Guideline Analyzes Methods for Detecting Nonvalvular Atrial Fibrillation

In patients with recent cryptogenic stroke, cardiac rhythm monitoring probably detects occult nonvalvular atrial fibrillation (NVAF), according to an evidence-based guideline drafted by the American Academy of Neurology (AAN). The guideline, which was published February 25 in Neurology, describes how to identify and treat patients with NVAF to prevent cardioembolic stroke. The document also provides advice about when to conduct cardiac rhythm monitoring and offer anticoagulants, including when to recommend newer agents in place of warfarin.

The guideline may already be outdated, however, because it does not take the results of the recent CRYSTAL-AF study into account. In that study, long-term cardiac rhythm monitoring of patients with previous cryptogenic stroke detected asymptomatic atrial fibrillation at a significantly higher rate than standard monitoring methods did.

The guideline also recommends extending the routine use of anti​coagulation to patients with NVAF who are generally undertreated or whose health was considered a possible barrier to their use, such as individuals age 75 or older, people with mild dementia, and people at moderate risk of falls.

“Cognizant of the global reach of the AAN, the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants,” said Antonio Culebras, MD, lead author of the guideline.

“The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions,” said Dr. Culebras, Professor of Neurology at the State University of New York, Syracuse. “Approximately one in 20 individuals with atrial fibrillation will have a stroke unless treated appropriately.”

The risk for stroke among patients with NVAF is highest in people with a history of transient ischemic attack or prior stroke. For this population, the risk of stroke is approximately 10% per year. Patients with no risk factors other than NVAF have a less than 2% increased risk of stroke per year.

The AAN issued a practice parameter on NVAF in 1998. At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was the recommended standard treatment for patients at risk of cardioembolic stroke. Aspirin was the only recommended alternative for patients unable to receive the vitamin K antagonist or for those who were deemed to be at low risk of stroke, although clinical trials had not established aspirin’s efficacy in these patients.

Since 1998, several new oral anticoagulants (NOACs) have become available, including the direct thrombin inhibitor dabigatran and two factor Xa inhibitors, rivaroxaban and apixaban, that have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring by various methods also has been introduced as a means to detect NVAF in asymptomatic patients.

The aims of the new AAN guideline were to analyze the latest evidence on the detection of atrial fibrillation using new technologies and to examine the efficacy of treatments to reduce the risk of stroke without increasing the risk of hemorrhage, compared with the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

A Comparison of Cardiac Monitoring Technologies
The authors identified 17 studies that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods were 24-hour Holter monitoring and serial ECG, but emerging evidence on newer technologies also was included in the analysis. The proportion of patients identified with NVAF ranged from 0% to 23%, and the average detection rate was 10.7% in all of the studies included.

“The guideline addresses the question of long-term monitoring of patients with NVAF,” said Dr. Culebras. “It recommends that clinicians ‘might’ [ie, with level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF.” The guideline also advises that monitoring might be needed for prolonged periods of one or more weeks, rather than for shorter periods such as 24 hours.

At the time the guideline was being prepared, however, data from the CRYSTAL-AF study were not available, which means that the guideline is already outdated, said Richard A. Bernstein, MD, PhD, Professor of Neurology at Northwestern University in Chicago. Dr. Bernstein was not a coauthor of the guideline.

Dr. Bernstein was a member of the steering committee for the CRYSTAL-AF trial, which found that an insertable cardiac monitor detected NVAF more often at six months than serial ECG or Holter monitoring (8.9% vs 1.4%). Approximately 74% of cases of NVAF that were detected were asymptomatic.

“CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete,” said Dr. Bernstein. “[The study] shows that even intermediate-term monitoring (less than one month) will miss the majority of atrial fibrillation in this population, and that most of the atrial fibrillation we find with long-term (greater than one year) monitoring is likely to be clinically significant.”

The AAN guideline includes “no discussion of truly long-term monitoring … which is unfortunate,” he added. Nevertheless, “anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial.”

Guideline Recommends Anticoagulants for Stroke Prevention
The AAN guideline also provides general recommendations on the use of NOACs as alternatives to warfarin. The authors note that in comparison with warfarin, rivaroxaban is probably at least as effective, and dabigatran and apixaban may be more effective. In addition, although apixaban is likely to be more effective than aspirin, it is associated with a similar risk of bleeding. NOACs’ advantages over warfarin include an overall lower risk of intracranial hemorrhage and their elimination of the need for routine anticoagulant monitoring.

Clinicians have the following options available, according to the AAN guideline: warfarin (INR, 2.0 to 3.0), dabigatran (150 mg bid), rivaroxaban (15 to 20 mg/dL), apixaban (2.5 to 5 mg bid), and triflusal (600 mg) plus acenocoumarol (INR, 1.25 to 2.0). If a patient is already taking warfarin and is well controlled, he or she should remain on that therapy and not switch to a newer oral anticoagulant, said the authors.

The combination of clopidogrel and aspirin is probably less effective than warfarin, but probably better than aspirin alone, according to the guideline. The risk of hemorrhage, however, is higher with clopidogrel and aspirin.

The combination of triflusal and acenocoumarol is “likely more effective” than acenocoumarol alone, said the authors. Triflusal is available in Europe, Latin America, and Southeast Asia, and acenocoumarol is available in Europe.

The document is not intended to dictate which treatment to use, Dr. Culebras explained. “The guideline leaves room on purpose for clinicians to use their judgment,” he said. “The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment.”

Although Dr. Bernstein criticized the guidelines for not recommending anticoagulants strongly enough, the recommendations on anticoagulant choice are “reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data,” he said. “This [approach] reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful.”

—Sara Freeman

In patients with recent cryptogenic stroke, cardiac rhythm monitoring probably detects occult nonvalvular atrial fibrillation (NVAF), according to an evidence-based guideline drafted by the American Academy of Neurology (AAN). The guideline, which was published February 25 in Neurology, describes how to identify and treat patients with NVAF to prevent cardioembolic stroke. The document also provides advice about when to conduct cardiac rhythm monitoring and offer anticoagulants, including when to recommend newer agents in place of warfarin.

The guideline may already be outdated, however, because it does not take the results of the recent CRYSTAL-AF study into account. In that study, long-term cardiac rhythm monitoring of patients with previous cryptogenic stroke detected asymptomatic atrial fibrillation at a significantly higher rate than standard monitoring methods did.

The guideline also recommends extending the routine use of anti​coagulation to patients with NVAF who are generally undertreated or whose health was considered a possible barrier to their use, such as individuals age 75 or older, people with mild dementia, and people at moderate risk of falls.

“Cognizant of the global reach of the AAN, the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants,” said Antonio Culebras, MD, lead author of the guideline.

“The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions,” said Dr. Culebras, Professor of Neurology at the State University of New York, Syracuse. “Approximately one in 20 individuals with atrial fibrillation will have a stroke unless treated appropriately.”

The risk for stroke among patients with NVAF is highest in people with a history of transient ischemic attack or prior stroke. For this population, the risk of stroke is approximately 10% per year. Patients with no risk factors other than NVAF have a less than 2% increased risk of stroke per year.

The AAN issued a practice parameter on NVAF in 1998. At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was the recommended standard treatment for patients at risk of cardioembolic stroke. Aspirin was the only recommended alternative for patients unable to receive the vitamin K antagonist or for those who were deemed to be at low risk of stroke, although clinical trials had not established aspirin’s efficacy in these patients.

Since 1998, several new oral anticoagulants (NOACs) have become available, including the direct thrombin inhibitor dabigatran and two factor Xa inhibitors, rivaroxaban and apixaban, that have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring by various methods also has been introduced as a means to detect NVAF in asymptomatic patients.

The aims of the new AAN guideline were to analyze the latest evidence on the detection of atrial fibrillation using new technologies and to examine the efficacy of treatments to reduce the risk of stroke without increasing the risk of hemorrhage, compared with the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

A Comparison of Cardiac Monitoring Technologies
The authors identified 17 studies that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods were 24-hour Holter monitoring and serial ECG, but emerging evidence on newer technologies also was included in the analysis. The proportion of patients identified with NVAF ranged from 0% to 23%, and the average detection rate was 10.7% in all of the studies included.

“The guideline addresses the question of long-term monitoring of patients with NVAF,” said Dr. Culebras. “It recommends that clinicians ‘might’ [ie, with level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF.” The guideline also advises that monitoring might be needed for prolonged periods of one or more weeks, rather than for shorter periods such as 24 hours.

At the time the guideline was being prepared, however, data from the CRYSTAL-AF study were not available, which means that the guideline is already outdated, said Richard A. Bernstein, MD, PhD, Professor of Neurology at Northwestern University in Chicago. Dr. Bernstein was not a coauthor of the guideline.

Dr. Bernstein was a member of the steering committee for the CRYSTAL-AF trial, which found that an insertable cardiac monitor detected NVAF more often at six months than serial ECG or Holter monitoring (8.9% vs 1.4%). Approximately 74% of cases of NVAF that were detected were asymptomatic.

“CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete,” said Dr. Bernstein. “[The study] shows that even intermediate-term monitoring (less than one month) will miss the majority of atrial fibrillation in this population, and that most of the atrial fibrillation we find with long-term (greater than one year) monitoring is likely to be clinically significant.”

The AAN guideline includes “no discussion of truly long-term monitoring … which is unfortunate,” he added. Nevertheless, “anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial.”

Guideline Recommends Anticoagulants for Stroke Prevention
The AAN guideline also provides general recommendations on the use of NOACs as alternatives to warfarin. The authors note that in comparison with warfarin, rivaroxaban is probably at least as effective, and dabigatran and apixaban may be more effective. In addition, although apixaban is likely to be more effective than aspirin, it is associated with a similar risk of bleeding. NOACs’ advantages over warfarin include an overall lower risk of intracranial hemorrhage and their elimination of the need for routine anticoagulant monitoring.

Clinicians have the following options available, according to the AAN guideline: warfarin (INR, 2.0 to 3.0), dabigatran (150 mg bid), rivaroxaban (15 to 20 mg/dL), apixaban (2.5 to 5 mg bid), and triflusal (600 mg) plus acenocoumarol (INR, 1.25 to 2.0). If a patient is already taking warfarin and is well controlled, he or she should remain on that therapy and not switch to a newer oral anticoagulant, said the authors.

The combination of clopidogrel and aspirin is probably less effective than warfarin, but probably better than aspirin alone, according to the guideline. The risk of hemorrhage, however, is higher with clopidogrel and aspirin.

The combination of triflusal and acenocoumarol is “likely more effective” than acenocoumarol alone, said the authors. Triflusal is available in Europe, Latin America, and Southeast Asia, and acenocoumarol is available in Europe.

The document is not intended to dictate which treatment to use, Dr. Culebras explained. “The guideline leaves room on purpose for clinicians to use their judgment,” he said. “The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment.”

Although Dr. Bernstein criticized the guidelines for not recommending anticoagulants strongly enough, the recommendations on anticoagulant choice are “reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data,” he said. “This [approach] reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful.”

—Sara Freeman

In patients with recent cryptogenic stroke, cardiac rhythm monitoring probably detects occult nonvalvular atrial fibrillation (NVAF), according to an evidence-based guideline drafted by the American Academy of Neurology (AAN). The guideline, which was published February 25 in Neurology, describes how to identify and treat patients with NVAF to prevent cardioembolic stroke. The document also provides advice about when to conduct cardiac rhythm monitoring and offer anticoagulants, including when to recommend newer agents in place of warfarin.

The guideline may already be outdated, however, because it does not take the results of the recent CRYSTAL-AF study into account. In that study, long-term cardiac rhythm monitoring of patients with previous cryptogenic stroke detected asymptomatic atrial fibrillation at a significantly higher rate than standard monitoring methods did.

The guideline also recommends extending the routine use of anti​coagulation to patients with NVAF who are generally undertreated or whose health was considered a possible barrier to their use, such as individuals age 75 or older, people with mild dementia, and people at moderate risk of falls.

“Cognizant of the global reach of the AAN, the guideline also examines the evidence base for a treatment alternative to warfarin or its analogues for patients in developing countries who may not have access to the new oral anticoagulants,” said Antonio Culebras, MD, lead author of the guideline.

“The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions,” said Dr. Culebras, Professor of Neurology at the State University of New York, Syracuse. “Approximately one in 20 individuals with atrial fibrillation will have a stroke unless treated appropriately.”

The risk for stroke among patients with NVAF is highest in people with a history of transient ischemic attack or prior stroke. For this population, the risk of stroke is approximately 10% per year. Patients with no risk factors other than NVAF have a less than 2% increased risk of stroke per year.

The AAN issued a practice parameter on NVAF in 1998. At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was the recommended standard treatment for patients at risk of cardioembolic stroke. Aspirin was the only recommended alternative for patients unable to receive the vitamin K antagonist or for those who were deemed to be at low risk of stroke, although clinical trials had not established aspirin’s efficacy in these patients.

Since 1998, several new oral anticoagulants (NOACs) have become available, including the direct thrombin inhibitor dabigatran and two factor Xa inhibitors, rivaroxaban and apixaban, that have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring by various methods also has been introduced as a means to detect NVAF in asymptomatic patients.

The aims of the new AAN guideline were to analyze the latest evidence on the detection of atrial fibrillation using new technologies and to examine the efficacy of treatments to reduce the risk of stroke without increasing the risk of hemorrhage, compared with the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

A Comparison of Cardiac Monitoring Technologies
The authors identified 17 studies that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods were 24-hour Holter monitoring and serial ECG, but emerging evidence on newer technologies also was included in the analysis. The proportion of patients identified with NVAF ranged from 0% to 23%, and the average detection rate was 10.7% in all of the studies included.

“The guideline addresses the question of long-term monitoring of patients with NVAF,” said Dr. Culebras. “It recommends that clinicians ‘might’ [ie, with level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF.” The guideline also advises that monitoring might be needed for prolonged periods of one or more weeks, rather than for shorter periods such as 24 hours.

At the time the guideline was being prepared, however, data from the CRYSTAL-AF study were not available, which means that the guideline is already outdated, said Richard A. Bernstein, MD, PhD, Professor of Neurology at Northwestern University in Chicago. Dr. Bernstein was not a coauthor of the guideline.

Dr. Bernstein was a member of the steering committee for the CRYSTAL-AF trial, which found that an insertable cardiac monitor detected NVAF more often at six months than serial ECG or Holter monitoring (8.9% vs 1.4%). Approximately 74% of cases of NVAF that were detected were asymptomatic.

“CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete,” said Dr. Bernstein. “[The study] shows that even intermediate-term monitoring (less than one month) will miss the majority of atrial fibrillation in this population, and that most of the atrial fibrillation we find with long-term (greater than one year) monitoring is likely to be clinically significant.”

The AAN guideline includes “no discussion of truly long-term monitoring … which is unfortunate,” he added. Nevertheless, “anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial.”

Guideline Recommends Anticoagulants for Stroke Prevention
The AAN guideline also provides general recommendations on the use of NOACs as alternatives to warfarin. The authors note that in comparison with warfarin, rivaroxaban is probably at least as effective, and dabigatran and apixaban may be more effective. In addition, although apixaban is likely to be more effective than aspirin, it is associated with a similar risk of bleeding. NOACs’ advantages over warfarin include an overall lower risk of intracranial hemorrhage and their elimination of the need for routine anticoagulant monitoring.

Clinicians have the following options available, according to the AAN guideline: warfarin (INR, 2.0 to 3.0), dabigatran (150 mg bid), rivaroxaban (15 to 20 mg/dL), apixaban (2.5 to 5 mg bid), and triflusal (600 mg) plus acenocoumarol (INR, 1.25 to 2.0). If a patient is already taking warfarin and is well controlled, he or she should remain on that therapy and not switch to a newer oral anticoagulant, said the authors.

The combination of clopidogrel and aspirin is probably less effective than warfarin, but probably better than aspirin alone, according to the guideline. The risk of hemorrhage, however, is higher with clopidogrel and aspirin.

The combination of triflusal and acenocoumarol is “likely more effective” than acenocoumarol alone, said the authors. Triflusal is available in Europe, Latin America, and Southeast Asia, and acenocoumarol is available in Europe.

The document is not intended to dictate which treatment to use, Dr. Culebras explained. “The guideline leaves room on purpose for clinicians to use their judgment,” he said. “The overall objective of the guideline is to reduce therapeutic uncertainty and not to issue commandments for treatment.”

Although Dr. Bernstein criticized the guidelines for not recommending anticoagulants strongly enough, the recommendations on anticoagulant choice are “reasonable in that they impute potential clinical profiles of patients who might particularly benefit from one NOAC over another, without making a claim that these recommendations are based on solid data,” he said. “This [approach] reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful.”

—Sara Freeman