1. health and fitness
2. therapy

Shot Through the Heart and I’m OK:
Procainamide Cardioversion of Recent-Onset Atrial Fibrillation
in the Emergency Department
Optimist
I’m in love.
Heart
Palpitations
Pessimist
I’m dying.
Molly Curran, Pharm.D.
PGY1 Pharmacy Resident
Department of Pharmacy, University Health System, San Antonio, TX
Division of Pharmacotherapy, The University of Texas at Austin College of Pharmacy
Pharmacotherapy Education and Research Center, University of Texas Health Science Center at San Antonio
January 9, 2015
Learning Objectives
1. Describe the pathophysiology and treatment strategies for pharmacological management of atrial fibrillation
2. Identify electrophysiological effects of procainamide and its effects on cardiac conduction
3. Discuss patient outcomes in emergency department management of recent-onset atrial fibrillation patients with
intravenous procainamide
4. Formulate an evidence-based recommendation for role of intravenous procainamide in recent-onset atrial fibrillation patients
I.
Atrial Fibrillation (AF)
A. Introduction 1–4
1. Most common supraventricular tachycardia (SVT)
2. Characterized by a fast and irregular heart rhythm
B. Incidence/Prevalence1,2,4,5
1. Between 2.7 and 6.1 million Americans are affected by AF
2. In US, overall prevalence 0.4 to 1%
a. Increases with:
i. Age (8% for patients >80 years old)
ii. Heart failure (50% for patients in New York Heart Association [NYHA] Stage IV)
3. Aging population in US; prevalence will increase
4. Lifetime risk for those ≥40 years old is 1 in 4
C. Characteristics1,2,4
1. Results from multiple reentrant loops in atria
a. In normal conduction, one impulse is spread throughout heart to create regular rhythm
Figure 1. Mechanism of AF1,2,4
Multiple electrical
wavelets appear
simulataneously in
atria
Rapid and
disorganized
atrial activation
No synchronized
contraction of
atria
Variable AV
activation
Irregular ventricle
activation
Irregularly
irregular Pulse
Figure 2. Comparison of Conduction Pathways7
Normal electrical conduction
Atrial fibrillation
Reprinted from: http://www.yalesurgery.org
2. “AF begets AF”1,2,7
a. May be harder to terminate long episodes because long-term tachycardia may induce mechanical and/or electrical remodeling
D. Complications1,2,4
1. Thromboembolic events (stroke) due to:
a. Stasis of blood in atrial appendage
b. Poorly adherent mural thrombi
c. Risk higher for AF lasting >48 hours
d. Validated tool for assessing risk is CHA2DS2-VASc score (Appendix A)
2. Hemodynamic instability with hypotension, acute coronary syndrome or pulmonary edema  medical emergency
3. Worsening left ventricular diastolic dysfunction due to:
a. Loss of atrial kick
4. Mortality rate with AF is approximately double that for patients in normal sinus rhythm (NSR)
E. AF Classification
1. Based on duration of episode
M. Curran | 2
Table 1. Atrial Fibrillation Classifications1,2,8
Recent-Onset AF
<48 hours in duration
Paroxysmal AF
Terminates spontaneously or with
intervention within
7 days of onset
Recurrent AF
Longstanding
Persistent AF
Persistent AF
Two or more episodes Continuous AF
of AF
lasting >7 days
Continuous AF >12
months of duration
Permanent AF
No more active
attempts to restore/
maintain sinus rhythm
F. Etiology
1. Often occurs in association with disease states that cause atrial stretch/distension1,2,4
a. Myocardial ischemia/infarction
b. Hypertensive heart disease
c. Valvular disorders
d. Acute pulmonary embolism
e. Congenital abnormalities
f. Lung disease  pulmonary hypertension, chronic obstructive pulmonary disease (COPD)
2. High adrenergic tone is also associated with AF1,2,8
a. Thyrotoxicosis
b. Surgery
c. Alcohol withdrawal
d. Sepsis
e. Excessive physical exertion
G. Clinical Presentation
1. May present with a variety of symptoms including:2,8,9
a. Light-headedness
b. Fatigue
c. Breathlessness
d. Palpitations
e. Chest-tightness/pain
2. Obtain a thorough history at presentation1,2,9–11
a. Time of onset
b. Previous history of AF episodes/treatments
c. Home medications - focusing on antiarrhythmic agents, anticoagulants
d. Cardiac history including:
i. Previous electrocardiogram (ECG)
ii. Prior myocardial infarction
iii. Congestive heart failure
iv. Hypertension
e. Assess thromboembolic risk factors via CHA2DS2-VASc score (Appendix A)
3. Clinical findings1,2,4,9,12
a. Irregularly irregular heart rhythm
Figure 3. ECG Findings in AF13
Reprinted from: http://ambulancetechnicianstudy.co.uk
b. Heart rate fluctuates between 110 and 180 beats per minute (BPM)
c. Typically hemodynamically stable
II. Pharmacological Management of AF
A. Emergency Management11,12,14,15
1. Assess potential for hemodynamic instability
2. Identify and treat underlying/precipitating cause of AF
3. Assess patient history for risk of thromboembolism
4. Consider emergent cardioversion with expert consultation
M. Curran | 3
B. Chronic Management: Rate v. Rhythm Control16–22
1. Rate control
a. Target ventricular rate control
i. Resting heart rate <80 BPM
ii. Six minute walk test <110 BPM
2. Rhythm control
a. Variety of antiarrhythmic agents available to maintain NSR
3. Evidence16–22
a. Does not address management of recent-onset AF
b. Five randomized controlled trials examine rate v. rhythm for patients with chronic AF (Appendix B)
i. Largest trial focused on patients ≥65 years old
ii. No significant difference in mortality between rate v. rhythm management in any individual trial
iii. Meta-analysis of results found a trend towards better outcomes with rate control driven by large patient
population in atrial fibrillation follow-up investigation of rhythm management (AFFIRM) trial
Figure 4. Odds Ratios for the End Point of All-cause Mortality in Major Rate v. Rhythm Control Trials16
Trial
HOT CAFE
PIAF
RACE
STAF
AFFIRM
Combined
Rate
1/101
2/125
18/256
8/100
310/2027
339/2609
Rhythm
3/104
2/127
18/266
4/100
356/2033
383/2630
Percentage
13.0
14.6
OR, 0.87 (95% CI; 0.74 - 1.02), P = .09
0.1
1
Rate
Control Better
10
Rhythm
Control Better
iv. Increased rates of hospitalization in rhythm control
1) Attributed to side effects of antiarrhythmic drugs
v. Limitations of trials
1) Did not include patients with
a) Paroxysmal AF at low risk of recurrence
b) Recent-onset AF
c) Low risk of thromboembolism
d) Heart failure
2) All open-label trials
3) Compared treatment strategies, not treatment agents
C. Anticoagulation
1. Initiate if AF lasts >48 hours and patient has risk factors for stroke with CHA2DS2-VASc score1
III. Clinical Practice - Guidelines
A. 2014 AHA/ACC/HRS AF Guideline1
1. Initial rate control strategy is reasonable for many patients, but there are several considerations for selecting
rhythm control
a. Persistent symptoms
b. Younger patients
c. Difficulty achieving rate control
d. First episode of AF
e. AF precipitated by acute illness
f. Patient preference
2. Recommendations for pharmacological cardioversion
a. Flecainide, dofetilide, propafenone, or intravenous ibutilide are recommended for pharmacological cardioversion of AF provided contraindications to the selected drug are absent (Level of Evidence: A; Class Ia recommendation)
b. Amiodarone is a reasonable option for pharmacological cardioversion of AF (Level of Evidence: A; Class IIa
recommendation)
3. Changes from 2006 recommendations8
a. Procainamide/quinidine were removed
b. Previously stated that both agents may be used for pharmacological cardioversion of AF, but that their usefulness was not established
M. Curran | 4
c. Included the need to assess patient for contraindications to agents
d. Removed definitive timeline for cardioversion effectiveness
i. Previously within 7 days of AF episode onset
B. 2010 AHA Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care11
1. Management of AF should focus on ventricular rate control, conversion of hemodynamically unstable AF to sinus
rhythm or both
a. Stable patients require ventricular rate control with IV beta-blockers or nondihydropyridine calcium channel
blockers (such as diltiazem)
2. Electric or pharmacological cardioversion should not be attempted unless patient is unstable
3. Alternatively, may elect cardioversion after anti-coagulation with heparin and performance of transesophageal echocardiography to ensure absence of a left atrial thrombus
4. No specific agent recommendations for cardioversion
i. Variety of agents are effective
ii. Recommend consulting an expert
C. Canadian Cardiovascular Society AF Guidelines 2010: Management of Recent-Onset Atrial Fibrillation and Flutter in the
Emergency Department (ED)9
1. ED should assess instability, identify and treat an underlying or precipitating cause, and assess a patient’s risk of a
thromboembolic event
2. May consider rate or rhythm control
a. If choosing rhythm control, there are several drug options that may be considered
Table 2. 2010 Canadian Cardiovascular Society’s Recommended Drugs for Pharmacologic Conversion in the ED9
Drug
Procainamide
Propafenone
Flecainide
Ibutilide
Dose
15–17 mg/kg IV over 60 min
450–600 mg PO
300–400 mg PO
1–2 mg IV over 10–20 min; pretreat with
1–2 g IV magnesium sulfate
Efficacy
++
+++
+++
++
Risks
5% hypotension
Hypotension, 1:1 flutter, bradycardia
Hypotension, 1:1 flutter, bradycardia
2–3% torsades de pointes
3. Amiodarone and sotalol are not recommended for recent-onset AF
a. No more effective than placebo in initial 6–8 hours
b. Associated with adverse reactions
IV. Recent-onset AF Management in the ED
A. Strategies for ED management of AF
1. Aggressive treatment = rhythm control12,23,24
a. Methods utilized in the ED include 25
i. Direct current cardioversion (DCC)25
1) Preferred method for unstable patients
2) Requires use of procedural sedation and fasting
ii. Pharmacological cardioversion 26
1) Typically lower conversion rates to sinus rhythm than DCC
2) Use limited by adverse effects of medications
3) Preferred agent varies by country
a) IV procainamide preferred in Canada
b) IV amiodarone preferred in US, UK, Australia
4) If successful, patient may be discharged home
5) Less commonly pursued in US than Canada (26% v. 65.9%)
Table 3. Benefits and Risks of Aggressive Treatment Approach in the ED1,9,12
Benefits
• Improved quality of life
• No hospitalization
• No tachycardiomyopathy
Risks
• Thromboembolic event
• Ventricular arrhythmias
2. Conservative treatment = rate control or observation approach12,23,24
a. Pursue rate control with anticoagulation in patients at risk for thromboembolic event
b. May alternatively consider allowing patient to convert spontaneously
c. Many centers admit patients to inpatient cardiology service
M. Curran | 5
Table 4. Benefits and Risks of Conservative Treatment Approach in the ED1,9,27
Benefits
Risks
• Lesser chance of
◦◦ thromboembolic event
◦◦ ventricular arrhythmia
• Hospitalization
• Symptoms of AF may continue
• Tachycardiomyopathy
B. Economic Perspective on ED Rhythm Control of AF
1. If successful, patients can be discharged home from the ED1,27,28
a. Benefits: minimal disruption of patient’s quality of life, reduced healthcare costs
2. Median costs for patients28
a. Cardioverted and discharged from the ED: $5,460
b. Admitted with no attempt at cardioversion: $23,202
C. ED Management Protocols
1. Canadian Cardiovascular Society AF Guidelines 2010: Management of Recent-onset Atrial Fibrillation and Flutter in
the ED based on Ottawa Hospital protocol for AF management in the ED9,27
Figure 5. Details of Ottawa Protocol for ED Patients with Recent-onset AF27
Assessment
Patient stable without ischemia,
hypotension or acute CHF?
Onset clear and less
than 48 hours?
Anticoagulated with warfarin
and INR therapeutic?
Severity of symptoms?
Previous episodes and
treaments?
Rate Control
Diltiazem IV
Metoprolol IV
If highly symptomatic or not planning to convert
Pharmacological cardioversion
Procainamide IV
1 g over 60 minutes
Hold if SBP <100 mmHg
Electrical cardioversion
Consider keeping patient NPO for 6 hr
Procedural sedation/analgesia per ED physician
150–200 J biphasic, synchronized shock
Anticoagulation
No heparin/warfarin if onset clearly <48 hr or if therapeutic INR >3 weeks
Disposition
Home within 1 hour
of cardioversion
No antiarrhythmic prophylaxis
or anticoagulation
If 1st episode,
arrange outpatient
echocardiography/
cardiology follow-up
For 2nd or future episodes,
arrange cardiology follow-up
Patients not treated with cardioversion
Achieve rate control
(HR <100 BPM)
Discharge home on rate control
medication/anticoagulation
Arrange follow up outpatient
echocardiography and cardiology
for elective cardioversion
M. Curran | 6
2. Retrospective cohort study evaluated the efficacy and safety of the Ottawa Aggressive Protocol
a. Results cited in 2010 guidelines management recommendations
Stiell IG, et al. Association of the Ottawa Aggressive Protocol with rapid discharge of emergency department patients with
recent-onset atrial fibrillation or flutter. Can J Emerg Med 2010; 12:181-91.27
Overview
Objective
To examine the efficacy and safety of the Ottawa Aggressive Protocol for patients with recent-onset episodes of atrial
fibrillation and flutter for patients treated between
Trial design
Retrospective consecutive cohort study using ED health records at Ottawa Hospital Civic Campus
Patients
Inclusion criteria
• Primary diagnosis of recent-onset AF or flutter
• Underwent aggressive attempt at cardioversion
Exclusion criteria
• Permanent AF diagnosis
• Symptoms >48 hours/unknown duration
• Other diagnosis requiring hospital admission
Outcomes
Primary
• Proportion of conversion to sinus rhythm before discharge from the ED
• Length of stay in the ED
• Final disposition (home or hospital admission)
• Adverse events: hypotension or arrhythmia
Secondary
• Death
• Stroke
• Relapse to AF within 7 days of index ED visit
Interventions
All patients were managed by ED physicians using the Ottawa Aggressive Protocol (see Figure 6)
• Rate control was often omitted per protocol unless highly symptomatic
• Pharmacological cardioversion with procainamide infusion 1g IV over 60 minutes
◦◦ Not used if patient is unstable or previous visits indicate resistance to agent
• Electrical cardioversion if pharmacological cardioversion fails
Results
Baseline
­characteristics
Primary outcomes
• AF patients, N = 628
• Mean age (range): 64.6 years (19–92)
• Primary presenting symptom, n (%): palpitations 491 (78.2)
• Past medical history, n (%): previous AF, 526 (83.8); coronary heart disease, 267 (42.5)
• Previous successful conversion with procainamide, n (%): 305 (48.6%)
• Number of ED visits during study period:
◦◦ One, n = 341; two, n = 108; three, n = 54; four or more, n = 153
Efficacy of Ottawa Aggressive Protocol
Table 5. Rates of Successful Cardioversion
n (%)
Procainamide only
376 (59.9)
Procainamide and electrical cardioversion
203 (32.3)
• Median (interquartile range, IQR) arrival to discharge, all AF patients, hr: 4.8 (3.3)
• Median (IQR) arrival to discharge, AF patients successfully cardioverted with
procainamide, hr: 3.9 (2.2)
Table 6. Patient Disposition from ED
Disposition
Home in NSR
Home
Admitted to hospital
n (%)
567 (90.3)
609 (97)
19 (3)
Safety of Ottawa Aggressive Protocol
• Hypotension (SBP <100 mmHg) in AF patients, n (%): 46 (7.3)
• Arrhythmias, n (%)
◦◦ AV Block: 2 (0.3)
◦◦ Ventricular tachyarrhythmia: 1 (0.2)
◦◦ Atrial tachyarrhythmia: 2 (0.3)
• No torsades de pointes observed
M. Curran | 7
Secondary
­outcomes
• No deaths or strokes were observed
• AF relapse within 7 days, n (%): 55 (8.8)
Conclusions
Author’s
­conclusions
• Recent-onset AF can be can be safely and quickly treated with medications or electrical cardioversion in the ED
• Procainamide has an excellent safety profile
• Rhythm control resulted in few adverse effects
Strengths
• Largest reported study of an aggressive ED treatment strategy for patients with recent-onset AF or atrial flutter
• Reported outcomes separately for AF v. flutter patients
• Majority of primary outcomes were objective variables that minimize potential bias
• Reviewed relapse rates at 7 days
• Evaluated adverse effects – thromboembolic event rate
Limitations
• Observational, retrospective study
• Only reported results in descriptive statistics - proportions, means, medians, IQR
◦◦ No 95% confidence intervals or significance tests
• Cardiology literature generally reports 30 day outcomes
• Did not report cardioversion rates for patients with repeat visits
• Limited information about excluded patients (n = 400) who did not receive aggressive management
Take-home points
• Ottawa Aggressive Protocol is highly effective for initial conversion of recent-onset AF patients
• No thromboembolic events were reported with 660 ED cardioversions
• Few new, dangerous arrhythmias observed
• Majority of patients (97%) discharged home
i. Provided evidence for IV procainamide as part of an aggressive management protocol
ii. Many pharmacoeconomic implications for patients
1)  healthcare cost
2)  quality of life
V. Focus on Antiarrhythmic Agents and Procainamide
A. Cardiac Electrophysiology
1. Definitions2,29
a. Conduction velocity: speed with which an electrical impulse can be transmitted through the heart
b. Refractory period: period of depolarization and repolarization of the cell membrane after excitation
i. Cell is unable to respond to a second stimulus during this period
c. Automaticity: capacity of cell to initiate an impulse without an external stimulus
Figure 6. Ion Channels and the Effect of Class Ia
Antiarrhythmic Agents on Cardiac Depolarization 2,30,31
0 mV
–85 mV
Na+
Ca2+
Na+ 3 Na+
Outside
ATP
Membrane
Inside
K+
Channel currents
K+
Ca2+
Pump Exchanger
K+
Na+
Ca2+
“Leak” currents
Adapted from: http://www.cvpharmacology.com
M. Curran | 8
Table 7. Role of Ion Channels in Cardiac Depolarization2,30
Open
Phase 0: Depolarization
Closed
• Fast Na+ channels: allow Na+ ions into cell
Phase 1: Peak
• Fast Na+ channels
Phase 2: Plateau
• L-type Ca++ channels: allow Ca++ ions to enter cell
• Slow delayed rectifier K+ channels: allow K+ to exit cell
Phase 3: Repolarization
• Slow delayed rectifier K+ channels: allow K+ to exit cell
• Rapid delayed rectifier K+ channels: allow K+ to reenter cell
Phase 4: Automaticity
• Slow delayed rectifier
• Sodium-potassium pump (K+ pump): pumps one Na+ ion out for one
K+ channels
K+ ion in to maintain electrical gradient
• Sodium-calcium exchanger (Ca++ exchanger): exchanges three Na+ ion • Rapid delayed rectifier
K+ channels
in for one Ca+ ion out to maintain electrical gradient
• L-type Ca++ channels
B. Vaughan Williams Classification System29
1. Most commonly used classification system for antiarrhythmic drugs
2. Categories are based on dominant electro-physiologic effect
3. Weaknesses32
a. Many antiarrhythmic drugs may fit into multiple categories
b. Does not differentiate drugs based on efficacy for different types of arrhythmias
c. Additional antiarrhythmic agents are not included in classification
i. Digoxin, adenosine, magnesium sulfate
Table 8. Vaughan Williams Classification of Antiarrhythmic Agents Studied in Recent-onset AF2,29
Class
Drugs
Conduction
Velocity
Refractory
Period
Automaticity
Ion Block
Ia
Procainamide
ê
é
ê
Na (intermediate)
K+
Ic
Propafenone
ê
0
ê
Na+ (slow on-off)
III
Amiodarone
Ibutilide
0
é
0
K+
+
Adapted from: Pharmacotherapy: A Pathophysiologic Approach, 9th Ed.
C. Antiarrhythmic drugs utilized in acute management of AF
Table 9. Properties of Key Agents Used in Recent-onset AF33
Drug
Procainamide34,35
Properties
Mechanism of action: Blocks fast sodium channels to prolong atrial conductive tissue recovery after repolarization  decreasing impulse conduction velocity in atria, His-Purkinje system and ventricular muscle; also has
variable effects on A-V node
Pharmacokinetics: Only available as intravenous medication in US; metabolized by acetyltransferase; forms
­N-acetyl procainamide (NAPA): active metabolite cleared renally; half-life: 2–5 hours; renal elimination
Black box warning: Fatal blood dyscrasias; cardiac arrhythmias; systemic lupus erythematosus
Major side effects: Hypotension, QT prolongation
Ibutilide36
Mechanism of action: Promotes influx of sodium through slow inward sodium channels  prolonging action
potential duration  slowing sinus rate/AV conduction
Pharmacokinetics: Intravenous agent; metabolized via oxidation in the liver; has 8 metabolites  only one metabolite has antiarrhythmic properties; half-life: 6 hours; renal and fecal elimination
Black box warning: Fatal arrhythmias
Major side effects: Ventricular tachycardias (e.g. torsades), hypotension, QT prolongation
M. Curran | 9
Amiodarone37
Mechanism of action: Inhibits potassium channels during plateau and repolarization phases  delaying repolarization of the cell  prolonging refractory period; mild inhibition of sodium fast channels  slows cell depolarization and impulse conduction; direct depression of sinoatrial (SA) and atrioventricular (AV) node automaticity 
slowing conduction in His-Purkinje system
Pharmacokinetics: Administered intravenously and orally; metabolized in liver via CYP450 enzymes: 3A4, 2C8;
half-life: 53 days; hepatic elimination
Black box warning: Cardiac arrhythmias; liver disease; pulmonary fibrosis/pneumonitis
Major side effects: Hypotension, cardiac arrhythmias, hypersensitivity pneumonitis
with long term use - corneal microdeposits, optic neuritis, skin discoloration, hepatic toxicity, thyroid
disorders (hypo- and hyper-), peripheral neuropathy, ataxia, tremor
Propafenone38
Mechanism of action: Inhibits fast sodium channels  increase recovery period after repolarization  decreasing
conduction velocity and automaticity
Pharmacokinetics: Oral agent; metabolized in liver via CYP450 enzymes: 2D6; half-life: ~10 hours; fecal and urine
elimination
Black box warning: Cardiac arrhythmias
Major side effects: Cardiac arrhythmias, bronchospasm, congestive heart failure (CHF)
VI. Literature review: Procainamide for Pharmacological Cardioversion of Recent-onset AF in the ED
Stiell IG et al. Emergency department use of intravenous procainamide for patients with acute atrial fibrillation or flutter. Acad Emerg Med
2007; 14:1158-64.39
Overview
Objective
To examine the efficacy and safety of IV procainamide for acute AF or flutter
Trial Design
Retrospective, consecutive cohort study using ED health records at Ottawa Hospital Civic Campus
Patients
Inclusion criteria
• Primary diagnosis of recent-onset AF or flutter
• Received IV procainamide
Exclusion criteria
• Visits after index visit (1st episode)
• Symptoms >48 hours/unknown duration
• Chronic AF (permanent or long-standing)
• Other diagnosis requiring hospital ­admission
Outcomes
Primary
• Efficacy:
◦◦ Rate of conversion to sinus rhythm before ED ­discharge
• Safety:
◦◦ Hypotension (SBP <100 mmHg)
◦◦ Bradycardia (HR <60 BPM)
◦◦ Syncope
◦◦ 2nd or 3rd degree heart block
◦◦ Ventricular tachyarrhythmia
◦◦ Atrial tachyarrhythmia
◦◦ Cerebrovascular accident
◦◦ Death
Secondary
• Time to conversion
• Average dose of IV procainamide required
• Admission to hospital
• QTc prolongation
Interventions
All patients were managed by ED physicians using the Ottawa Aggressive Protocol (see Figure 5)
• Rhythm control is routine care at Ottawa Hospital
• Pharmacological cardioversion with procainamide infusion: 1g IV over 60 minutes
◦◦ Discontinued if hypotension persists or bradyarrhythmia occurred
• Electrical cardioversion pursued if pharmacological cardioversion failed
Results
Baseline
­characteristics
• AF patients, N = 316
• Mean age (range): 68 years (19–92)
• Primary presenting symptom, n (%): palpitations, 236 (74.7)
• Past medical history, n (%): previous AF, 214 (67.7); coronary heart disease, 104 (32.9)
• Previous successful conversion with procainamide, n (%): 45 (14.2)
M. Curran | 10
Primary ­outcomes
Efficacy of IV procainamide
• Successful cardioversion of AF patients with procainamide only, n (%): 165 (52.2)
• Successful cardioversion of AF patients with procainamide and electrical
cardioversion, n (%): 116 (36.7)
◦◦ Median (range) total number of shocks given: 1 (1–5)
• AF patients discharge home in normal sinus rhythm, n (%): 281 (88.9)
• AF patients discharged to home, n (%): 299 (94.6)
Safety of IV procainamide
• Hypotension (SBP <100 mmHg) in AF patients, n (%): 27 (8.5)
• Arrhythmias, n (%)
◦◦ Bradycardia (HR <65 BPM): 2 (0.6)
◦◦ AV block: 2 (0.6)
◦◦ Ventricular tachyarrhythmia: 1 (0.3)
◦◦ Atrial tachyarrhythmia: 2 (0.6)
• No syncope, cerebrovascular accidents, torsades de pointes, myocardial infarction, or death observed
Secondary
­outcomes
• Median (range) time to conversion, min: 55 (2–390)
• Mean (range) procainamide dose, mg: 863.9 (250–1,500)
• QTc interval mean, ms
◦◦ Pre-conversion: 405.9
◦◦ Post-conversion: 428
• Admission to hospital, n (%): 17 (15.4)
• AF relapse within 7 days, n (%): 9 (2.9)
Conclusions
Author’s
­conclusions
• IV procainamide is a safe and effective option for treating acute AF in the ED
• Procainamide use resulted in median time to conversion <1 hour and brief ED visits
• Few significant adverse effects occurred
Strengths
• Largest review of IV procainamide for AF conversion in the ED
• Reported outcomes separately for AF versus flutter patients
• Majority of primary outcomes were objective variables that minimize potential bias
Limitations
• Observational, retrospective study
• Only reported results in descriptive statistics: proportions, means, medians
◦◦ No 95% confidence intervals or significance tests
• Cardiology literature generally reports 30 day outcomes
• May have missed adverse events that occurred after hospital discharge
• No comparator antiarrhythmic agents studied
Take-home points
• Use of IV procainamide in the ED was effective with >50% conversion rate
• Procainamide use does not preclude electric cardioversion
• Few clinically significant adverse events were reported
Volgman AS, et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous procainamide. J Am Coll Cardiol
1998; 31:1414-9.40
Overview
Objective
To compare the safety and efficacy of IV ibutilide with IV procainamide for the termination of recent-onset AF or flutter
Trial Design
Multicenter, double-blind, randomized, parallel-group, active control, repeated-dose design study
Patients
Inclusion criteria
• ≥18 years old
• Weighed between 132–300 lb.
• No previous exposure to IV ibutilide
• Ratio of 6 men:4 women at each study center
• AF/flutter persisting >3 hours and <90 days
• Hemodynamically stable with QTc interval ≤440 ms
• If AF/flutter >3 days, appropriate anticoagulation or
transesophageal echocardiography to confirm no atrial
clot present
• All females were surgically sterile or post ­menopausal
Exclusion criteria
• Symptoms of unstable angina or CHF
• Abnormal serum Na+ or Mg++
• Serum K+ <4.0 mEq/L
• Liver function tests >2x upper limit of normal
• SCr >2 mg/min
• History of myocardial infarction (MI) in last 30
days, torsades, 2nd or 3rd degree heart block or
any serious medical condition that could interfere
with results
• Amiodarone therapy
M. Curran | 11
Outcomes
Primary efficacy outcome
• Conversion rates of AF and flutter
Primary safety outcomes
• Mean change from baseline for systolic and diastolic blood pressure
• Significant 12-lead ECG changes from baseline
• Adverse events requiring termination of study infusions/occurring up to 72 hours after infusion
Methods
Interventions
• 10-minute baseline period before 1st infusion
• Treatment initiated for patients still in AF/flutter at end of baseline period
• During 30-minute infusion period
◦◦ Blood pressure and HR recorded every 5 min
◦◦ Continuous ECG monitoring
• Post-infusion period lasted for 1st 24 hours from end of infusion
Ibutilide group
• Up to two 10-minute IV infusions of 1 mg ibutilide, separated by 10-minute infusion of dextrose 5% in water (D5W)
Procainamide group
• Up to three 10-minute IV infusions of 400 mg procainamide
Other Considerations
• Treatment infusions were discontinued at time of arrhythmia termination or adverse event
◦◦ Threatening arrhythmias or changes in AV conduction, hypotension (decrease in SBP >20 mmHg or
SBP <80 mmHg)
• AV node blockers (Ca-channel blockers, beta-blockers, digoxin) were permitted for rate control
• Class I or Class III antiarrhythmic medications were discontinued at least 5 half-lives before infusion of study
­medicine
• Administration of additional antiarrhythmic medications delayed for 6 hours after end of infusion
Results
Baseline
­characteristics
• No significant differences between patient populations
Table 10. Characteristics of Ibutilide Versus Procainamide Treatment Groups
Characteristics
Ibutilide group (n = 60)
Procainamide group (n = 60)
64.3
67.7
22.3 ± 24.7
9.4
17 ± 23
4.6
22 (38.3)
32 (53.3)
Age (years)
Mean duration of arrhythmias (days)
Median
Coronary artery disease, n (%)
• Other variables evaluated included: weight, cardiovascular history, gender
Efficacy outcome
Figure 7. Rate of Successful Conversion of AF and Flutter in the Ibutilide and Procainamide Groups
Success rate (%)
Primary outcomes
80
70
60
50
40
30
20
10
0
**
*
***
Ibulide
Procainamide
Combined
Fluer
Fibrillaon
(*p < 0.0001 **p = 0.0001 ***p = 0.005)
M. Curran | 12
Primary outcomes
(continued)
Safety outcomes
• Three patients discontinued ibutilide secondary to adverse ECG changes - extra systole, non-sustained ventricular
tachycardia, QT prolongation
• Three serious medical events occurred in ibutilide group, but all were excluded from analysis
◦◦ Sustained polymorphic ventricular tachycardia
◦◦ Pre-syncope
◦◦ Acute delirium
Mean change from baseline (mmHg)
Figure 8. Mean Change from Baseline in Systolic Blood Pressure
Systolic Blood Pressure
5
Ibutilide
Procainamide
0
-5
-10
-15
-20
-20
0
5 10 15 20 25 30 35 40 60 1.5 2 4 6
8 16 24
Time in minutes to 60 minutes, then hours
• Statistically significant changes in systolic and diastolic blood pressure seen with procainamide infusion until 1.5 hours
• Three patients discontinued procainamide due to severe hypotension
Conclusions
Author’s
­conclusions
• Ibutilide is significantly more effective than procainamide in the acute conversion of AF/flutter
• Hypotension is a major adverse effect seen with IV procainamide
• Incidence of serious arrhythmias with ibutilide is low
Strengths
• Prospective study comparing IV procainamide to IV ibutilide with strict inclusion/exclusion criteria
• Multicenter study involving 16 hospitals across the US
• 72 hour post-infusion adverse effect follow-up
Limitations
• Included patients with AF up to 90 days in duration
• Hypotensive changes from baseline may have been due to aggressive procainamide administration
• Post-hoc analysis excluded patients suffering major adverse events from ibutilide group
• Hypotension based on change from baseline blood pressure not actual blood pressure readings
Take-home points
• May have over reported hypotensive effect
• Lacks external validity to readily apply results to patients presenting in first 48 hours due to inclusion of patients
with longer duration atrial fibrillation
• Ibutilide was associated with more serious pro-arrhythmias relative to procainamide
Kochiadakis, et al. A comparative study of the efficacy and safety of procainamide versus propafenone versus amiodarone for the
conversion of recent-onset atrial fibrillation. Am J Cardiol 2007; 99:1721-25.41
Overview
Objective
To compare the safety and efficacy of IV procainamide, propafenone, and amiodarone v. placebo in the restoration of
recent-onset AF to NSR
Trial Design
Randomized, placebo-controlled study
Patients
Inclusion criteria
Exclusion criteria
• AF <48-hour duration
• Cardiac history including recent MI, heart surgery in last 6 months, unstable angina,
acute myocarditis/pericarditis, hypertrophic obstructive cardiomyopathy, severe uncontrolled HF, cardiogenic shock
• Baseline SBP <100 mmHg
• Other comorbidities: COPD, pulmonary embolism, pneumonia, liver or kidney failure,
thyroid disease, electrolyte disturbances, digoxin intoxication
• Antiarrhythmic therapy (other than digoxin) within <5 half-lives of study drug
Outcomes
Primary efficacy outcome
• Progression rate to sinus rhythm
Primary safety outcomes
• Adverse events/drop outs during study period
M. Curran | 13
Methods
Interventions
• Patients randomized to receive procainamide, propafenone, amiodarone, or placebo
Procainamide group
• 1 g IV over 30 minutes, followed by 2 mg/min IV over 24 hours
Propafenone group
• 2 mg/kg IV over 15 minutes, followed by a total of 10 mg/kg IV over 24 hours
Amiodarone group
• 300 mg IV over 1 hour, followed by a total of 20 mg/kg IV over 24 hours
Placebo group
Received an identical amount of IV saline solution over 24 hours
Other considerations
• All patients received digoxin
◦◦ Initial 0.5 mg IV dose, followed by 0.25 mg after 2 hours and 0.25 mg every 6 hours until completion of anti­
arrhythmic infusion
• Treatment infusions were discontinued at time of arrhythmia termination or adverse event
◦◦ Threatening arrhythmias or changes in AV conduction, hypotension (decrease in SBP >0 mmHg or
SBP <80 mmHg)
• If NSR not achieved after study drug use, other antiarrhythmic drugs or electric cardioversion attempted after
21 days of anticoagulation therapy
• All patients underwent continuous ECG and blood pressure monitoring
• Kept under observation ≥2 days before discharge from hospital
Results
Table 11. Characteristics of Patients Enrolled
Baseline
­characteristics
Procainamide
(n = 89)
Characteristics
Age (years)
Underlying heart disease, n (%)
No. of episodes
Amiodarone
(n = 92)
Placebo
(n = 90)
64 ± 10
64 ± 11
65 ± 11
66 ± 9
37 (41.6)
36 (39.6)
39 (42.4)
37 (41.1)
5±5
6±5
5±6
6±6
Efficacy outcome
Figure 9. Cumulative Progression of Conversion to NSR
100
80
Drug
propafenone
60
% NSR
Primary outcomes
Propafenone
(n = 91)
procainamide
40
amiodarone
20
placebo
0
censored
0
6
12
18
24
30
Hours
Table 12. Conversion to NSR by group
Procainamide
(n = 89)
Conversion to NSR, n (%)
Mean Time to NSR (hours)
Propafenone
(n = 91)
Amiodarone
(n = 92)
Placebo
(n = 90)
61 (68.53)
73 (80.21)
82 (89.13)
55 (61.11)
9
8
12
17
• All 3 drugs superior to placebo in conversion and rate to progression (p < 0.001)
M. Curran | 14
Primary outcomes
(continued)
Safety outcomes
• Study treatment discontinued in:
◦◦ One amiodarone patient (allergy)
◦◦ Four propafenone patients (excessive QRS widening)
• Significant decreases in blood pressure (SBP <90 mmHg) occurred in 15 amiodarone patients and six procainamide
patients
◦◦ All responded to fluids
• Phlebitis in 17 amiodarone patients  continued treatment at more central site
• No proarrhythmic events in any treatment group
Conclusions
Author’s
­conclusions
• All three agents are effective and safe for restoration of NSR in recent-onset AF
• Amiodarone and propafenone are more efficacious than procainamide or placebo
• Procainamide and propafenone act more quickly than other agents studied
• Lack of serious arrhythmias may be due to stringent exclusion criteria
Strengths
• Prospective study comparing three commonly used antiarrhythmic agents including amiodarone
• Post-hoc Bonferroni analysis conducted to minimize error associated with multiple measurements
Limitations
• Results possibly confounded by digoxin use
• No post-study follow-up regarding adverse event rates
• All patients were admitted to hospital for ≥36 hours to complete study
Take-home points
• Less serious adverse effects with procainamide
• Safety of agents may be due to stringent exclusion of cardiac patients
• Similar efficacy rate of IV procainamide to studies in AF <48 hours
• Administration of fluids may help counteract hypotensive effect of procainamide
VII. Summary of Literature
A. Efficacy
1. IV procainamide may used for pharmacological cardioversion of recent-onset AF in the ED
a. Conversion to NSR occurs ~50 to 60% of patients if used within 48 hours of onset
b. Literature supports slow 1 g infusion over 30 to 60 minutes rather than many, smaller, rapid infusions over
10 minutes
i. No standardized dosing available
ii. Generally administered at rates of <20 mg/min and rate should not exceed 50 mg/min due to risk of
hypotension/decreased cardiac output
2. Use of IV procainamide does not prevent immediate use of direct current cardioversion for patients who fail to cardiovert with medication alone
3. If successful, allows for discharge home from the ED within a median time of 3.9 hours
B. Safety
1. IV procainamide associated with hypotension
a. Literature reports using IV fluids to maintain adequate blood pressure if significant decrease
b. Decreases in blood pressure may not always be clinically significant
c. Should have close cardiac monitoring during infusion period
2. Few serious arrhythmias noted with procainamide administration compared to other IV antiarrhythmic agents
3. Lower event rates in studies that excluded patients with active cardiovascular disease
C. Other Considerations
1. Literature largely driven by Ottawa Hospital and one author, I.G. Stiell
2. No long-term follow-up studies available for patients who undergo pharmacological cardioversion in the ED
VIII.Future Directions
A. Chemical v. Electrical Cardioversion for Emergency Department Patient with Acute AF
1. Randomized, double-blind clinical trial to compare IV procainamide v. electrical cardioversion in order to determine
ED length of stay, conversion rates to sinus rhythm, adverse events up to 30 days after treatment
(clinicaltrials.gov: NCT01994070)
B. Trial of Electrical Versus Pharmacological Cardioversion for Recent-onset Atrial Fibrillation and Flutter (RAFF) in the ED
­(RAFF-2)
1. Randomized, single blind trial of 468 RAFF patients to determine if a drug (procainamide) then shock if necessary
strategy will lead to more patients being converted to NSR than shock only and additionally, study heart rhythm at
discharge, need for hospital admission, ED length of stay, adverse events, patient satisfaction and 14-day follow-up
(Clinicaltrials.gov: NCT01891058)
M. Curran | 15
IX. Conclusions
A. No universally accepted approach for the management of acute AF in the ED
B. Limited evidence for rhythm control in recent-onset AF patients
C. Outcomes in limited trials suggest potential benefit of IV procainamide may outweigh risks (hypotension, arrhythmia in
select patients
D. Fully consider the risks and benefits of an aggressive approach to management of patients with recent-onset AF in the ED
1. Benefits of rhythm control
a. Effects of prolonged AF on quality of life
b. No hospitalization
c. Reduced healthcare costs
d. Tachycardiomyopathy due to long standing AF
e. Younger patients
f. Patient preference
2. Risks of rhythm control
a. Thromboembolic event
i. Consider duration of AF
1) If unknown or >48 hours, must rule out atrial thrombi before pursuing aggressive therapy
ii. Proarrhythmic episodes due to use of antiarrhythmic agents
E. Recommendations
1. Consider IV procainamide in select patients presenting to ED with recent-onset AF
2. Must inform patient of benefits and risks associated with each approach
a. Patient preference should be taken into account
Figure 10. Proposed Algorithm for Use of IV Procainamide in the ED
Hemodynamically stable with symptomatic AF
YES
Duration
> 48 hours or
unknown?
Proceed with anticoagulation
and rate control
YES
Collect thorough patient history
Significant
cardiac
history?
Proceed with anticoagulation
and rate control
YES
Evaluate need for
anticoagulation
NO
NO
Identify/address
precipitating factors
Normal
sinus
rhythm?
NO
Consider cardioversion with
IV procainamide
M. Curran | 16
X. References
1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a
report of the American College of Cardiology/American Heart Association task force on practice guidelines and the Heart Rhythm
Society. J Am Coll Cardiol. 2014;64(21):e1-e76.
2. Sanoski CA, Bauman JL. The Arrhythmias. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L, editors. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York (NY): McGraw-Hill; 2014. p.207-44.
3. Waktare JEP. Atrial fibrillation. Circulation. 2002;106(1):14-6.
4. Link MS. Clinical practice. Evaluation and initial treatment of supraventricular tachycardia. New Engl J Med. 2012;367(15):143848.
5. Aronow WS. Treatment of atrial fibrillation and atrial flutter: part II. Cardiol Rev. 2008;16(5):230-9.
6. Atrial fibrillation. Available at: http://www.yalesurgery.org/cardio/care/conditions/Atrial_Fibrillation.aspx - page1. Accessed
November 22, 2014.
7. Wijffels MC, Kirchhof CJ, Dorland R, et al. Atrial fibrillation begets atrial fibrillation : a study in awake chronically instrumented
goats. Circulation. 1995;92(7):1954-68.
8. ACC/AHA/ESC 2006 Guidelines for the management of patients with atrial fibrillation: executive summary. Circulation.
2006;114(7):700-52.
9. Stiell IG, Macle L, Committee CCSAFG. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: management of
­recent-onset atrial fibrillation and flutter in the emergency department. Can J Cardiol. 2011;27(1):38-46.
10. Verma A, Cairns JA, Mitchell LB, et al. 2014 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation. Can J Cardiol. 2014;30(10):1114-30.
11. Neumar RW, Otto CW, Link MS, et al. Part 8: adult advanced cardiovascular life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18 Suppl 3):S729-67.
12. Coll-Vinent B, Fuenzalida C, Garcia A, et al. Management of acute atrial fibrillation in the emergency department: a systematic
review of recent studies. Eur J Emerg Med. 2013;20(3):151-9.
13. ECG Rhythms. Available at: http://www.ambulancetechnicianstudy.co.uk/rhythms.html - .VI8WuIrF94M. Accessed November 12,
2014.
14. Raghavan AV, Decker WW, Meloy TD. Management of atrial fibrillation in the emergency department. Emerg Med Clin North Am.
2005;23(4):1127-39.
15. Stiell IG, Birnie D. Managing recent-onset atrial fibrillation in the emergency department. Ann Emerg Med. 2011;57(1):31-2.
16. de Denus S, Sanoski CA, Carlsson J, et al. Rate vs rhythm control in patients with atrial fibrillation: a meta-analysis. Arch Intern
Med. 2005;165(3):258-62.
17. Van Gelder IC, Hagens VE, Bosker HA, et al. A comparison of rate control and rhythm control in patients with recurrent persistent
atrial fibrillation. New Engl J Med. 2002;347(23):1834-40.
18. Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. New Engl J Med.
2010;362(15):1363-73.
19. Hohnloser SH, Kuck K-H, Lilienthal J. Rhythm or rate control in atrial fibrillation—pharmacological intervention in atrial fibrillation
(PIAF): a randomised trial. Lancet. 2000;356(9244):1789-94.
20. Opolski G, Torbicki A, Kosior DA, et al. Rate control vs rhythm control in patients with nonvalvular persistent atrial fibrillation: the
results of the Polish how to treat chronic atrial fibrillation (HOT CAFE) study. Chest. 2004;126(2):476-86.
21. Wyse DG, Waldo AL, DiMarco JP, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. New
Engl J Med. 2002;347(23):1825-33.
22. Carlsson J, Miketic S, Windeler J, et al. Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation. J Am
Coll Cardiol. 2003;41(10):1690-96.
23. Vinson DR, Hoehn T, Graber DJ, et al. Managing emergency department patients with recent-onset atrial fibrillation. J Emerg
Med. 2012;42(2):139-48.
24. Stiell IG, Clement CM, Brison RJ, et al. Variation in management of recent-onset atrial fibrillation and flutter among academic
hospital emergency departments. Ann Emerg Med. 2011;57(1):13-21.
25. Burton JH, Vinson DR, Drummond K, et al. Electrical cardioversion of emergency department patients with atrial fibrillation. Ann
Emerg Med. 2004;44(1):20-30.
26. Rogenstein C, Kelly AM, Mason S, et al. An international view of how recent-onset atrial fibrillation is treated in the emergency
department. Acad Emerg Med. 2012;19(11):1255-60.
M. Curran | 17
27. Stiell IG, Clement CM, Perry JJ, et al. Association of the Ottawa aggressive protocol with rapid discharge of emergency department patients with recent-onset atrial fibrillation or flutter. CJEM. 2010;12(3):181-91.
28. Sacchetti A, Williams J, Levi S, et al. Impact of emergency department management of atrial fibrillation on hospital charges. West
J Emerg Med. 2013;14(1):55-7.
29. Williams EMV. A classification of antiarrhythmic actions reassessed after a decade of new drugs. J Clin Pharmacol.
1984;24(4):129-47.
30. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium
­channel-blocking drugs. Ann Rev Pharmacol Toxicol. 1984;24:387-423.
31. Cardiac action potential. Available at: http://www.cvpharmacology.com. Accessed November 20, 2014.
32. Cobbe SM. Clinical usefulness of the Vaughan Williams classification system. Eur Heart J. 1987;8(suppl A):65-9.
33.Lexi-DrugsTM. Lexi-Comp OnlineTM [database online]. Hudson, OH: Lexi-Comp, Inc.; 2014. http://online.lexi.com.ezproxy.lib.
utexas.edu. Accessed November 22, 2014.
34. Procainamide. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. Available at
http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 21, 2014.
35. Procainamide package insert. Hospira, Inc., April 2014.
36. Ibutilide. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. Available at
http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 21, 2014.
37. Amiodarone. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. Available at
http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 21, 2014.
38. Propafenone. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. Available at
http://www.clinicalpharmacology-ip.com.ezproxy.lib.utexas.edu/. Accessed November 21, 2014.
39. Stiell IG, Clement CM, Symington C, et al. Emergency department use of intravenous procainamide for patients with acute atrial
fibrillation or flutter. Acad Emerg Med. 2007;14(12):1158-64.
40. Volgman AS, Carberry PA, Stambler B, et al. Conversion efficacy and safety of intravenous ibutilide compared with intravenous
procainamide in patients with atrial flutter or fibrillation. J Am Coll Cardiol. 1998;31(6):1414-9.
41. Kochiadakis GE, Igoumenidis NE, Hamilos ME, et al. A comparative study of the efficacy and safety of procainamide versus
propafenone versus amiodarone for the conversion of recent-onset atrial fibrillation. Am J Cardiol. 2007;99(12):1721-5.
Appendix A. CHA2DS2-VASc Score1
Condition
Points
C
Congestive heart failure (CHF) (or left
ventricular dysfunction)
1
H
Hypertension: blood pressure consistently >140/90 mmHg (or on anti-­
hypertensive medication for hypertension treatment)
1
A2
Age ≥75 years
2
D
Diabetes mellitus
1
S2
Prior stroke or transient ischemic attack
or thromboembolism
2
V
Vascular disease (e.g. peripheral artery
disease, MI, aortic plaque)
1
A
Age 65–74 years
1
Sc
Sex category (i.e. female sex)
1
Score
Risk
Anticoagulation Therapy
0
Low
No antithrombotic therapy (or aspirin [ASA])
1
Moderate
Oral anticoagulant (or ASA)
2+
High
Oral anticoagulant
M. Curran | 18
Appendix B. Evidence Table Rate v. Rhythm Control17,19–22
Trial
Pharmacological
Intervention in
Atrial Fibrillation
(PIAF)
n = 252
Year
Patient
Population
Intervention
2000 18 to 75 years • Rate control using
old with
diltiazem 90 mg two
symptomatic
or three times a
persistent AF
day with additional
between 7 and
therapy at discretion
360 days
of treating MD
• Rhythm control using
pharmacological and
electrical cardioversion, if necessary
followed, by antiarrhythmic therapy
with amiodarone
600 mg daily for
3 weeks
Endpoints
Major Results
Limitations
• Improvement in AF
symptoms (palpitations, dyspnea,
dizziness)
• Assessment of 6-min
walking tests
• Change in mean
heart rate during AF
• Number of hospital
admissions
• Quality of life
• No significant differences in symptomatic improvement
between 2 groups
• Significantly more
hospital admissions
in rhythm
• Small sample size
• Variable rhythm control strategy dependent on amiodarone
therapy
• No validated scoring
system for assessing
AF symptoms
Strategies of
2003 18 years or
Treatment of Atrial
older with
Fibrillation
either: AF for
>4 weeks,
(STAF)
left atrial size
n = 200
>45 mm, CHF,
NYHA class
II or greater,
LVEF <45%, 1+
prior cardioversion
• Rate control used
beta-blockers, digitalis, calcium channel
blockers or AV-node
ablation/modification
with or without pacemaker implantation
• Rhythm control
cardioverted by
external or internal
methods and then,
with the use of antiarrhythmic therapy
including sotalol,
class I antiarrhythmic
or amiodarone if impaired LV function
Rate Control
versus Electrical
Conversion
(RACE)
n = 522
• Rate control using
• Morbidity (death,
• Morbidity did not
• Can not generalize
digitalis and/or a calheart failure, serious
differ at a mean
to patients who have
cium channel blocker
side effects of drugs,
­follow-up of 2.3 years
not undergone elecand/or a beta blocker
­thromboembolic
trical cardioversion
• No significant differto target resting
complications,
ence in quality of life
heart rate <100 beats
bleeding, pacemaker
between groups
per minute
placement)
• Serial electrical
• Differences in quality
cardioversion with
of life
antiarrhythmic
therapy using sotalol,
flecainide or propafenone; or amiodarone
with relapses
2002 Persistent
AF and atrial
flutter with an
index episode
shorter than
one year with
prior cardioversion
• Composite of death, • No difference in
• Compared treatment
stroke/transient ischcomposite endpoint
strategies not specific
emic attack, systemic
between rate and
therapies
embolism, cardiopulrhythm control
• Few patients mainmonary resuscitation
groups (p = 0.99)
tained normal sinus
• Syncope
• Significantly more
rhythm at the end of
hospitalizations in
the study
• Bleeding
rhythm control group • Can not be applied to
• Quality of life
than rate control
asymptomatic AF or
• Echocardiograph
group
recent-onset AF
parameters
•
Higher
rate
of
cere• Resting HR
brovascular events in
• Maintenance of sinus
rhythm control group
rhythm
(5 v. 1)
M. Curran | 19
Appendix B (continued)
Atrial Fibrillation
Follow-up
Investigation of
Rhythm
Management
(AFFIRM)
n = 4,060
2002 Age ≥65 or
other risk factors for stroke
or death with
a diagnosis of
AF requiring
long-term
treatment
• Rhythm control
• Overall mortality
using choice of
combining death,
amiodarone, disopydisabled stroke,
ramide, flecainide,
disabling anoxic enmoricizine, procaincephalopathy, major
amide, propafenone,
bleeding, cardiac
quinidine, sotalol,
arrest
and combinations of • Secondary analyses
these drugs
conducted to adjust
• Rate control using
primary end point
beta-blockers, diltifor baseline characazem and verapamil
teristics
to target heart rate
(<80 BPM at rest and
<110 BPM during
6-min walking test)
How to Treat
Chronic Atrial
Fibrillation
(HOT-CAFE)
n = 205
2004 Age 50 to 75
years and
AF had to be
known for
7 days, but
not >2 years
• Rate control group
with target HR between 70–90 beats/
min during rest
• Rhythm control
underwent electrical
cardioversion with
antiarrhythmic drug
therapy including
propafenone, disopyramide, or sotalol
• More deaths
occurred in rhythm
control group than
rate control group
(p = 0.08; hazard ratio 1.15 [95% CI 0.99
to 1.34])
• Significantly more
hospitalization and
adverse drug events
in rhythm control
group
• Results can not be
generalized to younger patients without
risk factors for stroke
or paroxysmal atrial
fibrillation
• Composite of death • Composite end point • Small sample size
from any cause,
is not significantly
• Use of anticoagulathromboemboldifferent between
tion was low
ic complications,
rate and rhythm conintracranial or other
trol group (p > 0.71)
major hemorrhage
• Significantly more
• Rate control
hospitalizations in
rhythm control group
• Rhythm maintenance
(p = 0.001)
• Hospitalization
M. Curran | 20