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What to do with acute atrial fibrillation?
Editorial
What to do with acute atrial fibrillation? Robert M. Califf, MD Durham, NC
Acute atrial fibrillation is a commonly encountered medical problem for cardiovascular practitioners. Increasing information has been aggregated in recent years on the incidence of the problem (common), its associated comorbid conditions (many and serious), and its outcomes.The risk of death, stroke, and heart failure are substantially elevated in general in patients with atrial fibrillation, although the risk of each negative outcome depends highly on other patient characteristics. The October 1998 issue of the Journal (1998;136:63242) contained an interesting study concerning an important new therapeutic opportunity for this problem.1 Ibutilide is a type III antiarrhythmic agent developed as an acute pharmacologic approach to terminating atrial fibrillation and flutter. It is touted to be different from other class III agents because of its agonism of slow inward sodium channel currents. This study, reported by Abi-Mansour et al,1 included patients with atrial fibrillation or flutter sustained for more than 3 hours but less than 90 days and preferentially enrolled women to achieve a 40% representation. Patients with prolonged QTc interval; hemodynamic instability; myocardial infarction within 30 days; or significant endocrine, metabolic, or psychiatric problems were excluded.Two hundred sixty-two patients were entered into the study; 12 were excluded for administrative reasons. Of the remaining 250, approximately 20% were randomly assigned to placebo and the rest were treated with ibutilide.The abnormal rhythm terminated during the infusion in 34.9% of ibutilide-treated patients with a doubling of response rate in atrial flutter compared with atrial fibrillation.The price paid for this benefit was 16 serious medical events in the ibutilide group compared with none in the placebo group.Among these events were 9 episodes of ventricular arrhythmia— including 6 episodes of sustained ventricular tachycardia—2 strokes, 1 cardiac arrest, and 1 episode of pulmonary edema. The study provided some answers, but also raised a variety of interesting questions: 1. Ibutilide does convert a significant number of patients to sinus rhythm, obviating the need for
From the Division of Cardiology, Department of Medicine, Duke University Medical Center. Reprint requests: Robert M. Califf, MD, Director, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. Am Heart J 1999;137:601-2. 0002-8703/99/$8.00 + 0 4/4/94910
electrical cardioversion, a procedure that most patients would like to avoid. Unfortunately, the study was not designed to provide the end points of the total number of patients in each randomized group with sustained sinus rhythm free of other complications. In the end, what a practitioner and patient would want to know is the following: given a bout of atrial fibrillation, if a choice is made to start with ibutilide, conservative care, some other antiarrhythmic drug, or electrical cardioversion over the next 24-hour and 30-day periods, which regimen will be associated with fewer morbid events (death, stroke, pulmonary edema, respiratory arrest), better quality of life, and lower cost? Although this study is a good start, by design it does not give us insight into some of the most important, clinically relevant questions. 2. Despite intensive efforts with ibutilide, other pharmacologic therapies, and electrical cardioversion, 28% of patients could not be successfully cardioverted. It would be interesting to have a better description of the therapeutic course of these patients, their associated complications, and an analysis of risk factors for failure of cardioversion. 3. The majority of clinical research is funded by industry. Unfortunately, it has become commonplace for industry (in response to perceived regulatory requirements) to use generic case report forms to record adverse events in a free text manner that is subsequently coded with standard terminology. When not forced to record important outcomes in a “yes/no” manner, study coordinators and monitors have substantial latitude in the terms used and in the threshold for calling an event “adverse”; most often, the events that are important to the evaluation of the therapy are underreported while too much energy is spent on unimportant or irrelevant data recording for events that are not informative. In this study one hopes that the common cardiovascular complications seen in patients with atrial fibrillation were carefully recorded and that the incidences reported in the manuscript are accurate; but the reader must beware when the incidence of QT prolongation is reported at 1.4%.What were the criteria for minor symptoms such as nausea, rhinitis, and wheezing? Are we to make anything of these differences in poorly described symptoms such as hemic and lymphatic abnormalities? 4. As in most clinical trials, the exclusion criteria eliminated the patients in whom the information would
American Heart Journal April 1999
602 Califf
have been the most valuable. Patients were eliminated if they had had a recent myocardial infarction, symptoms of unstable angina or heart failure, or any comorbid illnesses.Although patients with these problems may not constitute a majority of patients with a new bout of atrial fibrillation or flutter, they certainly constitute a majority of the complications of the problem. Unfortunately, we have almost no prospective studies in these populations that would help with the difficult clinical decision-making that is required.The clinical community and regulatory authorities urgently need to consider policy approaches that would encourage clinical trials to address the most important clinical needs to inform practitioners.
These questions should not be taken as a specific critique of the recent excellent study by Abi-Mansour et al.1 Rather, the issues raised here are commonly encountered in research aimed at meeting regulatory requirements. Perhaps a concerted effort to bring drug development research and clinical evaluation research into better alignment would be worthwhile.The new information provided by this manuscript is welcome and important.
Reference 1. Abi-Mansour P, McCowan R, Henthorn R, Dunn G, Perry K, and the study investigators. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Am Heart J 1998;136:632-42.
What to do with acute atrial fibrillation? Robert M. Califf, MD Durham, NC
Acute atrial fibrillation is a commonly encountered medical problem for cardiovascular practitioners. Increasing information has been aggregated in recent years on the incidence of the problem (common), its associated comorbid conditions (many and serious), and its outcomes.The risk of death, stroke, and heart failure are substantially elevated in general in patients with atrial fibrillation, although the risk of each negative outcome depends highly on other patient characteristics. The October 1998 issue of the Journal (1998;136:63242) contained an interesting study concerning an important new therapeutic opportunity for this problem.1 Ibutilide is a type III antiarrhythmic agent developed as an acute pharmacologic approach to terminating atrial fibrillation and flutter. It is touted to be different from other class III agents because of its agonism of slow inward sodium channel currents. This study, reported by Abi-Mansour et al,1 included patients with atrial fibrillation or flutter sustained for more than 3 hours but less than 90 days and preferentially enrolled women to achieve a 40% representation. Patients with prolonged QTc interval; hemodynamic instability; myocardial infarction within 30 days; or significant endocrine, metabolic, or psychiatric problems were excluded.Two hundred sixty-two patients were entered into the study; 12 were excluded for administrative reasons. Of the remaining 250, approximately 20% were randomly assigned to placebo and the rest were treated with ibutilide.The abnormal rhythm terminated during the infusion in 34.9% of ibutilide-treated patients with a doubling of response rate in atrial flutter compared with atrial fibrillation.The price paid for this benefit was 16 serious medical events in the ibutilide group compared with none in the placebo group.Among these events were 9 episodes of ventricular arrhythmia— including 6 episodes of sustained ventricular tachycardia—2 strokes, 1 cardiac arrest, and 1 episode of pulmonary edema. The study provided some answers, but also raised a variety of interesting questions: 1. Ibutilide does convert a significant number of patients to sinus rhythm, obviating the need for
From the Division of Cardiology, Department of Medicine, Duke University Medical Center. Reprint requests: Robert M. Califf, MD, Director, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715. Am Heart J 1999;137:601-2. 0002-8703/99/$8.00 + 0 4/4/94910
electrical cardioversion, a procedure that most patients would like to avoid. Unfortunately, the study was not designed to provide the end points of the total number of patients in each randomized group with sustained sinus rhythm free of other complications. In the end, what a practitioner and patient would want to know is the following: given a bout of atrial fibrillation, if a choice is made to start with ibutilide, conservative care, some other antiarrhythmic drug, or electrical cardioversion over the next 24-hour and 30-day periods, which regimen will be associated with fewer morbid events (death, stroke, pulmonary edema, respiratory arrest), better quality of life, and lower cost? Although this study is a good start, by design it does not give us insight into some of the most important, clinically relevant questions. 2. Despite intensive efforts with ibutilide, other pharmacologic therapies, and electrical cardioversion, 28% of patients could not be successfully cardioverted. It would be interesting to have a better description of the therapeutic course of these patients, their associated complications, and an analysis of risk factors for failure of cardioversion. 3. The majority of clinical research is funded by industry. Unfortunately, it has become commonplace for industry (in response to perceived regulatory requirements) to use generic case report forms to record adverse events in a free text manner that is subsequently coded with standard terminology. When not forced to record important outcomes in a “yes/no” manner, study coordinators and monitors have substantial latitude in the terms used and in the threshold for calling an event “adverse”; most often, the events that are important to the evaluation of the therapy are underreported while too much energy is spent on unimportant or irrelevant data recording for events that are not informative. In this study one hopes that the common cardiovascular complications seen in patients with atrial fibrillation were carefully recorded and that the incidences reported in the manuscript are accurate; but the reader must beware when the incidence of QT prolongation is reported at 1.4%.What were the criteria for minor symptoms such as nausea, rhinitis, and wheezing? Are we to make anything of these differences in poorly described symptoms such as hemic and lymphatic abnormalities? 4. As in most clinical trials, the exclusion criteria eliminated the patients in whom the information would
American Heart Journal April 1999
602 Califf
have been the most valuable. Patients were eliminated if they had had a recent myocardial infarction, symptoms of unstable angina or heart failure, or any comorbid illnesses.Although patients with these problems may not constitute a majority of patients with a new bout of atrial fibrillation or flutter, they certainly constitute a majority of the complications of the problem. Unfortunately, we have almost no prospective studies in these populations that would help with the difficult clinical decision-making that is required.The clinical community and regulatory authorities urgently need to consider policy approaches that would encourage clinical trials to address the most important clinical needs to inform practitioners.
These questions should not be taken as a specific critique of the recent excellent study by Abi-Mansour et al.1 Rather, the issues raised here are commonly encountered in research aimed at meeting regulatory requirements. Perhaps a concerted effort to bring drug development research and clinical evaluation research into better alignment would be worthwhile.The new information provided by this manuscript is welcome and important.
Reference 1. Abi-Mansour P, McCowan R, Henthorn R, Dunn G, Perry K, and the study investigators. Conversion efficacy and safety of repeated doses of ibutilide in patients with atrial flutter and atrial fibrillation. Am Heart J 1998;136:632-42.