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Atrial fibrillation
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CMEEarn Category I CME credit by reading this article and "Evaluation and management of hypercalcemia" and successfully completing the post-test. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of June 2005.
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Atrial fibrillation (AF) has become so common that 5% of people in the Western world can be expected to develop this arrhythmia during their lifetimes. The overall prevalence of AF in this country is 0.5% to 1%, increasing to 10% in persons older than 80 years.1,2 Because of our aging population, the number of patients with AF is anticipated to increase 2.5-fold during the next 50 years.2 Given that AF increases the risk of stroke five-fold, health care providers need to be vigilant about diagnosis and treatment.1 AF is associated with a decrease in cognitive function in patients with Alzheimer’s disease; in addition, vascular dementia is more common in people with AF.3,4 The economic burden of AF is also significant, representing $1 billion in health costs each year in the United States.2
There are many hypotheses about the cause of AF. One suggests that there is enhanced automaticity of one or more atrial foci and re-entry circuits; these foci are usually located around the pulmonary veins.5 Another hypothesis is that wavelets form from the fractionation of depolarization wave fronts, and these wavelets lead to disorganized and less effective atrial contraction.5 Sick sinus syndrome may cause AF in some patients.6 Fish oil seems to protect against the development of AF.7
Regardless of etiology, the mere presence of AF can result in decreased cardiac output. While most cardiac output is produced by ventricular contraction, atrial contraction represents 25% of the total cardiac output.8 In a normal atrioventricular system, the rapid firing of the atria will produce an increased ventricular rate. This tachycardia results in decreased filling time, which leads to a weaker ventricular contraction and ultimately a drop in the ejection fraction.
Risk factorsHypertension (HTN) and coronary artery disease (CAD) are the primary and secondary risk factors for AF, respectively. Others are cardiomyopathy, nonrheumatic valvular disease, atrial septal defect, cardiac surgery, pulmonary disease, rheumatic heart disease, anemia/atrial myxoma, thyrotoxicosis/hyperthyroidism, sepsis, electrolyte disturbances, and acute ingestion of alcohol (“holiday heart syndrome”). A helpful mnemonic for remembering the differential diagnosis of AF is “IRREGULAR P WAVES” (see Table 1).9
The diagnosis of AF may be delayed in some patients because of a lack of signs and symptoms. Many people, however, will be symptomatic with palpitations, chest pain, and shortness of breath. Signs include an irregular pulse, tachycardia, peripheral pulse deficit, and an absent jugular venous a wave. If the clinician suspects AF, the next steps are a thorough history and physical examination, an ECG, and laboratory studies including a CBC and measurements of thyrotropin and free T4 to rule out secondary causes of AF such as anemia and hyperthyroidism. An ECG will likely demonstrate an irregularly irregular rate with no discernable P waves. The ventricular rate in a patient with normal atrioventricular conduction usually ranges from 100 to 160 beats per minute (bpm), but the ventricular rate may be slower in elderly patients secondary to fibrotic changes within the conduction system.8 Schedule Holter or event monitoring for patients with intermittent symptoms or for those in whom you strongly suspect AF even though you have not been able to record the arrhythmia in the office. Transthoracic echocardiography can confirm heart failure, valvular disease, left atrial enlargement, and thrombus formation.10
AFFIRM study Whether rate control or rhythm control is optimal for patients with persistent AF has been a matter of much debate. In the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study, patients with AF were placed in a rate-control group or a rhythm-control group.11 The rate-control group was given beta-blockers, calcium channel blockers (verapamil or diltiazem), digoxin, or combinations of these drugs. Target heart rate was less than 80 bpm at rest and less than 110 bpm during a 6-minute walk test. The rhythm-control group was given amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, or combinations of these drugs. Both groups were followed for a mean of 3.5 years, with the end point being overall mortality. When subgroups were compared in a multivariate analysis, no reduction in overall mortality was noted in the rhythm-control group as compared to the rate-control group. Interestingly, after the second year of follow-up there seemed to be a trend toward increased survival in the rate-control group, although it did not prove to be statistically significant. Hospitalizations and adverse drug reactions were more common in the rhythm-control group. The implication of this study was that if rhythm control proves unsuccessful, rate control would be considered an equivalent means to decrease overall mortality and should be tried quickly.11
RACE study Another study that attempted to determine whether rate or rhythm control was superior was the RACE (Rate Control Versus Electrical Cardioversion) trial.12 Patients with recurrent, persistent AF were again randomized into a rate-control or rhythm-control group. Digoxin, a nondihydropyridine calcium channel blocker (verapamil or diltiazem), a beta-blocker, or a combination was used to keep the resting heart rate at less than 100 bpm. Patients in the rhythm-control group were cardioverted and without previous antiarrhythmic drug treatment. Following cardioversion, sotalol, flecainide, or propafenone was started during hospitalization, or amiodarone was initiated on an outpatient basis. This study was designed to test whether rate control was an adequate alternative to rhythm control for avoiding the primary outcome of death from cardiovascular causes, heart failure, thromboembolic complications, bleeding, the need for implantation of a pacemaker, or severe adverse effects of antiarrhythmic drugs. At the 2-year follow-up, rhythm control was not superior to rate control; furthermore, only 39% of patients in the rhythm-control group were actually in sinus rhythm. In addition, patients in sinus rhythm did not have less morbidity and mortality than patients who had recurrent AF. At follow-up, rate control proved to be an adequate alternative to rhythm control for the treatment of AF.12
Choosing a strategy Each approach has advantages and disadvantages. While rate control appears to offer no survival advantage (or disadvantage), patients undergoing this therapy did not appear to have as many adverse effects from medication.12,13 Beta-blockers may be contraindicated in patients with chronic obstructive pulmonary disease or asthma, however, and they may cause sexual dysfunction and reduce exercise tolerance.13 Advantages to rhythm control include better hemodynamic stability in patients with heart failure,14 better exercise tolerance,13 and reduction of symptoms associated with AF.11 Rhythm control, however, fails to show a decrease in mortality when compared to rate control.12,13
A recent retrospective economic analysis looked at the results of the AFFIRM trial to evaluate the mean survival and cost-effectiveness of rhythm-control versus rate-control strategies in the management of chronic AF.15 Patients in the rate-control group had a mean survival gain of 0.08 years. However, rate control cost $5,077 less per person than did rhythm control. The range of savings was from $2,189 to $5,481 per person. In 95% of replicates, rhythm control was more costly.
A new area of research is aimed at the atrial remodeling theory (electrical, contractile, and structural remodeling), which emphasizes that AF begets AF.16 Recent evidence suggests that ACE inhibitors have an effect on atrial remodeling.17
A retrospective analysis of patients enrolled in the Studies of Left Ventricular Dysfunction (SOLVD) trial looked at the role of ACE inhibitors in AF prevention for patients with left ventricular (LV) dysfunction. There were 374 patients in this study; enalapril was given to 186, while the other 188 patients received placebo. After a mean follow-up of 2.9 years, 55 patients had AF. Ten (5.4%) of the patients with AF at follow-up were in the enalapril group, but the other 45 (24%) patients with AF at follow-up were in the placebo group. There was an 18.6% absolute reduction in the risk of developing AF in patients with LV dysfunction taking enalapril. A multivariate analysis showed that enalapril was the most powerful predictor of decreased risk for AF. Even though the exact mechanism by which ACE inhibitors reduce the risk of AF development in patients with LV dysfunction is unknown, most patients with AF have other risk factors for cardiovascular disease (CVD), including HTN. ACE inhibitors would be a wise choice for treatment in such patients.
There is a great deal of inconsistency in the use of oral anticoagulation (OAC), specifically warfarin, to prevent stroke in patients with AF. While many providers agree that OAC is indicated in patients with sustained AF, those with intermittent AF are rarely treated with OAC.
The Stroke and Atrial Fibrillation Ensemble (SAFE) II was an observational study designed to explore the reasons why patients with nonvalvular AF (NVAF) were not given OAC.18 Results showed that 70% of patients with NVAF who were admitted for stroke should have been receiving OAC, but only 25% of these patients were. Cardiologists and younger practitioners were independently associated with prescribing OAC. SAFE II also demonstrated that the main reasons that OAC was not prescribed for these patients were “potential contraindications” such as advanced age, low compliance, and a fear of bleeding; however, “no indication” for OAC use was also a leading reason OAC was not prescribed. The risk of bleeding while taking OAC can be decreased by normalizing the BP, treating peptic ulcers, avoiding NSAIDs, and prescribing proton pump inhibitors if NSAIDs must be used.19 Because the incidence of ischemic stroke in patients with AF is so high, a patient with AF taking warfarin would have to fall an estimated 295 times during the year for the risk of bleeding to equal the risk of stroke in that same patient.20 Recent clinical trials that have examined rate control versus rhythm control inadvertently suggest that the use of OAC may reduce mortality in patients with AF.11,12
In the AFFIRM study, OAC was recommended for all patients, with the international normalized ratio (INR) being maintained between 2.0 and 3.0.11 If sinus rhythm was maintained for 4 to 12 consecutive weeks in the rhythm-control group, with 12 weeks being optimum, then patients were allowed to discontinue the use of OAC. At the end of follow-up, the rate of ischemic stroke was 1% per year in both groups, but most of the thrombotic events had occurred in patients whose OAC was discontinued or whose INR had been suboptimal.11,21
The RACE study also indicated that OAC could be discontinued and changed to aspirin in the rhythm-control group if sinus rhythm was maintained for 1 month.12 Aspirin was also given to patients younger than 65 years in the rate-control group who did not have underlying heart disease. The target INR was 2.5 to 3.5. After the cessation of OAC therapy, six thromboembolic events (17.1% of the total number) occurred. With the exception of one case, each patient was still in sinus rhythm at the time of the event, suggesting the high incidence of intermittent AF leading to stroke in the rhythm-control group.
For the patients receiving warfarin, there was no significant difference in the incidence of bleeding between the rhythm-control and the rate-control groups. This most likely occurred because rhythm-controlled patients, only 39% of whom were in sinus rhythm, were required to continue on OAC. Because the risk of stroke in patients with paroxysmal AF is similar to the risk in patients with persistent AF, current guidelines recommend warfarin as the OAC of choice for patients with any frequency or duration of AF, as long as they have other risk factors for stroke.5,22
Ximelagatran, a long-acting thrombin inhibitor, is a new anticoagulant that is currently being studied. The Stroke Prevention by Oral Thrombin Inhibitor in Atrial Fibrillation III (SPORTIF III) trial looked at the prevention of stroke and systemic embolism in patients taking fixed-dose (36 mg twice daily) ximelagatran compared to those taking adjusted-dose warfarin (INR between 2.0 and 3.0).23 At a mean follow-up of 17.4 months, 56 patients in the warfarin group and 40 in the ximelagatran group had primary events. By intention-to-treat analysis, the primary event rate was 2.3% per year with warfarin compared to 1.6% per year in the ximelagatran group. The patients treated with ximelagatran experienced fewer minor and major hemorrhages when compared to those in the warfarin group.
When rhythm control fails and permanent AF is the result, the remaining options for treatment are usually nonpharmacologic. These therapies have been the focus of many research projects. In the past, options for patients who had AF with uncontrollable ventricular rates were dual-chamber pacemakers or atrial defibrillators.24 In 1996, a retrospective study of patients with paroxysmal or established AF looked at outcomes for those with atrioventricular junction (AVJ) ablation who received pacemakers.25 Patients who had intermittent AF were given dual-chamber pacemakers following successful ablation of the AVJ, and those with established AF were given single-chamber pacemakers following ablation. Both groups showed statistically significant increases in quality-of-life (QOL) indices, less frequent disabling symptoms from AF, increased ease in activities of daily living, and reductions in hospital admissions.
Pacemakers are the focus of much research in the treatment of chronic AF. Today’s pacemakers are dynamic, enabling them to be programmed for specific algorithms. The Atrial Dynamic Overdrive Pacing Trial (ADOPT) tested a suppression algorithm for the treatment of AF.26 Patients were enrolled based on the presence of symptomatic paroxysmal or persistent AF, as well as sinus node dysfunction. All patients received a pacemaker programmed to dual-chamber, dual-sensing, dual-mode of response and rate-modulation pacing (DDDR). They were randomized to either the treatment group (AF Suppression Algorithm) or to the control group (no algorithm). In the treatment group, if intrinsic P waves were detected, the AF Suppression Algorithm increased the pacing rate. If no intrinsic P waves were detected during the overdrive period, the algorithm allowed for gradual slowing of the rate. The algorithm slowed the rate either to the programmed base rate or to the sensor-defined rate. Atrial burden (total number of AF days divided by the cumulative follow-up days) and adverse events were the end points of the study.
There were no statistically significant differences between the two groups regarding mean number of AF episodes, total hospitalizations, and incidence of complications, adverse events, and deaths. AF burden, however, was 25% lower in the treatment group. Even though this represented only a small absolute decrease (2.5% in the treatment group versus 1.87% in the control group), small changes in AF burden may represent modest changes in a patient’s QOL. Nevertheless, the suppression algorithm is another tailored alternative for the patient with refractory AF who receives a pacemaker.
Focal ablation is now being performed as an alternative to pacemaker implantation in an effort to eliminate the spontaneous or catheter-induced trigger. Electrophysiologists are also performing linear ablations, which may prevent reentrant tachycardias.24 Most of the atrial foci responsible for AF are located near the pulmonary veins.5 These foci have been the target of pulmonary vein isolation (PVI) ablation techniques. Recent evidence suggests that 70% of paroxysmal AF can be abolished, and a 10% to 20% improvement in symptoms can be achieved, by PVI ablation techniques.27 Not only are symptoms improved by PVI, but QOL measures also improve.
A recent study examined 89 patients with paroxysmal AF that was refractory to drug therapy.28 Symptoms occurred more than once a week for less than 48 hours at a time. None of the patients had underlying heart disease, and all were selected for PVI ablation. QOL was assessed after PVI and compared to QOL in two control groups, neither of which received PVI. The first control group was comprised of healthy subjects (without AF) of the same age and sex; the second control group was made up of patients with AF having similar clinical scenarios, who were treated with antiarrhythmic drugs as opposed to ablation techniques. Baseline QOL scores were remarkably lower in the study group as well as in the control group who had AF; however, after PVI, changes in the study group’s QOL scores were noticed within the first month. At the 6-month follow-up, QOL scores in the study group were equivalent to the QOL scores in the healthy, age-matched control group.28
Radiofrequency (RF) ablation of spontaneous and catheter-induced ectopy had more conservative successes in 25 patients with paroxysmal or persistent AF.29 The absence of AF recurrences during follow-up (mean, 28 months), regardless of antiarrhythmic drug use, defined successful ablation. Spontaneous repetitive ectopy was seen in only three patients; all others exhibited catheter-induced ectopy. At follow-up, only 32% had successful ablation, with five patients using no antiarrhythmic drugs and three using antiarrhythmic drugs. The authors hypothesize that RF ablation may be more effective for spontaneous ectopies than for catheter-induced ectopies, and the infrequency of spontaneous ectopies in this study may account for lower success rates.
RF ablation continues to be an experimental treatment. More randomized clinical trials are needed, and long-term effects are still being studied. Therefore, only patients with AF who have failed drug therapy and have disabling complaints secondary to AF should be candidates for RF ablation.
Many of the risk factors for CVD—HTN, diabetes, smoking, hyperlipidemia—are also risk factors for AF. Is there a common thread? New theories on the cause of AF have recently emerged.
One is the oxidant stress theory.30 Recent evidence has shown that an imbalance in nitric oxide (NO) and reactive oxygen species (ROS)—for example, superoxide—may lead to AF. NO has beneficial effects in the body: It produces vasodilation, inhibits platelet activation, increases amounts of plasminogen activator inhibitor-1, decreases leukocyte proliferation, inhibits smooth muscle proliferation, and acts as an antioxidant. Conversely, oxidative stress, associated with ROS production and reduced NO bioavailability, appears to be associated with atherosclerosis and commonly known risk factors for CVD such as hypercholesterolemia, smoking, HTN, diabetes, heart failure, and AF.30
Coronary artery bypass graft surgery, a known initiator of AF, also causes an increase in ROS production—as does angiotensin II, although by a different mechanism.31 This is relevant to patients with AF because they are known to have increased levels of angiotensin-converting enzyme.32 The oxidant stress theory may demonstrate why AF usually progresses with age, from intermittent to persistent. The oxidative stress on the heart’s electrical activity can induce AF, which will, in turn, create more oxidative stress by increasing ROS and decreasing NO. This will promote the electrical remodeling that allows for AF’s progression.30 This theory may prove to open a new window into the management and possible prevention of AF.
REFERENCES
