The approach to the treatment of a variety of cardiovascular disorders has undergone remarkable change over the past two decades. The use of both percutaneous interventions in patients with acute myocardial infarction and automatic implantable cardiodefibrillators in patients with ventricular arrhythmias represent important examples. The cardiology community is currently in the process of another set of changes in the treatment of atrial fibrillation (AF). In this article, the authors discuss recent studies that have challenged and changed the way AF is treated. The authors address both the symptoms and risks associated with AF, as well as the treatment options aimed at reducing those risks. Finally, the authors review the limitations of the current studies and look at the future of AF to help assess the possibility for yet another paradigm shift.
AF is the most common arrhythmia in the US,1 affecting more than 2.2 million Americans, with a higher propensity in the elderly. One per cent of patients over 60 years of age suffer from AF. The number increases to 5% in patients older than 70, and continues to rise with increasing age.2 As the baby boomer generation ages, the number of AF cases in the US will grow to more than 4 million in the next decade.3 Morbidity and mortality is a major concern as these patients have a four- to five-fold increased risk of stroke.4-6 The ever-aging population will need and demand improved therapy for AF.
Rate Versus Rhythm
There are two fundamental approaches to the management of AF:
- re-establishing and maintaining sinus rhythm (rhythm control); and
- controlling ventricular rate with atrioventricular node blocking agents (rate control).
Historically, AF was treated with rate control. The advent of cardioversion and anti-arrhythmic medications led to a preference for restoring sinus rhythm. The benefits of sinus rhythm included decreasing symptoms, improved cardiac output and exercise capacity, and reduced risk for stroke.7,8 Recent studies have compared outcomes in patients using rhythm control with patients using rate control.9-13 None of these studies have shown benefit to rhythm control. In fact, some have shown improved outcomes with rate control. The authors will focus on the largest of these trials, the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial, and its impact on AF treatment.
The AFFIRM trial was a randomized multicenter study comparing rate versus rhythm control in patients with AF and a high risk of stroke or death. The primary end-point was overall mortality. A total of 4,060 patients were enrolled in the study. The rhythm control patients were treated with anti-arrhythmic medications chosen from the following list: amiodarone, sotalol, propafenone, flecainide, quinidine, moricizine, disopyramide, procainamide, and dofetilide. The treatment regimen was left to the discretion of the treating physician, who could also use the above medications in combination. Restrictions were in place for use of class 1 drugs in patients with known heart disease.
Rate control patients were treated with an approved list of medications that included: ╬▓-blockers, calcium channel blockers (verapamil and diltiazem), and digoxin. These drugs could also be used in combination. The goal of rate control called for a resting heart rate of less than 80 beats/min (BPM) and a six-minute walk heart rate of less than 110BPM.
There were 356 deaths among the patients assigned to rhythm control therapy and 310 deaths among those assigned to rate control therapy (p=0.06), showing a trend toward increased mortality in the rhythm group. More patients in the rhythm control group than in the rate control group were hospitalized and there were more adverse drug effects in the rhythm control group. The study concluded that a rhythm control strategy in AF offered no survival advantage over the rate control strategy. It went on to promote the advantages of rate control as a lower risk treatment approach avoiding the potential side effects of anti-arrhythmic drugs.13
The effect AFFIRM and other recent studies had on the cardiology community was widespread. One study showed a 32% drop in cardioversions performed at two local hospitals in the 21-month period following the release of the AFFIRM results. This coincided with a 33% increase in atrioventricular junction ablations over the same time period.14 These studies have caused a shift in the paradigm for treatment of AF, concluding that rate control is as good as, if not better than, rhythm control.
╬▓-blockers were the rate control drugs that were best tolerated, resulting in the least discontinuation of therapy. This is consistent with the authorsÔÇÖ overall understanding of the risk versus benefit of these drugs. A high percentage of patients with AF have a history of coronary artery disease (CAD), hypertension, or cardiomyopathy (CMP), all conditions in which ╬▓-blockers have been shown to increase survival. Other indications used for rate controlÔÇöincluding calcium channel blockers, digoxin, and amiodarone and other anti-arrhythmicsÔÇöhave been shown to actually increase mortality in several of the disease states. ╬▓-blockade for rate control with intravenous esmolol or metoprolol has also been shown to be equally effective to other classes of pharmacologic agents (see Table 1).
AFFIRM also further validated the need for anticoagulation in AF patients despite the type of treatment employed. A large proportion of ischemic strokes (113 of 157) occurred in patients in whom anticoagulation had been stopped (on the basis of re-established normal sinus rhythm) and who had a subtherapeutic international normalized ratio.13
Antithrombotic Therapy
The benefit of anticoagulation in AF patients is well documented, with warfarin being the most beneficial therapy at present.15 Although anticoagulation in AF with aspirin alone provides a 21% risk reduction for stroke over placebo, warfarin provides an additional 36% risk reduction in meta-analysis comparison.15 Regardless of the strategy used for treating AF, the use of anticoagulation in moderate- to high-risk groups is necessary (see Table 2).The major drawback for warfarin use is the difficulty of monitoring and maintaining therapeutic levels, making alternatives therapies highly desirable.16-18 Newer studies are now looking at oral antiplatelet and antithrombin therapies as alternatives to warfarin.
The Clopidogrel-Aspirin Atrial Fibrillation (CLAAF) trial was a small study (30 patients) comparing clopidogrel (Plavix) and aspirin with warfarin alone in a low-risk AF group. Both were equally protective against thromboembolism. Clopidogrel therapy would be very desirable due to the fact that monitoring is not required. It is also widely used and has a well-documented safety profile. Unfortunately, a larger study, Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE), was recently stopped secondary to increased events in the clopidogrel/aspirin study arm.
News of the disappointing findings in ACTIVE is certain to draw more attention to investigations looking at a new class of oral anticoagulants, direct thrombin inhibitors. These medications also benefit from consistent therapeutic levels without the need for continued monitoring. The first drug to be studied in this group is ximelagatran. The Stroke Prophylaxis using an ORal Thrombin Inhibitor in atrial Fibrillation (SPORTIF) V trial compared ximelagatran with coumadin using a double-blind protocol. The study included 3,922 patients and found no significant stroke or mortality difference between the two study groups. It also resulted in a lower total bleeding incidence (37% versus 47% per year; 95% confidence interval (CI): -14% to -6.0% per year; p<0.001).
However, serum alanine aminotransferase levels rose to more than three times the upper limit of normal in 6% of patients treated with ximelagatran. These levels typically declined whether or not treatment was continued. However, two deaths were attributed to fatal liver disease. The liver complications in SPORTIF V will require further testing to determine the safety of ximelagartan.19 Additional studies examining newer direct thrombin inhibitors are in various stages of planning.
Current recommendations for treatment of AF call for chronic anticoagulation in patients at moderate to high risk for stroke. However, some populations are at greater risk for hemorrhage, making anticoagulation more difficult.20-22 For those individuals, other therapeutic options are being assessed and tested. One such method of treatment is resection or occlusion of the atrial appendage.
AF creates a somewhat low flow environment predisposed for clot formation.23 Studies have shown that more than 90% of all thrombi in patients with non-rheumatic AF that form in the left atrium originate in the left atrial appendage (LAA).24-26 Surgical resection of the LAA has a long clinical history and is considered effective in reducing cerebral vascular events in patients with AF.24,27,28
Newer percutaneously delivered devices, such as Watchman (Atritech), are in trials to determine their safety and effectiveness in the prevention of stroke. These devices are placed in the LAA via a transeptal approach in patients not suitable for anticoagulation therapy. They consist of a self-expanding nitinol cage covered with an expanded mesh material that effectively closes off blood flow into the remaining part of the LAA. Initial studies are promising, but further studies are needed.29,30
Discussion
The findings in AFFIRM and other recent studies have dramatically changed the cardiology communityÔÇÖs approach to AF. Rate control has been quickly accepted as the goal in AF therapy in many centers across the US. However, there are limitations to the findings in AFFIRM.
AFFIRM was based on an intent-to-treat design. This is an ideal study protocol to assess treatment regimens, but it does not answer the question of whether sinus rhythm is better than rate control when the goal of therapy is achieved.
Many of the subjects in the rhythm arm of the AFFIRM trial continued to have AF, while members of the rate control group experienced spontaneous sinus rhythm with its presumed benefits. Similar experiences were seen in other AF studies. In the rate control arm of AFFIRM, 35% of patients achieved sinus rhythm spontaneously by year five. Nine to ten per cent of patients in rate control groups of three smaller studies (the Strategies of Treatment of Atrial Fibrillation (STAF), Rate Control versus Electrical Cardioversion (RACE), and Pharmacological Intervention in Atrial Fibrillation (PIAF) trials) also reverted back to sinus rhythm spontaneously.
As for the patients in the rhythm control arm of these same studies, 63% and 56% of the AFFIRM and PIAF patients were in sinus rhythm, respectively, while only 38% of the STAF and RACE patients were in sinus.9,31
When the AFFIRM data was analyzed to assess the benefits of sinus rhythm, it was found to be an independent predictor of survival. Patients in sinus rhythm were almost half as likely to die compared with those with AF (adjusted hazard ratio: 0.53; 99% CI: 0.39-0.72; p<0.0001).This was similar to the benefit of warfarin therapy (adjusted hazard ratio: 0.50; 99% CI: 0.37-0.69; p<0.0001).32 Mortality benefit of sinus rhythm has also been demonstrated in other studies.33,34
AFFIRM did not find a significant increase in mortality in the rhythm control arm, but it did identify a trend. This trend was attributed to the use of anti-arrhythmic medications. Follow-up analysis of the AFFIRM data reveled increased mortality associated with anti-arrhythmic use (adjusted hazard ratio: 1.49; 99% CI: 1.11-2.01; p=0.0005).32 When anti-arrhythmic drug effects and sinus rhythm were taken together, the mortality benefit of sinus rhythm was negated. The mortality effects of anti-arrhythmic medication have also been observed in other studies.35-38 The most desirable approach to AF treatment in the future will attempt to achieve the mortality and subjective benefits of sinus rhythm without the mortality risks of anti-arrhythmic medication. Treatment would also need to be able to address the most severely affected patients. Some currently available treatment approaches attempt to 'cureÔÇÖ AF with devices and procedures. These include new pacing protocols, surgical procedures, and percutaneous interventions.
Another limitation of AFFIRM was the study population. The investigators acknowledged that their study population may not have adequately assessed a population with severe symptoms. Local investigators may not have wanted to limit their treatment options in highly symptomatic subjects. This group of patients is the most difficult to treat and makes up approximately one-third of patients with AF.39
Device implantation geared toward AF treatment has focused on atrial pacing therapies and atrial defibrillation devices to achieve and maintain sinus rhythm.The atrial pacing devices attempt to inhibit AF by reducing atrial activation time, avoiding bradycardia, and limiting the opportunity for ectopic atrial beats. Studies are on-going, but there is no clear indication for pacing regimens to help prevent AF.40
Devices that function as atrial defibrillators are also being tested. These devices sense AF and defibrillate the rhythm. Defibrillation can be an automatic event or, depending on the userÔÇÖs preference, a programmed event. Atrial defibrillators have a high success rate for terminating AF, but the need for repeated shocks and the resulting patient discomfort has been intolerable for most patients.41
A more promising approach to restoring sinus rhythm is a procedure that attempts to terminate the circuitry that allows the initiation and propagation of AF. The Cox Maze is a surgical procedure that has been very effective in eliminating AF with the use of transmural surgical incisions that produce lines of electrical isolation in the atrium to interrupt the initiation and propagation of AF. The Cox Maze III procedure has been performed since 1988, resulting in long-term cure of AF in more than 90% of patients without the use of anti-arrhythmic medications.42,43 Recent work with radiofrequency and microwave energies to create isolating lesions during surgery has produced similar success rates and cut procedural times.44,45
Procedures to cure AF without the need of invasive surgery are being performed by percutaneous ablation, using cryotherapy, microwave, and radiofrequency energies. Initially, a multitude of methods for ablating AF existed.46Today, an increasing number of groups are focusing on isolating the four pulmonary veins. AF often originates (94%) in one or more of the pulmonary veins.47 Sites outside of the pulmonary veins may trigger AF, but this involves a small minority of the population. The recent studies using the four-pulmonary-vein isolation approach have resulted in cure rates (off chronic drug therapy) of around 80%.48-53 The cure seems to be durable, with some groups reporting that patients are AF-free after almost three years.48 The recurrences that do take place tend to occur early in follow-up (first six months) and rarely very late after ablation.54 As the success of percutaneous AF ablation mounts, there is interest in using the procedure as first-line therapy in AF.55,56
Summary
Despite the collective efforts of the cardiology community, AF treatment continues to be a difficult therapeutic problem. The authors of this article have tried to provide a concise assessment of the current practice preferences with an insight into possible future treatment approaches. At present, rate control is the best option for treating AF, along with continued anticoagulation in patients at moderate to high risk for stroke.Ôûá