Correspondence
Atrial Fibrillation — Rate versus Rhythm Control
N Engl J Med 2003; 348:1284-1286March 27, 2003
- Article
To the Editor:
The authors of the recently published Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial (Dec. 5 issue)1 conclude that rhythm control offers no advantage over rate control, although they saw a trend toward improved survival in the rate-control group. Because of the design of the trial, antiarrhythmic drugs were used primarily in the rhythm-control group. However, there is an important difference between the two study groups that was not addressed by the authors. The proportion of patients using beta-blocking drugs in the rhythm-control group was significantly smaller than that in the rate-control group, whether they were used as the initial treatment (21.8 percent vs. 46.8 percent) or at any time during the study (49.6 percent vs. 68.1 percent). This difference is essential, because there is accumulating evidence that beta-blocker treatment improves the prognosis in patients with heart failure2 or arterial hypertension,3 as well as in patients who have had a myocardial infarction.4 The predominant diagnoses in the AFFIRM trial were arterial hypertension, coronary artery disease, and congestive heart failure.
4 ReferencesVolker Kühlkamp, M.D.
Ludger Seipel, M.D.
Eberhard-Karls-Universität, 72076 Tübingen, Germany
volker.kuehlkamp@med. uni-tuebingen. de 1
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators
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Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-2007
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Olsson G ,Tuomilehto J ,Berglund G , et al. Primary prevention of sudden cardiovascular death in hypertensive patients: mortality results from the MAPHY Study. Am J Hypertens 1991;4:151-158
Web of Science | Medline4
Gottlieb SS ,McCarter RJ ,Vogel RA . Effect of beta-blockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 1998;339:489-497
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To the Editor:
The AFFIRM investigators report the results of a large trial showing no survival benefit of a rhythm-control strategy for atrial fibrillation over a rate-control strategy. The patients in the rhythm-control group had a significantly higher rate of adverse events described as pulmonary events than did the patients in the rate-control group. The rate of use of amiodarone, a drug known to have pulmonary toxicity, was much higher in the rhythm-control group, in which 62.8 percent of patients received it, than in the rate-control group, in which only 10.2 percent received it. In their initial description of the trial,1 the investigators reported that amiodarone would be used in a “low dose” (100 or 200 mg per day) or a “normal dose” (300 to 400 mg per day). It would be important to know how many of the pulmonary events were considered to be due to amiodarone toxicity and what dose of amiodarone the affected patients were receiving.
1 ReferencesEdward C. Healy, M.D.
University of Massachusetts Medical School, Worcester, MA 01655
healye@ummch.org 1
The Planning and Steering Committees of the AFFIRM Study for the NHLBI AFFIRM Investigators
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To the Editor:
Rhythm control was not superior to rate control according to the two studies comparing rate control with rhythm control in patients with atrial fibrillation — those by the AFFIRM Investigators and Van Gelder et al. (Dec. 5 issue).1 One situation in which the restoration of sinus rhythm would be rewarding is in patients with aortic stenosis in whom atrial fibrillation develops. In this group of patients, the loss of the atrial contribution to ventricular filling and the sudden decrease in cardiac output may cause serious hypotension.2 In such situations, one should promptly initiate cardioversion of atrial fibrillation to restore sinus rhythm.
2 ReferencesKrishna Bhaskarabhatla, M.D.
Saint Joseph's Regional Medical Center, Paterson, NJ 07503
baskarbhat@aol.com 1
Van Gelder IC ,Hagens VE ,Bosker HA , et al. A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med 2002;347:1834-1840
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Braunwald E, Zipes DP, Libby P, eds. Heart disease: a textbook of cardiovascular medicine. 6th ed. Vol. 2. Philadelphia: W.B. Saunders, 2001:1671-80.
To the Editor:
Although thromboembolism among patients with atrial fibrillation has commonly been attributed to the development and subsequent migration of atrial thrombi, the consistent finding of both the AFFIRM investigators and the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) Study Group (Van Gelder et al.) regarding the importance of anticoagulant therapy with warfarin for the prevention of clinical thromboembolism, irrespective of the subject's rhythm, highlights the potential effect of warfarin on the prevention of thromboembolism attributable to extracardiac sources. Thoracic aortic atherosclerosis is a well-recognized risk factor for stroke.1 Simple or complex aortic plaques are seen in more than 60 percent of patients with atrial fibrillation who have high clinical risk.2 In addition, both the prospective transesophageal-echocardiography substudy of the Stroke Prevention in Atrial Fibrillation III study2 and retrospective studies3 have demonstrated a significant reduction in the rate of clinical thromboembolism among patients receiving anticoagulant therapy with warfarin. Thus, the benefit of warfarin demonstrated by the AFFIRM and RACE studies may be related to warfarin's effect at “extra-atrial” sites — a possibility that would attenuate the potential benefit of rhythm control claimed by cardiologists and those seeking to obliterate the left atrial appendage.
3 ReferencesWarren J. Manning, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
wmanning@caregroup.harvard. edu 1
Amarenco P ,Cohen A ,Tzourio C , et al. Atherosclerotic disease of the aortic arch and the risk of ischemic stroke. N Engl J Med 1994;331:1474-1479
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The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography
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Ferrari E ,Vidal R ,Chevallier T ,Baudouy M . Atherosclerosis of the thoracic aorta and aortic debris as a marker of poor prognosis: benefit of oral anticoagulants. J Am Coll Cardiol 1999;33:1317-1322
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Dr. Wyse replies on behalf of the AFFIRM Investigators:
Drs. Kühlkamp and Seipel comment on the difference in the rate of use of beta-blockers in the two treatment groups in our study as a possible explanation for the difference in mortality between the two groups. We agree that the use of beta-blockers may be an important determinant of mortality, particularly among those with coronary artery disease. However, it is important to recognize that sotalol also has beta-blocking properties. To determine the true rate of use of beta-blockers in AFFIRM, one must add the rate of use of sotalol to that of the other beta-blockers that are listed separately in Table 2 of our article. We plan to examine this issue further in a multivariate analysis.
Dr. Healy inquires about doses of amiodarone and the proportion of pulmonary events in Table 4 of our article attributable to the pulmonary toxicity of amiodarone. The doses of amiodarone were recorded only at the time of major events. The mean dose of amiodarone in the rhythm-control group at the time of discontinuation due to an adverse event was 257 mg per day (for pulmonary adverse events, the mean was 228 mg per day; for nonpulmonary adverse events, the mean was 264 mg per day), and the mean dose at the time of death was 235 mg per day (for death from pulmonary causes, 247 mg per day; for death from nonpulmonary causes, 233 mg per day). With respect to the pulmonary toxic effects of amiodarone, it is important to remember that there are no widely accepted criteria for such a diagnosis, and the study was not double-blind. According to classification by investigators, 47 patients were ultimately assigned a diagnosis of amiodarone pulmonary toxicity, and 3 patients died from this cause. We are currently exploring this subject further.
Dr. Bhaskarabhatla's comment speaks to the generalizability of our results. We agree that patients with hemodynamically important aortic stenosis may benefit from sinus rhythm. Such patients were not enrolled in AFFIRM, and our results should not be extrapolated to populations of patients that were not included in the study.
We agree with Dr. Manning that some of the thromboembolic events in patients with atrial fibrillation may not be directly related to atrial fibrillation itself, and this may be part of the explanation for the importance of antithrombotic therapy, regardless of the approach taken for rhythm control. However, symptomatic and, more important, asymptomatic atrial fibrillation continue in spite of apparent pharmacologic rhythm control, and a cardioembolic origin directly related to atrial fibrillation is probably also part of the explanation.
D. George Wyse, M.D., Ph.D.
University of Calgary, Calgary, AB T2N 4N1, Canada
leong@axioresearch.com Author/Editor Response
The results of the RACE study apply to all patients for whom both rate control and rhythm control are alternatives. In other words, patients with atrial fibrillation who had unacceptable and even life-threatening symptoms were not included. Clearly, such patients should undergo cardioversion, and all efforts should be made to maintain sinus rhythm. This imperative also holds for patients with aortic-valve stenosis, as Dr. Bhaskarabhatla points out. Nevertheless, even in such patients, rate control may appear to be a good choice, especially if sinus rhythm cannot be achieved because of structural remodeling of the atria.
Studies of secondary prevention previously demonstrated that heart rhythm is not an independent risk factor for stroke in patients with nonvalvular atrial fibrillation.1 Instead, other factors, including age, history of stroke, and hypertension, are important. Therefore, it is not surprising that rhythm control does not reduce the rate of stroke, especially in view of the fact that many patients have relapses to atrial fibrillation. We therefore agree with Dr. Manning that AFFIRM and RACE both support the notion that migrating (artery-to-artery) emboli originating in the thoracic aorta and the carotid arteries contribute to stroke. The relative contribution of cardiac and artery-to-artery emboli to the rate of stroke is not known. In the substudy of the Stroke Prevention in Atrial Fibrillation III study,2 the yearly rate of stroke was 7.8 percent among patients with left atrial abnormalities only, 12.0 percent among patients with complex aortic plaques only, and 20.5 percent among patients with both risk factors. The primary threat to patients with atrial fibrillation, whether or not they are in sinus rhythm, comes from all sources of emboli.
Clearly, warfarin is not the full answer. First, warfarin does not prevent all embolic mechanisms. Second, instability of anticoagulation is associated with thrombus formation and bleeding, both of which contribute to stroke.3 It is clear that effective control of stroke requires a multifaceted approach and should not only or mainly focus on artery-to-artery emboli, as suggested by Dr. Manning. To render physicians and patients less dependent on unreliable anticoagulation with warfarin, interventions aimed directly at all sources of emboli may appear to be instrumental. In this respect, the stabilization of plaque with statins and antihypertensive drugs or closure of the left atrial appendage are appealing options. In addition, new anticoagulant agents that provide a more stable level of anticoagulation are eagerly awaited, since these would make the source of the embolus less important.
3 ReferencesIsabelle C. Van Gelder, M.D.
University Hospital Groningen, 9700 RB Groningen, the Netherlands
i.c. van. gelder@thorax. azg. nl Harry J.G.M. Crijns, M.D.
University Hospital Maastricht, 6202 AZ Maastricht, the Netherlands1
Hart RG ,Pearce LA ,Rothbart RM ,McAnulty JH ,Asinger RW ,Halperin JL . Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy. J Am Coll Cardiol 2000;35:183-187
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The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography
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Hylek EM ,Skates SJ ,Sheehan MA ,Singer DE . An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 1996;335:540-546
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