open-label trial)

Canada

204

60 (22–92)

70 F, 134 M

ED

procainamide

15 mg/kg in 500 mL of normal saline solution, over 30 min (max dose 1500 mg)

106

23 (14–35)**

ECV

age ≥75 years 29, CAD 16, CHF 6, COPD or asthma 19, DM type I 18, HVD 17, HTN 75, pacemaker or ICD 3, stroke or TIA 15

Y

Stoneman et al.

XI 2017

prospective, single-center

Ireland

42

57.7 (32–82)

10 F, 32 M

ED

vernakalant

3 mg/kg (max 113 kg) 10 min iv infusion

83%

8.8 (2–30), 9 required 2nd infusion

2nd iv infusion 2 mg/kg (max 113 kg), 10 min

HTN 20

Y

Su et al.

V 2017

retrospective

USA

48

68.9 ±14.0

12 F, 36 M

ICU

amiodarone

150 mg bolus iv followed by 1 mg/min for 6 h, then 0.5 mg/min for 18 h for a total of 1050 mg

not stated

not stated

not stated

AGE 33, reduced LV EF 6, LV hypertrophy 20, pulmonary HTN 14, prior MI 6, DM 13, OBE 11, THY 1

N

Tsanaxidis et al.

IV 2017

RCT

Greece

173

68 ±10

80 F, 93 M

not stated

amiodarone 81 ± ranolazine 92

AMIO: 5 mg/kg in 1 h followed by 50 mg/h; R: 1 g po

90%

10–15 h

not stated

HTN: A 53, A+R 65; IHD: A 13, A+R 29; OBE: A 32, A+R 27; DM: A 9, A+R 7

Y

Urtubia et al.

II 2016

retrospective single-center

Spain

12

56

1 F, 11 M

ED

vernakalant

3 mg/kg in 10 min

10

not stated (8 cardioverted with single dose)

2 mg/kg in 10 min, ECV

DM 2, HTN 6, stroke 2

Y

Vinson et al.

I 2018

retrospective cohort

USA

361

60.9 (14.8)

142 F, 219 M

ED

ibutilide

1 mg iv over 10 min

204

at 90 min was 44% (95% CI 38.9% to 49.3%), at 4 h it was 54.8% (95% CI 49.6% to 60.1%), and at ED discharge it was 56.5% (95% CI 51.2% to 61.7%)

2nd dose or ECV

HTN 202, DM 39, HF 18

N

Vogiatzis et al.

IV 2017

single-center RCT + cost-effectiveness analysis

Greece

78

63.72 ±6.67

22 F, 56 M

CD

vernakalant, ibutilide

V: 3 mg/kg iv over 10 min; I: 1 mg iv over 10 min

V 19, I 22

V 11.8 ±4.3, I 33.9 ±20.25 min

V 2 mg/kg, I 1 mg

HTN: V 27, I 23; CAD: V 18, I 13; HVD: V 5, V 6; lone AF: V 7, I 7

Y

Wu et al.

II 2019

retrospective, single-center

China

181

60.1±8.5

22 F, 159 M

ICU

amiodarone

2 mg/kg in 10 min at 1 mg/kg/h until AF remission or 24 h

42

1584 (1.1 days)

ECV if hemodynamically unstable

all after esophageal or lung surgery, CAD 36, DM 39, HTN 71, OBE 51

Y

Wybraniec et al.

X 2018

retrospective, single-center, observational

Poland

450

65.5 ±11.9

238 F, 212 M

ED

antazoline, amiodarone, propafenone

AMIO: infusion in 5% glucose ± bolus 150 mg iv; PROP: 150 mg po or 70 mg in 100 mL 0.9% NaCl iv over 3 min; ANT: 100–200 mg iv bolus over 3 min or in 100 mL 0.9% NaCl iv over 5–15 min

314/450

not stated

not stated

HTN 328, DM 79), CAD/PAD 144

Y

Yarlagadda et al.

XII 2017

single-center retrospective study of consecutive patients

USA

378

64 ±11

dofetilide (205 M, 93 F), sotalol (46 M, 34 F)

not stated

D (n = 298), S (n = 80)

dofetilide, sotalol

D (125/215, 58%), S (30/48, 62.5%)

not stated

ECV

HTN (D: 252, 84.5%) (S: 67, 83.7%); DM (D: 63, 21.1%) (S: 20, 25%); CAD (D: 93, 31.2%) (S: 41, 51.2%)

Y

Zeemering et al.

VII 2018

retrospective

Netherlands

221

succ 61 ±13; fail 57 ±15

succ (93 M, 64 F); fail (52 M, 12 F)

not stated

flecainide

2 mg/kg (max 150 mg) iv infusion

157/221 (71%)

not stated

not stated

COPD 10, DM 15, HTN 95,

Y

Zeriouh et al.

V 2014

observational

Germany

24

69.6 ±6.3

F 26.1%

not stated

vernakalant ± flecainide

3 mg/kg/min iv infusion over 10 min

14

15–375

V: 2 mg/kg/min over 10 min; F: 300 mg po

DM 17.4%; HTN 78.3%

Y

Zhang et al.

XII 2018

single-center, open-label RCT

China

41

A: 72 ±13, A+W: 71 ±12

A: 11 F, 10 M; A+W: 12 F, 8 M

not stated

amiodarone 21, amiodarone + Wenxin Keli 20

5 mg/kg in 1 h iv followed by 50 mg/h iv ± Wenxin Keli 18 g thrice daily for 24 h

A 17, A+W 14

A 291 ±235, A+W 725 ±475

ECV or radiofrequency ablation

DM (A: 3, A+W: 9), HTN: (A: 14, A+W: 15)

Y

Zheng et al.

VII 2017

retrospective

China

48

63 ±12

A: 27 M

not stated

amiodarone

0.6 g/day (0.2 g tid) in the 1st week and then 0.4 g/day (0.2 g bid) in the 2nd week followed by 0.2 g/day (0.2 g qd) in the 3rd week and lasted for 11.5 months

A 43

A 211 ±126

not stated

CAD (A 36); CMP (A 7); HTN (A 40); HF (A 3)

Y

Table 4. Articles describing PCV performed using a contraidicated drug

Author(s)

Year of publication

Country

PCV setting

PCV drug

AF guideline adherence issue

Amin et al.

2015

Netherlands

CER

flecainide

11 patients had CAD

Balik et al.

2017

Czech Republic

ICU

amiodarone

5 patients had hyperthyroidism

Beatch et al.

2017

China, Hong-Kong, India, Korea, Taiwan

not stated

vernakalant

5 patients had HF (2 had NYHA III), 2 patients had HVD (not specified if aortic stenosis or not)

Bonora et al.

2017

Italy

ED

flecainide or propafenone, amiodarone

18 patients with IHD received flecainide or propafenone, 53 patients with HVD received flecainide or propafenone, 23 patients with THY received amiodarone

Carbajosa et al.

2017

Spain

ED

vernakalant

15 patients had HF (patients with NYHA IIIV HF were excluded)

Cosin-Sales et al.

2016

Spain

ED

vernakalant

1 patient had HF (NYHA not specified)

Costabel et al.

2015

Brazil

ED

vernakalant

“Patients with severe valvular heart disease, restrictive cardiomyopathy, hypertrophic cardiomyopathy, and those with known ejection fraction (EF) <35% were excluded” and yet 5.3% of 121 patients had EF < 55%

Dalyanoglu et al.

2018

Germany

CSD

vernakalant

21 patients had LVEF < 50%

Dong et al.

2017

China

not stated

ibutilide, amiodarone

29.71% of the patients had HF and received ibutilide, 28.35% had HF and received ibutilide + amiodarone (patients with LVEF < 35% were excluded)

Farkowski et al.

2016

Poland

ED

propafenone

14 patients had IHD, 2 patients had HVD

Hamilton et al.

2015

UK

ED

flecainide, amiodarone

52 patients had HVD, 5 had previous congenital heart disease, 162 had IHD (not stated how many of them received flecainide); 48 patients had unspecified THY (not stated how many received amiodarone)

Kriz et al.

2016

Austria

ED

ibutilide, flecainide, vernakalant

1 patient with HF/LV dysfunction received flecainide; 3 patients with HF/LV dysfunction received ibutilide, 4 patients with HF/LV dysfunction received vernakalant (elsewhere in the article it is stated that patients with HF and “severely reduced left ventricular ejection fraction” were excluded)

Lieberman et al.

2018

USA

PED

flecainide

6 patients had CMP + 3 patients had HVD

Nemati et al.

2016

Iran

not stated

propafenone

9 patients had COPD (not stated if patients had bronchospasm or dyspnea at the time of PCV)

Simon et al.

2016

Austria

ED

ibutilide

49 patients had HF (NYHA I) and 2 patients had NYHA II (patients with NYHA III and IV were excluded)

Su et al.

2017

USA

ICU

amiodarone

1 patient had hyperthyroidism

Vinson et al.

2018

USA

ED

ibutilide

18 patients had HF (3 of which had EF < 40%)

CAD – coronary artery disease; CER – cardiac emergency room; CMP – cardiomyopathy; ED – emergency department; EF – ejection fraction; HF – heart failure; HVD – heart valve disease; ICU – intensive care unit; LV – left ventricular; NYHA – New York Heart Association; PED – pediatrics department; THY – thyroid disease.

Figures


Fig. 1. Flowchart of the literature search strategy
Fig. 2. Number of analyzed articles describing pharmacological cardioversion in the particular country’s patient population (illustration by Zu).
Fig. 3. Number of analyzed articles published in a given year

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