AAN issues nonvalvular atrial fibrillation stroke prevention guideline

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], 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 lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "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 was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that 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. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], 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 lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "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 was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that 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. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.

A new evidence-based guideline on how to identify and treat patients with nonvalvular atrial fibrillation to prevent cardioembolic stroke from the American Academy of Neurology suggests when to conduct cardiac rhythm monitoring and offer anticoagulation, including newer agents in place of warfarin.

But the guideline might already be outdated in not considering the results of the recent CRYSTAL-AF study, in which long-term cardiac rhythm monitoring of patients with a previous cryptogenic stroke detected asymptomatic patients at a significantly higher rate than did standard monitoring methods.

The guideline also extends the routine use of anticoagulation for patients with nonvalvular atrial fibrillation (NVAF) who are generally undertreated or whose health was thought a possible barrier to their use, such as those aged 75 years or older, those with mild dementia, and those at moderate risk of falls.

"Cognizant of the global reach of the AAN [American Academy of Neurology], 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 lead author Dr. Antonio Culebras in an interview.

"The World Health Organization has determined that atrial fibrillation has reached near-epidemic proportions," observed Dr. Culebras of the State University of New York, Syracuse. "Approximately 1 in 20 individuals with AF will have a stroke unless treated appropriately."

The risk for stroke among patients with NVAF is highest in those with a history of transient ischemic attack (TIA) or prior stroke, at an absolute value of around 10% per year. Patients with "lone NVAF," meaning they have no additional risk factors, have less than a 2% increased risk of stroke per year.

The AAN issued a practice parameter on this topic in 1998 (Neurology 1998;51:671-3). At the time, warfarin, adjusted to an international normalized ratio (INR) of 2.0, was, and largely remains, the recommended standard for patients at risk for cardioembolic stroke. Aspirin was the only recommended alterative for those unable to receive the vitamin K antagonist or who were deemed to be at low risk of stroke, although the evidence was scanty.

Since then, several new oral anticoagulant agents have become available, including the direct thrombin inhibitor dabigatran (Pradaxa), and two factor Xa inhibitors – rivaroxaban (Xarelto) and apixaban (Eliquis) – which have been shown to be at least as effective as, if not more effective than, warfarin. Cardiac rhythm monitoring via a variety of methods has also been introduced as a means to try to detect NVAF in asymptomatic patients.

The aim of the AAN guideline (Neurology 2014;82:716-24) was therefore to look at the latest evidence on the detection of AF using new technologies, as well as the use of treatments to reduce the risk of stroke without increasing the risk of hemorrhage versus the long-standing standard of therapy, warfarin. Data published from 1998 to March 2013 were considered in the preparation of the guideline.

Cardiac rhythm monitoring for NVAF

Seventeen studies were found that examined the use of cardiac monitoring technologies to detect new cases of NVAF. The most common methods used were 24-hour Holter monitoring and serial electrocardiograms, but some emerging evidence on newer technologies was included. The proportion of patients identified with NVAF ranged from 0% to 23%, with the average detection rate 10.7% in all of the studies included.

"The guideline addresses the question of long-term monitoring of patients with NVAF," Dr. Culebras said. "It recommends that clinicians ‘might’ [level C evidence] obtain outpatient cardiac rhythm studies in patients with cryptogenic stroke without known NVAF to identify patients with occult NVAF." He added that the guideline also recommends that monitoring might be needed for prolonged periods of 1 or more weeks rather than for shorter periods, such as 24 hours.

However, at the time the guideline was being prepared, recent data from the CRYSTAL-AF study were not available, and this means the guideline is already outdated, Dr. Richard A. Bernstein, professor of neurology at Northwestern University, Chicago, said in an interview. He was not a guideline author.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF trial, which assessed the performance of Medtronic’s Reveal XT Insertable Cardiac Monitor and found that the implanted device could detect NVAF better than serial ECGs or Holter monitoring (8.6% vs. 1.4%; P = .0006); most (74%) cases of NVAF found were asymptomatic.*

"CRYSTAL-AF represents the state of the art for cardiac monitoring in cryptogenic stroke patients and makes the AAN guidelines obsolete," Dr. Berstein said. "[The study] shows that even intermediate-term monitoring (less than 1 month) will miss the majority of AF in this population, and that most of the AF we find with long-term (greater than 1 year) monitoring is likely to be clinically significant."

With regard to the AAN guideline, he added: "There is no discussion of truly long-term monitoring in the guideline, which is unfortunate." That said, "anything that gets neurologists thinking about long-term cardiac monitoring is likely to be beneficial."

Anticoagulation for stroke prevention

The AAN guideline also provides general recommendations on the use of novel oral anticoagulant agents (NOACs) as alternatives to warfarin. Specifically, it notes that in comparison with warfarin, these NOACs are probably at least as effective (rivaroxaban) or more effective (dabigatran and apixaban). Additionally, while apixaban is also likely to be more effective than aspirin, it is associated with a similar risk for bleeding. NOACs have the following advantages over warfarin: an overall lower risk of intracranial hemorrhage and no need for routine anticoagulant monitoring.

From a practical perspective, the AAN guideline suggests that clinicians have the following options available: warfarin to reach an INR of 2.0-3.0, dabigatran 150 mg twice daily, rivaroxaban 15-20 mg/dL, apixaban 2.5-5 mg twice a day, and triflusal 600 mg plus acenocoumarol to reach an INR target of 1.25-2.0. If a patient is already taking warfarin and is well controlled, then they should remain on that therapy and not switch to a newer oral anticoagulant.

The guideline also notes that clopidogrel plus aspirin is probably less effective than warfarin, but the combination is probably better than aspirin alone. However, the risk of hemorrhage is higher.

Where used, triflusal plus acenocoumarol is "likely more effective" than acenocoumarol alone. Triflusal is an antiplatelet drug related to aspirin, used in Europe, Latin America, and Southeast Asia. Acenocoumarol is mostly used in European countries.

Dr. Culebras explained that the guideline was not intended to dictate which treatment to use. "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 was critical of the guidelines for not advocating the use of anticoagulants strongly enough, he said that 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. This reflects how doctors make decisions when we don’t have direct comparative studies, and I think that is helpful."

The guideline was developed with financial support from the American Academy of Neurology. None of the authors received reimbursement, honoraria, or stipends for their participation in the development of the guideline.

Dr. Culebras has received one-time funding for travel from J. Uriach & Co, and he serves on the editorial boards of MedLink, UpToDate.com, and the International Journal of Stroke. He has received royalties from Informa Healthcare and Cambridge University Press, and has held stock in Clinical Stroke Research. Other authors reported current or past ties to companies marketing oral anticoagulants and stroke treatments.

Dr. Bernstein was on the steering committee for the CRYSTAL-AF study and is a paid speaker, researcher, and consultant for Medtronic, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and Lifewatch.

*Correction, 4/8/2014: The article previously misstated what the implantable device was detecting in the CRYSTAL-AF study.