Atrial Fibrillation Guidelines Across the Atlantic
Atrial Fibrillation Guidelines Across the Atlantic
The published changes in the AF management guidelines in Canada, Europe, and the USA between 2010 and 2012 exemplify that guidelines are not meant to be universal truths, but are comprehensive, living documents which attempt to authoritatively represent a constantly changing knowledge base. This systematic comparison of the recommendations of three major cardiological guideline sets yielded two major observations:
While the impact of expert consensus in areas of patchy evidence seems widely appreciated and monitored, the impact of differences in regulatory decisions and of 'medical culture' on guideline recommendations warrant further evaluation. A more detailed discussion covering the different areas of AF management can be found in the Supplementary material online of this article.
Guidelines are meant to apply to the majority of patients, and laid out in a way that can be followed in clinical practice. Henceforth, medications that are not available or not approved are usually not covered in guidelines written for that part of the world. For example, vernakalant is only covered in the European guidelines. There are other, more subtle effects on the interpretation of regulators on the available clinical trial data that can be traced in the recommendations, e.g. the dosing of the new oral anticoagulants: The dosing recommendations for rivaroxaban are not different between the three sets of guidelines, nor are the dosing recommendations for apixaban, for which approval had not been granted at the time of publication. The recommended doses reflect the doses tested in the trials. The dosing recommendations for dabigatran, in contrast, show remarkable differences that can be explained by the different regulatory approval in Canada and Europe: Although dabigatran has been tested in two doses (110 and 150 mg b.i.d.), the FDA only approved the use of the higher dose (150 mg b.i.d.). In Canada, both doses are approved. The EMA approved both doses, but the label suggests consideration of a lower dose for some patients >75 years, and only approved the lower dose for patients 80 years and older, thereby limiting the use of the higher, more effective dose. Without clinical outcome data, the FDA furthermore approved the use of a 75 mg b.i.d. dose for patients with severe chronic kidney disease (MDRD IV-V, glomerular filtration rate <30 mL/min), while dabigatran is not available for such patients in Europe or in Canada. These approved dosings are reflected in the different guidelines, resulting in marked dosing differences in the recommendations.
Another area where the influence of regulators on guideline recommendations can be tracked is found in the recommendations for the monitoring of liver function on dronedarone therapy, where the recommended intensity of monitoring during the follow-up varies markedly and directly reflects the revised labels of the drug. The European guidelines furthermore reflect the revised EMA label of dronedarone, which excludes the use of this medication in heart failure, while the FDA did not include such a cautious note in their revised label of dronedarone. The CCS update accepts the use of dronedarone in patients with moderate heart failure symptoms, provided that they have a preserved left ventricular ejection fraction. Likewise, the ACCF/AHA/HRS focused update did not change their statement on the use of dronedarone in heart failure patients.
Overall, there is a marked, traceable influence of the regulatory approval on the recommendations in the three AF guideline sets compared here. These observations raise questions towards the justification of guideline recommendations based on regulatory approval, i.e. regulatory interpretation of evidence, as opposed to evidence itself.
Cultural issues also influence guideline recommendations. An example relates to the interpretation of a Class I recommendation. In Europe a Class I recommendation is generally regarded as an instruction which should be followed. An echocardiogram for all patients with AF is likely to be a valuable investigation, although there is no evidence to support this. Indeed, the US guidelines recommend and echocardiogram (Class I). However, this is not feasible in many parts of Europe, and the European Class I recommendation is restricted to obviously needful cases, in part reflecting the fact that many patients with AF are managed in a primary care setting without involvement of cardiologists in most of Europe. In addition, estimations of cost-effectiveness are increasingly shaping local decisions for reimbursement and approved use of new therapies, adding a further level of 'cultural' differences that will influence wording and grading of recommendations.
Discussion
Main Findings
The published changes in the AF management guidelines in Canada, Europe, and the USA between 2010 and 2012 exemplify that guidelines are not meant to be universal truths, but are comprehensive, living documents which attempt to authoritatively represent a constantly changing knowledge base. This systematic comparison of the recommendations of three major cardiological guideline sets yielded two major observations:
When solid evidence exists, guidelines tend to put forward identical or largely overlapping recommendations. This applies to many aspects of AF management, especially to anticoagulant therapy and rate control therapy.
Differences in recommendations stem from three main sources, namely the need to fill evidence gaps by writing group consensus, differences in regulatory appraisal of available evidence, and differences in the 'culture of medical practice'. Such differences between guideline recommendations can be found, e.g. in antithrombotic therapy in low-risk patients, or the choice of rhythm control therapy. This obviously calls for further studies to fill evidence gaps.
While the impact of expert consensus in areas of patchy evidence seems widely appreciated and monitored, the impact of differences in regulatory decisions and of 'medical culture' on guideline recommendations warrant further evaluation. A more detailed discussion covering the different areas of AF management can be found in the Supplementary material online of this article.
Tracing the Influence of Regulators in Current AF Guidelines
Guidelines are meant to apply to the majority of patients, and laid out in a way that can be followed in clinical practice. Henceforth, medications that are not available or not approved are usually not covered in guidelines written for that part of the world. For example, vernakalant is only covered in the European guidelines. There are other, more subtle effects on the interpretation of regulators on the available clinical trial data that can be traced in the recommendations, e.g. the dosing of the new oral anticoagulants: The dosing recommendations for rivaroxaban are not different between the three sets of guidelines, nor are the dosing recommendations for apixaban, for which approval had not been granted at the time of publication. The recommended doses reflect the doses tested in the trials. The dosing recommendations for dabigatran, in contrast, show remarkable differences that can be explained by the different regulatory approval in Canada and Europe: Although dabigatran has been tested in two doses (110 and 150 mg b.i.d.), the FDA only approved the use of the higher dose (150 mg b.i.d.). In Canada, both doses are approved. The EMA approved both doses, but the label suggests consideration of a lower dose for some patients >75 years, and only approved the lower dose for patients 80 years and older, thereby limiting the use of the higher, more effective dose. Without clinical outcome data, the FDA furthermore approved the use of a 75 mg b.i.d. dose for patients with severe chronic kidney disease (MDRD IV-V, glomerular filtration rate <30 mL/min), while dabigatran is not available for such patients in Europe or in Canada. These approved dosings are reflected in the different guidelines, resulting in marked dosing differences in the recommendations.
Another area where the influence of regulators on guideline recommendations can be tracked is found in the recommendations for the monitoring of liver function on dronedarone therapy, where the recommended intensity of monitoring during the follow-up varies markedly and directly reflects the revised labels of the drug. The European guidelines furthermore reflect the revised EMA label of dronedarone, which excludes the use of this medication in heart failure, while the FDA did not include such a cautious note in their revised label of dronedarone. The CCS update accepts the use of dronedarone in patients with moderate heart failure symptoms, provided that they have a preserved left ventricular ejection fraction. Likewise, the ACCF/AHA/HRS focused update did not change their statement on the use of dronedarone in heart failure patients.
Overall, there is a marked, traceable influence of the regulatory approval on the recommendations in the three AF guideline sets compared here. These observations raise questions towards the justification of guideline recommendations based on regulatory approval, i.e. regulatory interpretation of evidence, as opposed to evidence itself.
Medical 'Culture' Impacts Guidelines
Cultural issues also influence guideline recommendations. An example relates to the interpretation of a Class I recommendation. In Europe a Class I recommendation is generally regarded as an instruction which should be followed. An echocardiogram for all patients with AF is likely to be a valuable investigation, although there is no evidence to support this. Indeed, the US guidelines recommend and echocardiogram (Class I). However, this is not feasible in many parts of Europe, and the European Class I recommendation is restricted to obviously needful cases, in part reflecting the fact that many patients with AF are managed in a primary care setting without involvement of cardiologists in most of Europe. In addition, estimations of cost-effectiveness are increasingly shaping local decisions for reimbursement and approved use of new therapies, adding a further level of 'cultural' differences that will influence wording and grading of recommendations.
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