New Developments in Atrial Fibrillation

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Atrial fibrillation (AF) is the most common sustained, medically significant, and troublesome arrhythmia encountered in clinical practice. AF has been associated with decreased quality of life (symptoms), serious morbidity (thromboemboli and tachycardia-induced cardiomyopathy), and increased risk of mortality. Several articles1,2 have reviewed this arrthymia in depth including its presentations, prognosis and management. This review will focus on new developments in the management of AF.

When a patient presents with AF, four issues must be routinely addressed. First, is there is an underlying etiology that will be self-terminating or correctable? In these cases, AF itself is not likely to become a chronic or recurring disorder. Such etiologies include pneumonia, pericarditis, thyrotoxicosis, and thoracic surgery. In the absence of such correctable or limited entities, AF is likely to recur and thus become an on-going disorder requiring significant attention over the course of time.AF may then present in paroxysmal, persistent, or permanent forms.

The second issue is ventricular rate control. In the absence of intrinsic atrioventricular (AV) nodal dysfunction, the ventricular rate during AF will be rapid, as a result of the ultrarapid (>400-600 beats per minute (bpm)) atrial rates. Control (restoration of physiologic rates) of the ventricular response is essential both for symptom reduction and to prevent the development of a tachycardia-induced dilated cardiomyopathy (which may occur with chronic rates of 90-100bpm or higher). Control is usually achieved with the administration of one or more AV nodal depressant drugs, such as a ├ş-blocker, verapamil, diltiazem, or digitalis. There are guidelines on their relative efficacies and the factors that should underlie the specific selection in a given patient.3

Efficacy in each patient is best determined with a 24-hour ambulatory electrocardiograph (ECG) recorder so that the average heart rate is <90bpm, the peak ventricular rate is no greater than would be present during the same level of activity if normal sinus rhythm (NSR) were present, and the minimum rate is not excessively slow. When pharmacotherapy fails to provide adequate ventricular rate control because of either drug inefficacy or intolerance, AV node ablation and implantation of a modern rate-responsive pacemaker become the therapy of choice. Thus, rate control can be achieved in 100% of patients and is essential.

Anticoagulation is the third issue.Whether patients have paroxysmal atrial fibrillation (PAF), persistent AF awaiting cardioversion, or permanent AF, considerations regarding anticoagulation must be addressed.A simplified view of current guidelines3 would state that the presence of recognized risk factors that indicate an increased risk for an embolic event dictate the administration of warfarin (to an international normalized ratio (INR) value of 2.0-3.0), whereas the absence of such risk factors does not, and usually results in the use of aspirin 325mg per day. Such risk markers include age >65 years, prior emboli, hypertension, diabetes, ventricular failure, rheumatic disease, and selected echocardiographic identifiers that may be useful in particular circumstances.3 When any of these risk markers is present, clinical trials have shown a greater efficacy and risk-benefit ratio for warfarin than for aspirin.

Fourth, and finally, is the issue of whether and when to pursue the return and maintenance of NSR, rather than to allow the patient to remain in AF, even if rate-controlled and adequately anticoagulated. Clearly, if the patient continues to have symptoms from AF and a less than desirable quality of life (QOL) despite rate control, sinus rhythm must be considered. For persistent AF, cardioversion would be applied and then, as with PAF, the maintenance of NSR would be sought, initially with the use of an antiarrhythmic drug (AAD).The selection of the AAD to be employed should be guided by the now internationally developed guidelines recommended jointly by the American College of Cardiology (ACC), the American Heart Association (AHA), the European Society of Cardiology (ESC), and the North American Society of Pacing and Electrophysiology (NASPE) in October 2001.

While each of the four issues regarding AF detailed previously are well recognized and reviewed, each of them has been influenced by newer or developing forms of therapy and/or by recent clinical trial data indicating that certain additional considerations regarding these four issues now require attention.

Underlying Etiology

In the past, correction of underlying etiology focused on an associated disorder that initiated or contributed to maintaining the presence of AF. In recent years, the focus has shifted, aspects of the heart itself are beginning to be targeted, with the intention of curing AF. In this respect, two broad areas of atrial electrophysiology require attention - remodeling and focal initiators.

Remodeling4 is a term that has been applied to the changes that occur in the atrium as a result of persistently rapid rates (whether iatrogenic, as with rapid pacing experiments, or spontaneous, as with atrial tachyarrhythmias). Rapid rates in the atrium in themselves lead to shortening of atrial refractory periods, dilation of the atrium, and alterations in atrial metabolic characteristics (the constellation of remodeling), which allow a greater number of re-entrant wavelets to form and persist and which thereby increase the ability of AF to be maintained. As such, AF begets AF. Several investigative examinations have suggested that remodeling is, at least in part, a product of calcium overload and may be reduced or prevented by the administration of a calcium channel blocker (most of the work has been done with verapamil) before or shortly after the initiation of AF. Thus, while verapamil itself is not an agent that will cause cardioversion of AF back to normal or will be useful in the long-term as an antiarrhythmic drug (AAD) to prevent recurrent AF, verapamil has been shown to reduce early recurrence of AF after cardioversion and to prevent the atrial remodeling effects of recent AF. It may facilitate other AADs in this circumstance and may be the first-choice agent for rate control of recentonset AF, in the absence of a contraindication.5

The term 'focal triggersÔÇÖ refers to the finding that, in many patients, particularly those with very frequent episodes of PAF and no associated structural heart disease, AF appears to be initiated by localized (focal) atrial foci that fire repetitively and often rapidly - conduction from these foci breaks down in the atrial tissue and results in AF. In most of these patients, the foci have been located in one or more of the pulmonary veins, where bands of atrial muscle extend several centimeters into and/or around the mouth of the veins. In some patients, similar findings have occurred in other atrial venous inflow structures, such as the Venae cavae.When such regions are identified, ablative energy, applied to eliminate the trigger or to isolate electrically the source from the body of the atrium, has been effective in preventing further AF episodes and may be viewed as a cure. Unfortunately, there is not yet uniformity to the methodologic approach - the available techniques and equipment still require long, often multiple repeated procedures, are laboratory-dependent, and carry significant risk. They may be best viewed as still investigational, although they are carried out routinely in some laboratories worldwide. Because of the complexity of the procedure and the risks (including pulmonary vein stenosis with chronic pulmonary hypertension, cardiac perforation, emboli, and death), patients in most laboratories are usually selected from those with highly symptomatic, drug-resistant AF, and the procedure should not yet be considered a first-line therapy.

As an outgrowth of this approach, catheter ablation techniques are being developed for more diffuse atrial lesions in hopes of achieving a cure for permanent as well as paroxysmal AF. Candidates for focal ablation are best characterized by minimal or no structural heart disease, frequent symptomatic PAF despite rate control, and repeated bursts every day during Holter monitoring. Because these patients have failed to respond to at least two types of antiarrhythmic drugs, they are willing to accept the procedural risks, a high likelihood of repeated procedures, and only a modest success rate.

The catheter ablation approach to AF grew out of the surgical approach to AF, known as the Cox-Maze procedure.6 In this procedure and its subsequent modifications, the right and left atria are sectioned into maze-like channels so that sustained re-entrant loops supporting AF cannot be maintained. Using modern surgical methods, New York-Presbyterian Hospital in New York City, and other centers are now modifying this technique so that it mimics the focal approach to catheter ablation in many respects.

Limited surgical lesions, created by radiofrequency, cryoablation, and/or incisions, can be applied to target areas, around the pulmonary veins for example, via a thoracoscopic approach (sometimes robotically) without an open chest procedure and with very short postsurgical hospital stays. The New York-Presbyterian Hospital is comparing the different approaches and analyzing which has the highest efficacy and safety profile as initial therapy. Some patients obtain the best results with a combination of the surgical and catheter approaches. The hospital has used the surgical approach in combination with other cardiac surgical procedures, such as valve replacement, but also as an independent procedure in patients who require an AF cure for situational purposes, such as a commercial airline pilot.

Ventricular Rate Control

As previously indicated, ventricular rate control is required in all patients with AF and can be achieved in all patients if both drug and nonpharmacologic approaches are thoroughly explored. Also, as indicated above, recent data support the use of verapamil as the initial rate control drug for new-onset AF unless the underlying etiology, such as post-MI, would strongly favor an alternative agent, or unless comorbid disease or therapy prevents its use. For example, the use of dofetilide (Tikosyn, Pfizer) as an AAD precludes the use of verapamil, and indicates caution if diltiazem is employed.

Also new in the realm of rate control is the appreciation of the fact that most patients with AF have both symptomatic and asymptomatic periods/episodes7 and that, in general, the asymptomatic episodes have slower ventricular rates than the rates found in symptomatic episodes. Thus, the absence of AF symptoms does not provide proof positive of the absence of recurrent AF episodes, especially in patients with documented rate control. Accordingly, one cannot use the history of an absence of symptoms to assure the absence of AF episodes. Thus, one cannot use such a history to decide when or whether to discontinue the use of an anticoagulant regimen. Accordingly, memory-loop event recorders have been modified not only to allow patient-triggering for evaluation of appropriate symptoms, but also to auto-trigger for periods of AF. These recorders are currently available from commercial sources but do not appear to be used yet with an appropriate frequency as a guide to control of total AF burden. In patients who not only have AF but also have an indwelling device (pacemaker or defibrillator) for a concomitant cardiac dysrhythmia, interrogation of the device may also allow recognition of periods of AF that may not have been recognized by the patient. This should be a routine part of the follow up protocol for patients with such devices.

Anticoagulation

There have been detailed reviews of anticoagulation for AF and, since these, no new end-point guidelines or new therapeutic agents have been introduced in the US. As noted previously, however, what has become apparent is that many, if not most, patients have recurrent episodes of AF that go unrecognized. As such, there remains a risk of thromboembolism if anticoagulation is discontinued without thorough documentation of perfect (or near-perfect) control of sinus rhythm. It is the presence of AF, not its symptoms, that determines the existence of embolic risk.

Experts therefore currently recommend that anticoagulation, once initiated, be continued indefinitely in a patient with AF unless, or until it is certain that, recurrences are either absent or can reliably be recognized during the first day that they recur so that anticoagulation can be immediately reinstituted, and it is clear that episodes are infrequent and always too brief to be of clinical importance. Accordingly, warfarin should only be discontinued in patients whose prompt and correct recognition of episodes has been repeatedly documented and in whom self checking of the pulse twice a day has become a regular part of their health routine, wherein they contact their physician as soon as a persistently irregular pulse is noted.

Fortunately, in the near future, warfarin use is likely to be replaced in most patients with the exciting class of agents now under development known as oral thrombin inhibitors. Furthest along appears to be the drug known as ximelagatran (Exanta, AstraZeneca). Ximelagatran is being studied in the therapy of venous thrombosis, the prevention of venous thrombosis and pulmonary embolism, and the therapy of AF; it is being compared with standard anticoagulant regimens in these situations.8,9

Ximelagatran is an oral agent that is given in the same dose in all subjects, has a short half-life (allowing it to reach therapeutic levels in a day), has no drug or food interactions, and requires no anticoagulant blood test monitoring during its use. It appears likely (though not definite) that this agent will be added to the clinical armamentarium by the middle of this decade.

Sinus Rhythm Control

The fourth of the issues to consider during the approach to AF, as noted previously, is the issue of sinus rhythm control - whether or not to pursue the restoration and maintenance of sinus rhythm or leave the patient in AF and, if sinus rhythm is to be pursued, how best to help maintain it.

There are only two general reasons to treat patients with any disorder - to make them feel better and/or to make them live longer. As previously noted, for patients with AF who are symptomatic despite ventricular rate control, sinus rhythm should become the target of therapy, and the choice of which AAD(s) to select and which to avoid has clearly become defined by the algorithmic approach published in the American College of Cardiology (ACC), American Heart Association (AHA), European Society of Cardiology (ESC), Association of School Psychologists (NASPE) and other similar internationally developed guidelines.3 In this arena, however, investigational antiarrhythmic drugs are under development that offer the promise of more convenient dosing, lower toxicity, fewer drug interactions, and/or better tolerance.

These include azimilide (Stedicor, Procter & Gamble), dronaderone (Sanofi-Synthelabo), piboserod (GlaxoSmithKline), and others not yet as far along in their development. As (and if) they become available, the details of their clinical trials and the clinical trial databases should allow them to fit effectively into the recommended algorithms.

More problematic has been the issue of whether to pursue sinus rhythm goals in AF patients whose QOL is acceptable after attainment of ventricular rate control and who are appropriately anticoagulated.Will NSR in itself extend their life expectancy? Teleologically, we might believe that NSR, the native rhythm of our birth, should be better for us than AF; but in AF patients, NSR usually comes only with the application of some therapy (drug or procedure) whose risks may or may not offset any potential benefit of sinus rhythm itself. To examine this issue, five trials have been conducted (see Tables 1 and 2).10-17 Three were small pilot studies and two were larger trials. They included studies known as Strategies of Treatment of Atrial Fibrillation (STAF), Pharmacological Intervention in Atrial Fibrillation (PIAF),HOT CAFÉ (a Polish study published so far only in abstract form without definition of the acronym), Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE), and Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM). Each of these has been presented at a major scientific meeting; STAF and HOT CAFÉ have been published in abstract form; PIAF, RACE, and AFFIRM18,19 have been published as full manuscripts.10-17

STAF compared outcomes in two randomly assigned groups of 100 patients, one group assigned to a strategy of rate control and one assigned to a strategy of rhythm control (cardioverted and then maintained on an AAD). There was no difference in the primary end point events (composite of total mortality, stroke, emboli, and cardiopulmonary resuscitation) or in secondary endpoints (LA and LV size by echocardiography, syncope, hospital admissions, QOL scores, and heart failure) except for more hospitalizations in the rhythm control arm. Of note, however, only 23% of the patients assigned to the rhythm control arm maintained sinus rhythm at three years (despite up to four AAD trials), and most events in this arm of the trial occurred while the patients were in AF.

PIAF compared outcome in 252 patients randomized to a rate control strategy (with diltiazem being the first agent tried) versus rhythm control (using amiodarone as the first agent tried) with a followup of one year. There was no difference in adequate symptom reduction, QOL scores, or mortality between the two arms, whereas amiodarone provided a longer six-minute-walk test but also led to more hospitalizations and a higher rate of adverse effects requiring discontinuation of therapy.

HOT CAFÉ compared outcome in 205 patients randomized to a rate-control strategy versus a rhythm control strategy (cardioverted, then sequentially tried on disopyramide, propafenone, sotalol, and amiodarone as needed). After one year, 75% of the patients in the rhythm control arm were in sinus rhythm. However, the rhythm control arm had more hospitalizations and more strokes, while New York Heart Association (NYHA) heart failure class improved in both groups. There was no difference in mortality.

RACE was a prospective, randomized trial of rate control (n=256 patients) versus electrical cardioversion and rhythm control (n=266 patients) for persistent AF. Total mortality was significantly lower in the rate control arm (17.2%) than in the rhythm control arm (22.6%), especially in patients with hypertension. In those patients, total mortality, emboli, or other severe complications occurred in 19% versus 31%.

AFFIRM was the largest of the five trials, randomizing 4,060 patients to a rate control versus rhythm control strategy. Anticoagulation was strongly encouraged in both arms. Patients had to be at least 65 years old or have risk markers for adverse outcome in AF so that endpoints were likely to be seen. Total mortality was the primary outcome. The AF could be persistent or paroxysmal. Mean follow-up was 3.5 years. Most patients were male (61%), had underlying structural heart disease, and had had recurrent AF before enrollment. Overall, 24% had a reduced left ventricular ejection fraction. In the rate control arm, digitalis was used in 51% of patients, ├ş-blockers in 49%, and calcium channel blockers in 41%. In the rhythm control arm, amiodarone was used in 39%, sotalol was used in 33%, and 29% received a class I AAD (class I drugs were dropped from assignment partway through the trial). Ultimately, amiodarone was used in over 60% of the rhythm control patients. AV node ablation and pacing were used in about 5% of the rate control patients. The probability of being in normal sinus rhythm at the one- and five-year visits, respectively, was 81% and >60% in the rhythm control arm and 42% and 38% in the rate control arm. Successful rate control (meeting rest and ambulatory criteria) was 63% at one year and 80% at five years. Therefore, success with NSR decreased over time and success with rate control increased. Cross-over was greater in the rhythm control to the rate control arm (20% at two years, 37% at five years) than in the rate control to the rhythm control arm (9% at two years, 12% at five years). Analysis was by the intention-to-treat (ITT) approach. Total mortality was higher in the rhythm control arm than in the rate control arm (356 versus 306 patients; P=0.058).

Moreover, there were more ischemic strokes in the rhythm control arm (7.3% versus 5.7%), probably because warfarin was often discontinued after attainment of persistent sinus rhythm according to clinical judgment. Most of the embolic strokes (65/84) were with an INR <2.0 or off warfarin. The implications, as stated earlier, are generally not to discontinue anticoagulation. There were more hospitalizations, bradycardic arrests, and torsades de pointes in the rhythm control arm, while QOL scores and major bleeds were similar in the two arms. An on-therapy analysis of events has not yet been presented, but would be of interest given the STAF observations.

If these five trials are examined in composite, they appear to have taught us that a strategy of rhythm control, in contrast to rate control, is associated with more hospitalizations, greater cost, minimally better symptom relief, and a tendency toward more strokes and greater total mortality, using current therapies. Hence, rate control is an acceptable primary therapy when patients are rendered comfortable with this approach, and rhythm control should be pursued when symptoms are sufficient to dictate pursuit of NSR despite the risks now demonstrated to be present with this strategy. None of the studies revealed greater survival or lower embolic risk with NSR, despite teleologic assumptions.

Whether or not these trials would have had the same results had the AADs, now under investigation, been used instead of those now available, or had curative ablative procedures been widely applied in place of AAD therapy, warfarin anticoagulation been appropriately continued, or an oral thrombin inhibitor been available, cannot be known. What is certain is that in these trials, using current treatments, no demonstration of a survival benefit from a strategy of sinus rhythm was apparent; rather, a risk may exist. Consequently, one may interpret them as indicating that a strategy of allowing AF to continue so long as it is rate-controlled, anticoagulated, and well tolerated is a reasonable and medically acceptable strategy. When symptom relief demands, NSR may be pursued, but it does, in fact, require close attention to the approaches used, as the international guidelines now dictate. Alternatively, one may interpret the trial outcomes as a failure of the strategy to maintain NSR, rather than of sinus rhythm itself. This interpretation is supported by the fact that the trial results were interpreted mainly by an intention-to-treat approach. Also, many patients failed to maintain NSR and many events in the patients assigned to the rhythm control arms actually occurred during a period of AF. The hope remains that the development of newer drugs and the maturation of ablational approaches as a cure of AF will provide the additional benefit we continue to seek. Ôûá

This article has been reprinted with permission: Reiffel, J A, ÔÇ£New Developments in Atrial Fibrillation:, Cardiology Special Edition,Volume 9, number 1, 2003.

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