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Address for reprints: Gyorgy Frendl, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, CWN-L1, 75 Francis St, Boston, MA 02115.
Department of Cardiovascular Medicine, Heart and Vascular Institute, Department of Molecular Cardiology, Lerner Research Institute Cleveland Clinic, Lerner College of Medicine of Case Western Reserve University Cleveland Clinic, Cleveland, Ohio
Division of Cardiovascular Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OhioHarrington Heart & Vascular Institute, University Hospitals Case Medical Center, Cleveland, Ohio
Our mission was to develop evidence-based guidelines for the prevention and treatment of perioperative/postoperative atrial fibrillation and flutter (POAF) for thoracic surgical procedures. Sixteen experts were invited by the American Association for Thoracic Surgery (AATS) leadership: 7 cardiologists and electrophysiology specialists, 3 intensivists/anesthesiologists, 1 clinical pharmacist, joined by 5 thoracic and cardiac surgeons who represented AATS (see Online Data Supplement 1 for the list of members and Online Data Supplement 2 for the conflict of interest declaration online).
Methods of Review
Members were tasked with making recommendations based on a review of the literature, with grading the quality of the evidence supporting the recommendations, and with assessing the risk-benefit profile for each recommendation. The level of evidence was graded by the task force panel according to standards published by the Institute of Medicine (Table 1). For the development of the guidelines we followed the recommendations of The Institute of Medicine (IOM) 2011 Clinical Practice Guidelines We Can Trust: Standards for Developing Trustworthy Clinical Practice Guidelines; www.iom.edu/cpgstandards.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
The Society of Thoracic Surgeons practice guideline on the prophylaxis and management of atrial fibrillation associated with general thoracic surgery: executive summary.
; rather we focused on new information and advances in diagnosis and therapy, and present these current guidelines within the framework of the new IOM recommendations. In order to meet these standards, most societies (American Heart Association and AATS included) initiated the revision
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Table 1Size of treatment effect and level of evidence for its impact
Schema used to guide the grading of available published evidence and the expected effect of the interventions for their impact on patient outcomes (the arrow indicates the direction of increased effect size). COR, Class of recommendation.
Task force subgroups were formed and tasked with preparing a summary of the available literature for each subtopic. Literature searches were conducted using PubMed, focused on articles published since 2000 except in rare circumstances. Both the summaries and original articles were made available to each task force member via a shared electronic folder. The subgroup summaries as well as the original literature were presented and discussed at 9 scheduled teleconferences. The conferences were recorded. Articles were selected for inclusion based on consensus opinion by task force members. Writing groups were formed to develop the draft guidelines for each subtopic, with 3 to 7 members and a leader for each group. Group recommendations were submitted before being presented for discussion and voting at a 1-day face-to-face conference.
Members were specifically asked to assess the applicability of the available evidence to patients undergoing thoracic surgery. All recommendations were subjected to a vote. Acceptance for the final document required greater than 75% approval of each of the recommendations.
A final draft was prepared by the chairman of the task force and made available in a written form to each member for final comments. Subsequently, the recommendations were posted for public comments for AATS members (via REDCap), and then peer reviewed by outside experts selected by the AATS Council.
The following recommendations are based on the best available evidence from thoracic surgery. When evidence specific to thoracic surgery was not available, we extrapolated from the cardiac surgical literature. In the absence of direct evidence, we present the best expert opinion based on cardiology/cardiac electrophysiology experience and best practices.
An executive summary was prepared for publication in a printed format; this more extensive guideline was prepared for online publication with additional comments, data, and a comprehensive list of references.
AATS Member Survey
Our survey of the AATS members (results presented in Online Data Supplement 3) indicated the need for a guideline update and identified opportunities for improvement in the areas of prevention, standards for postoperative electrocardiography (ECG) monitoring, and for the possible use of novel oral anticoagulants. When asked how the AATS could help members improve their practices; 29% of respondents recommended “initiating studies,” whereas 58% recommended that the AATS “issue guidelines” and promote uniform practices.
Target Audience and the Patient Population
These guidelines are intended for all noncardiac intrathoracic surgeries and esophagectomies, as well as for patients whose risk factors and comorbidities place them at intermediate to high risk for POAF, independent of the procedure. In assessing the patient's risk for POAF, it must be noted that the risks posed by the procedure and by patient factors/comorbidities will likely be additive, if not synergistic. Therefore, these factors should be evaluated in combination during the preoperative assessment.
The target audience includes not only thoracic surgeons and anesthesiologists but all providers who participate in the care of thoracic surgical patients.
The following novel information is included in this 2014 document: (1) standardized definitions for atrial fibrillation (AF) and (2) recommendations for: (a) ECG monitoring, (b) postdischarge management, (c) use of the new class of novel oral anticoagulants (NOAC); and (d) obtaining cardiology consultation. In addition, flow diagrams summarize the strategies for acute and chronic management. Specific drug recommendations and dosing tables are also included.
Epidemiology of POAF, Its Impact on Outcomes, Cost, and Morbidity
AF, the most common sustained arrhythmia after pulmonary and esophageal surgery, is a major, potentially preventable, adverse outcome. POAF peaks on postoperative days 2 to 4, and 90% to 98% of new-onset POAF resolves within 4 to 6 weeks. Postoperative atrial fibrillation has multiple negative implications. In the acute setting, the tachyarrhythmia can lead to hemodynamic instability, necessitating prompt intervention. A sustained increased heart rate can result in heart failure, a less common but clinically devastating situation, the incidence of which is not reported in the literature.
The incidence of POAF varies widely based on the intensity of surgical stress (Table 2, A
Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection.
Atrial fibrillation following lung transplantation: double but not single lung transplant is associated with long-term freedom from paroxysmal atrial fibrillation.
). Some of the risk factors for AF such as hypertension, obesity, and smoking, are modifiable, whereas others, such as older age, Caucasian ancestry, and male sex, are not.
Table 2, aRisk stratification of thoracic surgical procedures for their risk of POAF
Type of procedures
Risk of POAF by surgical procedures
Low risk procedures (<5% incidence)
Intermediate risk procedures (5%-15% incidence)
High risk procedures (>15% incidence)
Intrathoracic/airway procedures
Minor procedures
Flexible bronchoscopy with and without biopsy Photodynamic therapy Tracheal stenting Placement of thoracostomy tube or PleurX catheter (CareFusion Corporation, San Diego, Calif) Pleuroscopy, pleurodesis, decortication
Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection.
Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection.
Atrial fibrillation following lung transplantation: double but not single lung transplant is associated with long-term freedom from paroxysmal atrial fibrillation.
Thoracic surgical procedures were divided into low (<5%), moderate (5%-15%) and high (>15%) risk groups based on their expected incidence of POAF in order to facilitate the preoperative risk stratification of patients. POAF, Postoperative atrial fibrillation; PEG, percutaneous endoscopic gastrostomy.
Derived from the 2014 American Heart Association Atrial Fibrillation Guidelines and relevant literature for thoracic surgery. Patient risk factors and comorbidities that were shown to increase the risk of atrial fibrillation (AF) are listed. Much of this information was extracted from the general population, thoracic surgery–specific references are listed when available. These risk factors/comorbidities should be assessed in conjunction with the procedure-related risks of AF in order to determine the true risk of POAF. MI, Myocardial infarction; VHD, valvular heart disease; LV, left ventricle; LVH, left ventricular hypertrophy.
Thromboembolic events such as stroke or acute limb ischemia are the most serious and feared consequences of AF. Studies have reported a wide range of the incidence of stroke related to POAF, although the risk for cardiac and thoracic surgery seems to be 50% to 200% higher than for general surgery.
The AFFIRM Investigators Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study.
Given that patients with other significant comorbidities or who are undergoing more complex operations are more likely to experience POAF, it is unclear to what extent the arrhythmia itself contributes to mortality. It is feasible that the contribution of POAF to mortality is more significant for those patients with fewer other comorbidities, however this independent effect is more difficult to measure and has not been well reported in the literature.
POAF is associated with longer intensive care unit and hospital stays, increased morbidity (including strokes/new central neurologic events) with incidence of 1.3%-1.7%
The AFFIRM Investigators Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) study.
Multiple studies have consistently demonstrated an increase in length of hospital stay in patients who develop POAF, generally by a mean of 2 to 4 days.
demonstrated that, in patients undergoing lobectomy or greater resection for lung cancer, the presence of POAF lengthened hospital stay by a median of 3 days. The cost of hospitalization is likewise increased for patients who develop POAF, with an increase reported in the literature anywhere from 30% to 68%.
To some extent, this increase reflects comorbid conditions that occur along with POAF, but POAF itself is associated with an increase in cost. Vaporciyan and colleagues
found that for patients who developed POAF without any other complications, the cost of care increased by more than US$6000, representing a greater than 30% increase.
The Possible Mechanisms of POAF After Thoracic Surgery
The mechanisms that initiate and sustain AF, including POAF, are complex and require both a vulnerable atrial substrate
and a trigger to initiate AF (Table 3). Today they remain incompletely understood. The role of triggers from the pulmonary veins and other atrial sites initiating AF
is well appreciated. However, it remains to be understood why they occur and what exact mechanisms are essential for their propagation. The identified risk factors for the development of sustained POAF are mostly identical to those known to make the atrium vulnerable to development of AF in the nonsurgical setting. They include several risk factors that are associated with atrial fibrosis, such as increasing age, atrial dilatation, myocardial ischemia, volume overload, and a history of heart failure.
They also include risk factors such as increased norepinephrine levels and increased vagal tone, both of which shorten atrial wavelength, the latter known to increase atrial vulnerability to AF.
2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
In addition, surgical procedures are associated with local or systemic inflammation (such as pericarditis), an important risk factor affecting the vulnerability of the atrial substrate to POAF.
Insight into the mechanism of POAF can be gained by examining what prophylactic therapies decrease the rate of POAF occurrence after thoracic surgery. Higher norepinephrine levels were found in patients on preoperative β-blockers who had their β-blocker therapy interrupted than in patients not receiving a β-blocker at all. This was associated with a significantly higher incidence of POAF.
This is believed to be related to its effects of decreasing pulmonary vascular resistance. It is known that pulmonary hypertension and dilatation of the right side of the heart are associated with an increased incidence of POAF.
2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in partnership with the European Society of Cardiology and in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Magnesium has been consistently shown to decrease the incidence of POAF after cardiac surgery, and the only prospective, randomized study on patients undergoing thoracic surgery also showed a significant decrease in the incidence of POAF.
In the presence of a vulnerable substrate, additional electrophysiologic abnormalities (drivers) will sustain AF.
Recommendations and Reasoning
1 Recommend the Use of the Following Definitions for the Diagnosis of POAF
Class I
1.1.
Electro-physiologic definition/diagnosis: ECG recordings (1 or more ECG leads) that demonstrate the presence of characteristic ECG features of AF lasting at least for 30 seconds or for the duration of the ECG recording (if shorter than 30 seconds)
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.
Circulation.April 10, 2014; ([Epub ahead of print])
Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
(level of evidence LOE C). Clinical symptoms may include hypotension, dizziness, decreased urinary output, fatigue, and so on.
1.2.
Clinical definition/diagnosis: clinically significant POAF (Table 4) is AF in the (intra- and) postoperative setting that requires treatment with rate or rhythm control agents, or requires anticoagulation, and/or extends the duration of hospitalization (LOE C). Clinical symptoms may include hypotension, dizziness, decreased urinary output, fatigue, and so on.
Table 4Recommended definitions for the diagnosis of POAF
Definitions
COR
Electrophysiologic definition/diagnosis
ECG recordings (1 or more ECG leads) with ECG features of AF lasting at least for 30 seconds or for the duration of the ECG recording (if <30 seconds) (LOE C)
I
Clinical definition/diagnosis
Clinically significant POAF: intra- and postoperative AF requiring treatment, or anticoagulation, and/or extending the duration of hospitalization (LOE C)
I
These measures should be included in the clinical documentation and reported in the clinical trials/studies. POAF, Postoperative atrial fibrillation; ECG, electrocardiography; COR, class of recommendation; LOE, level of evidence; AF, atrial fibrillation.
We recommend that both electrophysiologically documented AF and clinically diagnosed AF be included in the clinical documentation and reported in the clinical trials/studies.
2 Physiologic (ECG) Monitoring of Patients at Risk for POAF
Recommendations for ECG monitoring of patients at risk for POAF are presented in Table 5.
Class I
2.1.
Patients should be monitored with continuous ECG telemetry postoperatively for 48 to 72 hours (or less if their hospitalization is shorter) if:
2.1.1.
They are undergoing procedures that pose intermediate (5%-15% expected incidence of AF) or high (>15%) risk for the development of postoperative AF or have significant additional risk factors (CHA2DS2-VASc ≥2) for stroke (LOE C).
2.1.2.
They have a history of preexisting or periodic recurrent AF before their surgery. These patients should also receive ECG monitoring in the immediate preoperative period if procedures (eg, epidural catheter or other regional anesthesia blocks) are performed (LOE C).
Class IIa
2.2.
Not using routine ECG telemetry is reasonable for patients who undergo low-risk (<5% expected incidence of AF) procedures, and have neither a previous history of AF nor significant risk for stroke (based on CHA2DS2-VASc score), and have no relevant comorbidities (such as heart failure or previous stroke) (LOE C).
Class I
2.2.1.
If patients exhibit clinical signs of possible AF while not monitored with telemetry, ECG recordings to diagnose POAF and ongoing telemetry to monitor the period of AF should be immediately implemented (LOE C).
Table 5Recommendations for physiologic (ECG) monitoring
Recommendations for monitoring
COR
Patients should be monitored with continuous ECG telemetry postoperatively for 48-72 h (or less if their hospitalization is shorter) if:
•
they are undergoing procedures that pose high (>15% expected incidence of AF) or intermediate (5%-15%) risk for POAF or
•
they have significant additional risk factors (CHA2DS2-VASc >2) for stroke (LOE C)
•
they have a history of preexisting or periodic recurrent AF before their surgery
These patients should also receive ECG monitoring in the immediate preoperative period if procedures (epidural catheter, regional anesthesia blocks, and so forth) are performed (LOE C)
I
Not using routine ECG telemetry is reasonable for patients who
•
undergo low risk surgery (<5% expected incidence of AF) and
•
had no previous history of AF, or
•
have no significant risk for stroke and
•
have no relevant comorbidities (eg, heart failure or previous stroke) (LOE C)
IIa
If patients exhibit clinical signs of possible AF while not monitored with ECG telemetry, ECG recordings to diagnose POAF and continuous telemetry to monitor the period of AF should be immediately implemented (LOE C)
I
ECG, Electrocardiography; COR, class of recommendation; AF, atrial fibrillation; POAF, postoperative atrial fibrillation; LOE, level of evidence.
Part 8: Adult advanced cardiovascular life support 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Conversion to sinus rhythm: 20-50 mg/min IV continuous infusion until AF terminated, hypotension occurs, or QRS duration prolonged by 50%, or cumulative total dose of 15 mg/kg reached Alternative dose: 100 mg IV every 5 min until AF terminated or other conditions as listed above are met If available orally, could be used for maintenance
Hypotension QT interval prolongation Torsades de pointes Contraindicated in patients with heart failure with reduced left ventricular ejection fraction Contraindicated in patients with pretreatment QTc interval >470 ms (men) or 480 ms (women)
Part 8: Adult advanced cardiovascular life support 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.
Conversion to sinus rhythm: 200-300 mg single oral dose Maintenance of sinus rhythm: 50-150 orally once every 12 h
Dizziness Blurred vision Sinus bradycardia AV block Contraindicated in patients with heart failure with reduced left ventricular ejection fraction Contraindicated in patients with coronary artery disease/structural heart disease
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Conversion to sinus rhythm: 450-600 mg single oral dose Maintenance of sinus rhythm: 150-300 mg orally every 8 h (immediate release); 225-425 mg orally every 12 h (extended release)
Dizziness Blurred vision Sinus bradycardia AV block Contraindicated in patients with heart failure with reduced left ventricular ejection fraction Contraindicated in patients with coronary artery disease/structural heart disease
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Prophylaxis: 300 mg IV bolus, then 600 mg orally twice daily for 3-5 d Treatment: 150 mg IV over 10 min; then 1 mg/min IV continuous infusion for 6 h; the 0.5 mg/min IV continuous infusion for 18 h or change to oral administration at 100-400 mg daily
Bradycardia QT interval prolongation Pulmonary toxicity has not been demonstrated at this dose Bradycardia Hypotension QT interval prolongation Pulmonary toxicity has occurred at cumulative IV doses >2150 mg in patients undergoing pneumonectomy
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Not ideal for conversion to sinus rhythm in the postoperative setting; may take 2-3 d to convert to normal sinus rhythm, which would require commitment to anticoagulation Maintenance of sinus rhythm: calculated CrCl 20-40 mL/min: 125 μg orally once every 12 h Calculated CrCl 40-60 mL/min: 250 μg orally once every 12 h Calculated CrCl >60 mL/min: 500 μg orally every 12 h
QT interval prolongation Torsades de pointes Risk of torsades de pointes is greater in patients with heart failure Dose adjustment is important in patients with acute kidney injury or chronic kidney disease Contraindicated in patients with calculated CrCl <20 mL/min Contraindicated in patients with pretreatment QTc interval >470 ms (men) or 480 ms (women) Monitor ECGs 2 h after doses, telemetry for at least 3 d
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Conversion to sinus rhythm: Weight ≥60 kg: 1 mg IV administered over 10 min Weight <60 kg: 0.01 mg/kg IV administered over 10 min If the AF does not terminate within 10 min of completion of the first infusion, a second dose of equal strength may be administered IV over 10 min Not indicated for maintenance of sinus rhythm
QT interval prolongation Torsades de pointes Risk of torsades de pointes greater in patients with heart failure Nonsustained ventricular tachycardia Sinus pauses after AF conversion Contraindicated in patients with pretreatment QTc interval >470 ms (men) or 480 ms (women)
Corvert prescribing information 2006; Pfizer, Inc
Sotalol
Maintenance of sinus rhythm: 40-160 mg orally every 12 h Dosing interval should be adjusted in patients with acute kidney injury or chronic kidney disease: If the calculated CrCl is 30-59 mL/min: administer every 24 h If the calculated CrCl is 10-29 mL/min: administer every 36-48 h
Sinus bradycardia AV block QT interval prolongation Torsades de pointes Heart failure exacerbation Risk of torsades de pointes greater in patients with heart failure Bronchospasm Dose adjustment is important in patients with acute kidney injury or chronic kidney disease Use with extreme caution in patients with calculated CrCl <10 mL/min and in patients undergoing hemodialysis Contraindicated in patients with pretreatment QTc interval >470 ms (men) or 480 ms (women)
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
To optimize the efficacy and safety of amiodarone, it is reasonable to exercise caution when selecting its doses or intravenous versus oral route, because cases of acute respiratory distress syndrome (ARDS) have been reported following pneumonectomy with cumulative intravenous doses more than 2150 mg
Rate control agents: their mechanisms of action and side effects
3.2.1. β-Blockers
β-Blockers are Vaughan Williams class II antiarrhythmic agents that inhibit sympathetic nervous system activity and slow the rate of phase IV repolarization, thus slowing the discharge from the sinus node.
This antiadrenergic activity inhibits the renin-angiotensin-aldosterone system, inhibits apoptosis, and reduces hyperphosphorylation of calcium-releasing channels.
Metoprolol and atenolol are relatively selective β-1 receptor antagonists (primarily affecting cardiac tissue) and in moderate doses have less effect on the β-2 receptors in smooth muscle cells in the vasculature and bronchial tree. Propranolol and esmolol are nonselective, and carvedilol is nonselective and possesses α-receptor blocking activity.
Intravenous administration of metoprolol, propranolol, and esmolol reduces ventricular response in patients with AF within 5 minutes of administration,
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
AFFIRM Investigators The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation.
Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of 5 drug regimens.
AFFIRM Investigators The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation.
Ventricular rate control in chronic atrial fibrillation during daily activity and programmed exercise: a crossover open-label study of 5 drug regimens.
The major adverse effects of β-blockers are bronchospasm in patients with asthma, particularly if the asthma is not well controlled; worsening of symptoms in patients with severe peripheral arterial disease; hypotension; and worsening of heart failure symptoms in patients with decompensated heart failure with reduced ejection fraction. Intravenous β-blockers should not be used in patients with suspected accessory conduction pathways.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Profound bradycardia can result from acute concomitant administration of β-blockers and diltiazem or verapamil.
3.2.2. Diltiazem
Diltiazem is a nondihydropyridine calcium channel antagonist and class IV Vaughan Williams agent. Diltiazem inhibits L-type calcium channels in vascular and conduction tissue, and especially in nodal tissue.
In addition, diltiazem affects the transient outward and ultrarapid delayed rectifier potassium currents in atrial myocytes. Intravenous diltiazem administered as a bolus and continuous infusion can control ventricular response in 70% to 90% of patients with the recent-onset of AF. The onset of action of diltiazem is 2 to 7 minutes.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation.
Oral treatment with diltiazem in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial was efficacious in controlling rest and exercise heart rate in approximately 60% of patients, and in 66% and 79% of patients, respectively, when combined with digoxin.
AFFIRM Investigators The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation.
Diltiazem can worsen heart failure in patients with reduced ejection fraction, and can cause important gastrointestinal adverse effects including ileus. Diltiazem must be used cautiously, especially acutely, in patients concomitantly receiving β-blockers, and is contraindicated in patients with an accessory pathway.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Digoxin inhibits sodium potassium adenosine triphosphatase (ATPase), thereby increasing intracellular sodium concentration leading to increased intracellular calcium concentrations. In addition, digoxin administration is associated with an increase in baroreceptor sensitivity disproportionate to hemodynamic improvement, and imparts vagomimetic (parasympathetic) effects. The vagomimetic effects of digoxin occur at low serum concentrations and contribute to decreasing sinus and atrioventricular (AV) nodal conduction. At higher serum concentrations, the parasympathetic effects actually shorten the refractory period of nonnodal specialized conduction tissue.
Intravenous digoxin in acute atrial fibrillation. Results of a randomized, placebo-controlled multicentre trial in 239 patients. The Digitalis in Acute Atrial Fibrillation (DAAF) Trial Group.
With additional intravenous bolus doses of 0.25 mg every 2 to 6 hours after the first dose, up to a total dose within 24 hours of 1.25 to 1.5 mg, 75% of patients with AF can achieve rate control at rest.
Intravenous diltiazem is superior to intravenous amiodarone or digoxin for achieving ventricular rate control in patients with acute uncomplicated atrial fibrillation.
AFFIRM Investigators The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation.
Digoxin should not be administered to patients with suspected accessory pathways or obstructive hypertrophic cardiomyopathy. The potential for digoxin toxicity, including accelerated junctional rhythm, accelerated ventricular escape rhythms (sometimes heralded by regularization of the longest R-R intervals), nausea, and visual symptoms is increased in the presence of hypokalemia, hypomagnesemia, hypercalcemia, and concomitant therapy with amiodarone, dronedarone or verapamil.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial.
Amiodarone is a Vaughan Williams class III agent that inhibits inward potassium current, prolonging the action potential. However, amiodarone also has properties that could place it in the other 3 Vaughan Williams classes. It has antisympathetic and calcium-blocking activity that leads to important effects on the sinoatrial (SA) and AV nodes, and the drug also has sodium channel–inhibiting properties that increases the threshold for depolarization.
in: Wiggins B.S. Sanoski C.A. Emergency Cardiovascular Pharmacotherapy: A Point-of-Care Guide. American Society of Health-System Pharmacists,
Bethesda, Md2012: 61-68
Intravenous amiodarone, administered as a bolus and continuous infusion, has an effect on heart rate within 4 hours that is similar to intravenous diltiazem and intravenous digoxin, and improves ventricular rate in 74% of patients with AF by 24 hours.
Oral amiodarone can require days for effective rate control to occur. Chronic oral amiodarone therapy for rate control can have effects similar to those of digoxin.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Amiodarone is highly lipophilic, and intravenous administration may exert effects that are different from those following oral administration. Intravenous amiodarone can be associated with AV block, vasodilation, and hypotension. Intravenous amiodarone should not be used in patients who have a suspected accessory pathway.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
American College of Cardiology/American Heart Association Task Force on Practice Guidelines, European Society of Cardiology Committee for Practice Guidelines, European Heart Rhythm Association, Heart Rhythm Society, ACC/AHA/ESC 2006 guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society.
Amiodarone inhibits the metabolism of warfarin and inhibits elimination of the new oral anticoagulants. Amiodarone administration can restore sinus rhythm so patients who receive it after 24 to 48 hours of AF require anticoagulation.
3.3.
Antiarrhythmic medications (mechanisms of action, side effects)
3.3.1.
Amiodarone (see section 3.2.4)
3.3.2.
Flecainide
Flecainide is a Vaughan Williams class IC antiarrhythmic agent that is a potent inhibitor of fast sodium conduction.
Flecainide may also inhibit IKr current, and prolongs the duration of atrial and ventricular action potential. In patients without structural heart disease, oral flecainide is relatively well tolerated; adverse effects include dizziness (15%-20%) and visual abnormalities, including blurred vision and difficulty in focusing (up to 15%), which can usually occur during dose uptitration.
However, in patients with structural heart disease, flecainide is associated with more severe adverse effects. Flecainide is associated with ventricular proarrhythmia in this population; this proarrhythmia is not torsades de pointes (TdP), but rather monomorphic ventricular tachycardia. This proarrhythmia was the likely cause of death associated with flecainide (and encainide) in the Cardiac Arrhythmia Suppression Trial (CAST),
in which patients with a history of myocardial infarction and symptomatic or asymptomatic ventricular ectopy (≥6 ventricular premature depolarizations VPDs per hour) were randomized to receive flecainide, another Vaughan Williams class IC agent encainide, or placebo for VPD suppression. Patients randomized to receive therapy with flecainide or encainide had an increased risk of total mortality and an increased risk of nonfatal cardiac arrest and death from arrhythmia. The risk of proarrhythmia associated with Vaughan Williams class IC antiarrhythmic agents seems to be highest in patients with ventricular conduction delays (QRS duration >120 milliseconds), structural heart disease, ventricular scar tissue, or left ventricular (LV) dysfunction.
Consequently, flecainide should be avoided in these patients.
In addition to the risk of proarrhythmia, flecainide has potent negative inotropic activity, and has been associated with worsening heart failure in patients with coronary artery disease or preexisting heart failure (New York Heart Association NYHA class II to IV and/or LV ejection fraction <30%).
Therefore, flecainide is contraindicated in patients with heart failure and reduced ejection fraction.
Intravenous flecainide is not available in the United States, but is available in other countries. In addition to the potential for ventricular proarrhythmia in patients with structural heart disease and worsening of heart failure in patients with LV dysfunction, intravenous flecainide may be associated with hypotension.
3.3.3. Magnesium
Magnesium administered intravenously is often referred to as a physiologic calcium channel blocker, due to its antagonism of L- and T-type calcium channels.
Efficacy and safety of oral dofetilide in converting to and maintaining sinus rhythm in patients with chronic atrial fibrillation or atrial flutter the symptomatic atrial fibrillation investigative research on dofetilide (SAFIRE-D) study.
Efficacy of dofetilide in the treatment of atrial fibrillation-flutter in patients with reduced left ventricular function: a Danish investigations of arrhythmia and mortality on dofetilide (diamond) substudy.
it has not been studied specifically for prevention or management of AF after noncardiac thoracic surgery. As a result of its propensity to inhibit IKr and prolong ventricular repolarization, dofetilide may cause TdP, with an incidence of approximately 1% in patients with normal LV function.
Dofetilide in patients with congestive heart failure and left ventricular dysfunction. Danish Investigators of Arrhythmia and Mortality on Dofetilide Study Group.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Dronedarone is a Vaughan Williams class III antiarrhythmic agent that was developed as a potentially safer congener of amiodarone. Dronedarone is similar to amiodarone in that it inhibits multiple ion currents, including fast Na+ current, IKr, acetylcholine-activated K+ current, and L-type calcium current.
Dronedarone is also a noncompetitive β-adrenergic inhibitor. Unlike amiodarone, however, which possesses 2 iodine atoms that compose 37% of its molecular weight, dronedarone's structure does not include iodine atoms. In addition, the half-life of dronedarone (13 to 31 hours) is much shorter than that of amiodarone (10 to 40 days).
and therefore is contraindicated in patients with NYHA class III to IV heart failure, and in those patients with unstable NYHA class II heart failure.
Dronedarone has been shown to be effective for maintenance of sinus rhythm in patients with nonsurgical paroxysmal AF. Dronedarone is contraindicated in patients with permanent AF, due to increased mortality associated with dronedarone in that patient population.
Ibutilide, a methanesulfonanilide antiarrhythmic, is a potent blocker of the rapidly activating delayed rectifier K+ current (IKr) in AT-1 cells. Concentration-, time-, voltage-, and use-dependent effects.
Efficacy and safety of repeated intravenous doses of ibutilide for rapid conversion of atrial flutter or fibrillation. Ibutilide Repeat Dose Study Investigators.
Ibutilide is not available in an oral dosage form, and therefore is not used for maintenance of sinus rhythm. Ibutilide has been shown to be effective for conversion to sinus rhythm of AF occurring after coronary artery bypass graft surgery.
The efficacy of ibutilide for conversion to sinus rhythm of AF after noncardiac surgery has not been investigated.
The primary adverse effect associated with ibutilide is TdP, which occurs in 1% to 3% of patients. The incidence of TdP is 2- to 3-fold higher in patients with heart failure as a result of reduced ejection fraction, which is a known risk factor for TdP. Ibutilide may also cause nonsustained monomorphic ventricular tachycardia in up to 8% of patients.
3.3.7. Procainamide
Procainamide is a Vaughan Williams class IA antiarrhythmic agent that exerts its antiarrhythmic effects through inhibition of fast sodium current as well as inhibition of IKr. In addition, a primary metabolite of procainamide, N-acetylprocainamide, inhibits IKr current and contributes to the overall antiarrhythmic activity of procainamide. Procainamide is effective for conversion of nonoperative AF to sinus rhythm.
The efficacy of procainamide for conversion to sinus rhythm of AF after noncardiac thoracic surgery has not been investigated. Procainamide is no longer available in an oral dosage form, and therefore is no longer indicated for maintenance of sinus rhythm in patients with nonsurgical AF.
The primary adverse effects associated with intravenous procainamide are hypotension, QT interval prolongation and TdP, and lengthening of the QRS complex.
3.3.8. Propafenone
Propafenone is a Vaughan Williams class IC antiarrhythmic agent that is a potent inhibitor of sodium conductance.
Propafenone may also inhibit the transient outward potassium current (Ito) and the ultrarapid delayed rectifier potassium (Ikur) current in atrial myocytes.
The efficacy of propafenone for prophylaxis or management of AF after noncardiac thoracic surgery has not been investigated.
Oral propafenone is well tolerated overall. Adverse effects include dizziness and blurred vision. However, propafenone possesses negative inotropic activity, and is contraindicated in patients with heart failure due to reduced ejection fraction.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
In addition, propafenone is contraindicated in patients with coronary artery disease or a history of myocardial infarction. Although propafenone was not studied in the CAST trial, the effects of flecainide and encainide in that study are believe to be to the result of potent sodium channel inhibition, and contraindications in patients with structural heart disease have been applied to propafenone.
3.3.9. Sotalol
Sotalol is an adrenergic β-receptor blocking agent
Maintenance of sinus rhythm with oral d,l-sotalol therapy in patients with symptomatic atrial fibrillation and/or atrial flutter. d,l-Sotalol Atrial Fibrillation/Flutter Study Group.
Sotalol has not been shown to be effective for conversion of AF to sinus rhythm. Sotalol has been used to reduce the risk of AF after coronary artery bypass graft (CABG) surgery.
Study of prevention of postoperative atrial fibrillation. A comparison between oral antiarrhythmic drugs in the prevention of atrial fibrillation after cardiac surgery: the pilot study of prevention of postoperative atrial fibrillation (SPPAF), a randomized, placebo-controlled trial.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Quinidine may prolong the QT interval and cause TdP. The efficacy of quinidine for prevention or management of AF after noncardiac thoracic surgery has not been evaluated.
3.4.
Serum drug concentration monitoring
3.4.1.
Digoxin
Serum drug concentration monitoring may be warranted only if toxicity is of concern.
Digoxin has a narrow therapeutic index, meaning that serum concentrations required for efficacy are similar to those that may cause toxicity. When used for heart failure, the desired therapeutic range is 0.5 to 0.9 ng/mL.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.
The optimal therapeutic range for digoxin for the management of AF has not been established. The incidence of adverse effects associated with digoxin increases with serum concentrations greater than 2 ng/mL.
During the management of AF after noncardiac thoracic surgery, monitoring of serum digoxin concentrations for assessment of efficacy is not necessary, as a strong relationship between rate control efficacy and serum digoxin concentration has not been established. Determination of serum digoxin concentration may be warranted if patients exhibit symptoms of digoxin toxicity, including nausea, vomiting, anorexia, or ventricular arrhythmias. If a serum concentration is believed to be necessary, the blood sample should be obtained at least 12 hours, and preferably 24 hours, after the previous digoxin dose, as a result of the prolonged tissue distribution phase
(pp410-439); if the blood sample is obtained less than 12 hours after the dose, the serum concentration may be falsely increased, as a result of incomplete distribution of digoxin from serum to tissue.
To reduce the risk of digoxin toxicity in patients receiving the drug for AF after noncardiac thoracic surgery, serum digoxin concentration monitoring may be warranted if digoxin therapy must be continued for longer than 1 week, for those patients who remain in AF after hospital discharge. For patients with normal kidney function, the half-life of digoxin is approximately 36 hours; therefore, steady state serum concentrations require approximately 1 week. Routine determination of a steady state serum digoxin concentration after 1 week of therapy is not required in all patients. However, determination of a serum digoxin concentration after 1 week of therapy may be warranted in patients with chronic kidney disease or acute kidney injury, or in patients who are treated concomitantly with a drug that inhibits digoxin elimination, such as amiodarone, dronedarone, propafenone, quinidine, and verapamil.
(pp440-462) However, this therapeutic range was determined using suppression of ventricular premature depolarizations and prevention of episodes of ventricular tachycardia. Serum procainamide concentrations have not been correlated with efficacy in AF, and therefore, desired serum procainamide concentrations for efficacy in AF are unknown. Serum concentration monitoring for intravenous procainamide for management of AF after noncardiac thoracic surgery is not warranted. The risk of adverse effects associated with intravenous procainamide can be minimized by terminating the loading dose of 20 to 50 mg/min continuous infusion if hypotension occurs, QRS duration is prolonged by 50%, or a cumulative intravenous dose of 17 mg/kg has been administered.
Part 8: Adult advanced cardiovascular life support 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.
Amiodarone: serum drug concentration monitoring is not warranted
Serum amiodarone concentration monitoring has been performed during therapy for ventricular arrhythmias. However, a relationship between serum amiodarone concentrations and efficacy for prevention or management of AF has not been established. Similarly, a relationship between serum amiodarone concentrations and most of the adverse effects of amiodarone, particularly those that occur during short-term therapy, has not been established. Therefore, monitoring of serum amiodarone concentrations during prophylaxis or management of AF after noncardiac thoracic surgery is not warranted. However, to minimize the risk of pulmonary toxicity, it is recommended to keep total cumulative intravenous amiodarone doses to less than 2150 mg.
3.4.4.
Flecainide: serum drug concentration monitoring is not warranted
The therapeutic range for serum flecainide concentrations is often cited as 0.3 to 2.5 mg/L.
(pp440-462) However, this therapeutic range was developed using suppression of ventricular premature depolarizations as an end point, rather than efficacy for the management of AF. A relationship between serum flecainide concentrations and efficacy for prophylaxis or management of AF, particularly that occurring after noncardiac thoracic surgery, has not been established. Serum flecainide concentration monitoring for prophylaxis or treatment of AF after noncardiac thoracic surgery is not warranted.
3.5.
Key limitations of drugs
3.5.1.
Pulmonary toxicity
A primary concern regarding the administration of intravenous amiodarone following lung resection is pulmonary toxicity, specifically ARDS. This concern was prominently identified by Van Mieghem and colleagues,
who initiated a study to determine the comparative effectiveness of amiodarone, verapamil, or placebo for prevention of AF after pulmonary resection. The study was terminated prematurely due a high incidence of ARDS in amiodarone-treated patients, specifically in patients who had undergone pneumonectomy. At the time of discontinuation of the amiodarone arm, the drug had been administered to 32 patients, of whom 21 had undergone lobectomy and 11 had undergone pneumonectomy. No patients who underwent lobectomy developed amiodarone-associated ARDS. In contrast, 3 of 11 patients (27%) in the amiodarone group who underwent pneumonectomy developed ARDS. The investigators recommended avoiding amiodarone administration for patients undergoing pulmonary resection.
Other investigators have administered intravenous amiodarone to patients undergoing lung surgery without adverse effects. In a prospective, randomized, unblinded amiodarone prophylaxis,
the incidence of ARDS among the 65 amiodarone-treated patients (of whom 40 underwent lobectomy, 8 underwent bilobectomy, and 17 underwent pneumonectomy) was 0%. Barbetakis and colleagues
administered intravenous amiodarone to 43 patients for treatment of AF after lung resection. No patients developed ARDS; 21 of these patients underwent pneumonectomy. Riber and colleagues
conducted a randomized, prospective, double-blind, placebo-controlled study of amiodarone for prevention of AF after lung resection. Only 2 patients of the 122 who received amiodarone underwent pneumonectomy; the remainder underwent right-side lobectomy or bilobectomy. No patients in this study developed ARDS or any pulmonary toxicity.
One potential difference in patients undergoing pneumonectomy in the Van Miegham study
include the cumulative intravenous amiodarone dose administered. In the Van Mieghem study, intravenous amiodarone was administered as a bolus of 150 mg over 2 minutes, followed by a continuous infusion of 1200 mg over 24 hours for 3 consecutive days, for a possible cumulative intravenous amiodarone dose of 3750 mg. The 3 patients who developed amiodarone-induced ARDS received cumulative intravenous amiodarone doses of 2150, 3750, and 3350 mg before discontinuation of therapy. In the more recent studies, patients received a cumulative intravenous amiodarone dose of 1050 mg, after which oral amiodarone was initiated,
intravenous amiodarone was administered as a loading dose of 5 mg/kg over 5 minutes, followed by 15 mg/kg for an undefined time period. In addition, in the Van Miegham study, the 3 patients who developed amiodarone-associated ARDS underwent right-sided pneumonectomy, which is associated with a higher risk of postoperative ARDS than other types of lung surgery.
Overall, administration of amiodarone at the dose shown to be effective by Riber and colelagues
(300 mg intravenous loading dose followed by 600 mg orally twice daily for 5 days) seems to be safe and effective for prevention of AF after pulmonary resection.
3.5.2.
QT interval prolongation/torsades de pointes
Several of the drugs that may be used for prophylaxis or management of postoperative AF may cause QT interval prolongation, and therefore pose a risk for the life-threatening polymorphic ventricular arrhythmia known as TdP.
Drugs that prolong the QT interval are generally those that inhibit IKr, and include amiodarone, procainamide, dofetilide, dronedarone, ibutilide, sotalol, and quinidine. A Bazett-corrected QT (QTc) interval greater than 500 ms markedly increases the risk for drug-induced TdP.
Patients receiving a drug that prolongs the QTc interval should have the QTc interval measured from a rhythm strip or 12-lead ECG at least once daily during therapy. In addition, because the occurrence of TdP is highly dependent on the presence of other risk factors (female sex, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, heart failure, increased serum drug concentrations),
modifiable risk factors should be corrected. Serum potassium, magnesium, and calcium concentrations should be maintained in the normal range. Drug interactions leading to increased concentrations of a QT interval–prolonging drug should be avoided. Doses of renally eliminated QT interval–prolonging drugs (dofetilide, procainamide, sotalol) should be appropriately adjusted for declining kidney function. In addition, concomitant therapy with other QT interval-prolonging drugs, particularly noncardiovascular QT interval-prolonging drugs (fluoroquinolone and macrolide antibiotics, azole antifungal agents, antidepressants, antipsychotics, many others)
Several drugs administered intravenously for prophylaxis or management of postoperative AF may cause hypotension, including diltiazem, esmolol, metoprolol, procainamide, and amiodarone. Drug-associated hypotension is more likely to occur when patients are volume depleted, which is often the case after thoracic surgery. In the population with AF after coronary artery bypass graft, hypotension associated with intravenous diltiazem was more likely when the pretreatment systolic blood pressure was less than 115 mm Hg.
Drugs used for ventricular rate control can also result in bradycardia through inhibition of sinus node function or AV nodal conduction. These drugs include amiodarone, propafenone, flecainide, esmolol, metoprolol, sotalol, and diltiazem.
The risk is higher when combinations of sinus node or AV node-inhibiting drugs are used.
3.5.5.
Exacerbation of heart failure with reduced LV ejection fraction
Several drugs used for prophylaxis or treatment of postoperative AF possess negative inotropic activity and are contraindicated in patients with heart failure with reduced LV ejection fraction. These drugs include diltiazem, procainamide, propafenone, and flecainide.
4 Prevention Strategies and Their Efficacy
Recent evidence suggest that some prevention strategies (avoiding β blockade withdrawal for those chronically on those medications, correction of serum magnesium when abnormal) may be effective for all patients for reducing the incidence of POAF. By surveying the AATS membership, we also found that many of these strategies are currently underused (Figure 1).
Figure 1Prevention strategies and their efficacy for postoperative atrial fibrillation (POAF). LOE, Level of evidence; PVI, pulmonary vein isolation; i.v., intravenous; LVEF, left ventricular ejection fraction; AF, atrial fibrillation.
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Intravenous magnesium supplementation may be considered to prevent postoperative AF when serum magnesium level is low or it is suspected that total body magnesium is depleted.
Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
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.
Circulation.April 10, 2014; ([Epub ahead of print])
Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
Catheter or surgical pulmonary vein isolation (at the time of surgery) is not recommended for prevention of POAF for patients who have no previous history of AF
Complete or partial pulmonary vein isolation at the time of (even bilateral) lung surgery should not be considered for prevention of POAF, as it is unlikely to be effective
A comparison of atrial arrhythmias after heart or double-lung transplantation at a single center: insights into the mechanism of post-operative atrial fibrillation.
For those patients at increased risk for the development of POAF, preventive administration of medications (diltiazem or amiodarone) may be reasonable. However, these strategies may not be useful for all thoracic surgical patients.
4.2.
Recommended prevention strategies for intermediate to high-risk patients
Class IIa
4.2.1.
It is reasonable to administer diltiazem to those patients with preserved cardiac function who are not taking β-blockers preoperatively in order to prevent POAF
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.
Circulation.April 10, 2014; ([Epub ahead of print])
It is reasonable to consider the postoperative administration of amiodarone to reduce the incidence of POAF for intermediate and high risk patients undergoing pulmonary resection
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.
Circulation.April 10, 2014; ([Epub ahead of print])
2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
Circulation.April 10, 2014; ([Epub ahead of print])
Recommended prevention strategies for the highest-risk patients
Class IIb
4.3.1.
Left atrial appendage excision may be considered at the time of extensive left lung surgery for patients with preexisting AF who are considered too high a risk for anticoagulation in the perioperative period
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.
Circulation.April 10, 2014; ([Epub ahead of print])
Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
AF, the most common sustained arrhythmia after pulmonary and esophageal surgery, is associated with longer intensive care unit and hospital stays, increased morbidity and mortality, and higher utilization of health care resources.
POAF also represents a major potentially preventable adverse outcome. Several randomized controlled studies and meta-analyses have examined the efficacy of a variety of agents including antiarrhythmics, β-blockers, and novel agents such as magnesium and statins to prevent the development of POAF in patients undergoing thoracic surgery. However, it should be appreciated that there is a dearth of data indicating that prophylactic therapy for AF improves outcomes after thoracic surgery (eg, stroke) and reduces length of hospital stay, and many of the recommendations are extrapolated from the cardiac surgery arena.
The recommendation to avoid withdrawal of β-blockers in all patients undergoing thoracic surgery is mainly derived from the cardiac surgery literature. Nattel and colleagues
showed that abrupt propranolol withdrawal was associated with increased sensitivity to isoproterenol, and a large meta-analysis of randomized studies confirmed that acute withdrawal of β-blockers before cardiac surgery increases the risk of developing POAF.
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