Atrial Fibrillation: Is Slowing the Rate Sufficient?
Abstract & Commentary
Synopsis: Rate control alone "can result in substantial benefit," using the combination of digoxin and diltiazem; in addition to an equivalent quality of life, the substantially fewer hospital admissions in the rate control group should result in major cost savings.
Source: Hohnloser SH, et al. Lancet 2000;356:1789-1794.
Atrial fibrillation (AF) has become a growth industry, stimulated by the recognition that AF is the most common clinical arrhythmia, almost ubiquitous in patients who undergo surgery, as well as in the aging population. While most cardiologists have traditionally believed that maintenance of sinus rhythm (SR) is the optimal therapeutic strategy, doing so requires considerable effort, expense, testing, and often-repeated electrical cardioversion. The question is to whether adequate rate control alone would be comparable to efforts to maintain SR in garden variety patients with AF has never been answered. Two trials, one the North American Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study and the German Pharmacological Intervention in Atrial Fibrillation (PIAF) trial study, have been designed to address this issue. AFFIRM has not been completed but PIAF has recently been published.
PIAF is an open label, randomized study testing a rate-slowing strategy to one of the efforts to maintain SR in patients with AF. While Hohnloser and associates consider PIAF a pilot study, no mention is made as to whether a larger trial has or will be instituted by this group of 21 German hospitals. Eligibility criteria included the presence of AF in symptomatic patients 18-75 years of age; the arrhythmia had to be persistent for at least one week but no more than one year. Exclusion criteria included sick patients, active coronary artery disease, slow ventricular rate, recent cardiac surgery, intracardiac thrombus, and history of embolization. Trial duration was 12 months, with regular visits over this period. All patients underwent baseline echocardiography, 24-hour Holter monitoring to assess mean heart rate, and a six-minute walk test period. In addition, a quality of life health survey was used. The primary end point consisted of cardiac symptom assessment and included the three most common symptoms of AF: palpitations, dizziness, and dyspnea. Symptomatic improvement was defined by elimination or reduction of the frequency of any of these symptoms in a hierarchical order. Statistics included an efficacy analysis based on the intention-to-treat principle. Patients randomized to rate control (Group A) received 90 mg of diltiazem 2-3 times daily, and most were on digoxin at entry. Patients randomized to maintenance of SR (Group B) were given 600 mg of amiodarone for three weeks and then 200 mg per day. All patients were anticoagulated. In the SR group, cardioversion was performed after three weeks if pharmacologic conversion to SR did not occur.
The patient groups were equally balanced; 92% were male with a mean age of 60. Approximately 60% had hypertension, 30% CAD, and 20% valve disease. Dyspnea and palpitations were present in 80-90% of patients at baseline; 37% reported dizziness. Mean duration of AF was approximately 3-4 months in the 252 patients enrolled. Of all the patients, 70% were on digoxin at baseline, and 10% on beta-blockers. Patients were not allowed to receive antiarrhythmic agents during the study.
Results: there were a total of two deaths. The primary end point of symptomatic improvement was comparable in both groups; there were no differences between them at three,12, 24, and 52 weeks. The mean heart rate was 80-90 in both groups, slightly slower in the amiodarone patients. In group A, 10% of the patients were in sinus rhythm by the end of the study, compared to 56% of group-B patients, (P < 0.001). Amiodarone alone restored SR in 23% of group B patients;15% of group B patients underwent two electrical cardioversions, and 3% were cardioverted three times. The maintenance dose of amiodarone at one year was 211 mg. Exercise tolerance was significantly different between the groups, with a greater improvement in the 6-minute walking distance in the amiodarone patients at one year. The separation of walk test time between the two groups began at 12 weeks and was present at 24 and 52 weeks. Of group A patients, 24% were admitted to the hospital during the year vs. 70% of the group B patients (most of these admissions were for electrical cardioversion, 67%, or amiodarone toxicity, 27%). Seventy percent of group A admissions were for drug side effects. Quality of life improved in both groups with no difference between groups.
Hohnloser et al state that quality of life was "lower at baseline compared with the U.S. norm in individuals with sinus rhythm." They conclude that "neither of the two therapeutic strategies is superior in terms of improvement in atrial fibrillation-related symptoms." They further stress that this study has major implications with respect to care and cost of treating patients with AF who are symptomatic. They believe rate control alone "can result in substantial benefit," using the combination of digoxin and diltiazem; in addition to an equivalent quality of life, the substantially fewer hospital admissions in the rate control group should result in major costs savings (no data are provided). Hohnloser et al recognize that their protocol called for one cardioversion, and that other antiarrhythmic drugs or repeated electrical cardioversion might have led to a greater percentage of patients in SR at one year. The rate of maintenance of SR was somewhat lower than the Canadian Trial of Atrial Fibrillation (69% maintenance). They acknowledge that the sample size is relatively small, but nevertheless conclude, "it seems appropriate to choose the best therapeutic strategy according to the needs of the individual patients."
Comment by Jonathan Abrams, MD
This is a useful trial for clinicians who care for the increasing number of patients with AF. Clearly, in spite of the hypothetical rationale that it is better to be in SR (less atrial remodeling, less left atrial dilatation, lower embolic rate, better hemodynamics), the one-year results of PIAF are reassuring that a policy of rate control only in selected individuals does not produce harm. All patients were anticoagulated and all were symptomatic. Not all physicians would use the same pharmacologic guidelines in similar AF individuals in their practice. I am of the opinion that at least one electrical cardioversion should be performed in any patient with symptomatic AF, although this may not be necessary in a patient who is clinically stable and feels well with rate control alone. The PIAF study also supports a rate control strategy following initial cardioversion, if not successful or if SR was not maintained; thus, a careful period of rate control might be better than pursuing additional electrical cardioversion. On the other hand, for patients who remain symptomatic in AF, vigorous efforts should be made to achieve and maintain SR. Thus, if amiodarone did not work, other drugs (class I or class III) might be initiated, as well as repeat cardioversion and even consideration for AF ablation therapy.
The limitations of this trial are its small number and the relatively short follow-up period. However, the data are reassuring for the rate control strategy, particularly for the many older patients who are not particularly active and have a relatively low level of symptoms with heart rate control. Also, a recent article confirms that only a minority of intermittent AF patients will develop permanent AF, with increased age and presentation in AF at onset predicting permanent AF.1 Another caveat is that beta-blockers were not widely used in this study. It appears that these patients had relatively little difficulty in achieving heart rate control, which was documented to be adequate on 24-hour Holter recording. The results of the very large AFFIRM mortality trial enrolling patients without sustained AF are eagerly awaited.
Reference
1. Al-Khatib SM, et al. Am Heart J 2000;140:142-145.
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