Atrial fibrillation (AF) is the most frequent serious arrhythmia encountered in clinical practice. It is usually symptomatic; can reduce quality of life; commonly results in hospitalization; typically requires multiple drugs in its treatment; and can result in heart failure, embolization and its consequences, and death. Even when AF itself does not directly provoke symptoms leading to its awareness by the patient, it may still result in tachycardia-induced cardiomyopathy, embolic phenomena, and mortality.This 'silent' or 'asymptomatic' AF occasionally exists in the absence of symptomatic AF (<20% of AF patients) or may coexist with alternate periods of symptomatic AF (up to 70% of AF patients).1,2 Generally, but not consistently, periods of asymptomatic AF have slower ventricular rates than symptomatic periods, whether spontaneously or via rate-control agents).Asymptomatic AF also appears to occur relatively frequently following ablative procedures targeting the elimination of AF, speculatively due to incomplete success but alteration of sensory nerve signals.
Therapeutically, the management of AF is a challenge to even the most sophisticated practitioner, and confronting the challenges of AF can be difficult at best to exhausting on occasion. Such challenges revolve around issues of:
- rate control versus rhythm control as the primary management approach in the patient at hand;
- methods of rate control and/or rhythm control;
- definitions of therapeutic success;
- anticoagulation; and
- the use of 'ancillary' pharmacologic agents.
In an attempt to confront these challenges, perhaps we would do best to address them one by one.
Rate Controlversus Rhythm Control
Most clinicians are likely now aware that in the past half-decade or so, multiple clinical trials have been performed in a variety of AF populations to assess whether the pursuit and attainment of sinus rhythm affords a benefit to the AF patient in contrast to the benefits attained using a strategy of rate control as the primary management goal. These trials included the small Pharmacological Intervention in Atrial Fibrillation (PIAF), Strategies of Treatment of Atrial Fibrillation (STAF), and How to Treat Chronic Atrial Fibrillation (HOT-CAFÉ) studies, the intermediate-sized A Comparison of Rate Control and Rhythm Control in Patients With Recurrent Persistent Atrial Fibrillation (RACE) trial, and the large Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial.3-7
Although the outcome end-points in each of these trials differed somewhat, as did the nature of the population enrolled, the common themes were that:
- there was no survival benefit to a strategy of rhythm control using currently available therapeutic approaches;
- both rate control and rhythm control could improve the quality of life (QOL) of the AF patient, but not to that of the healthy normal subject; and
- when a risk-marker for embolism exists such that the AF patient requires anticoagulation with warfarin, the risk of embolism is generally not sufficiently reduced by the apparent attainment of sinus rhythm such that anticoagulation can be discontinued.6,7
Many practitioners appear to have taken these results to mean that a strategy of rate control (with anticoagulation as indicated) can now be considered as an acceptable primary therapeutic end-point for most, if not all, AF patients. As a result, in the author's center, referrals for both cardioversion and antiarrhythmic therapy (taking all antiarrhythmic approaches together) have fallen in the wake of these trials. Unfortunately, that is not the proper message to take away from these trials and one of the challenges we need to face is correcting this misconception. In trials such as AFFIRM and the others detailed above, it must be understood that in order for a patient to be enrolled in the trial, the patient must be expected to have a reasonable likelihood of tolerating rate control as adequate for QOL since there is a 50% likelihood that they would be randomized to that arm of the trial. Consequently, for the large body of AF patients who have already declared themselves still symptomatic despite rate control, exclusion from such a trial would have occurred, and the trial results, as least insofar as QOL is concerned, cannot be taken to apply to them. Similarly, in these trials, anticipated end-points were needed in order to assess a difference in outcome between therapy arms and, in order to assure such end-points, the trials were enriched with patients who had substantial risk factors for complications of their AF or its therapy (such as advanced age, comorbid cardiovascular conditions and risk markers, prior embolism, and the like).
Since the risk of proarrhythmia from antiarrhythmic drugs is enhanced by structural heart disease (SHD), it cannot be assumed that the risks from antiarrhythmic drug therapy as seen in these trials would necessarily exist in the younger, healthier AF patient, were they given an antiarrhythmic drug that has a low risk of either proarrhythmia or organ toxicity in patients without SHD.
This is an important consideration since, in AFFIRM, the benefits of sinus rhythm in reducing mortality that were evident in a sophisticated sub-analysis (a risk-reduction of approximately 45%) were almost exactly counterbalanced by an increased mortality risk from the use of antiarrhythmic drugs (mainly amiodarone) in the relatively sick patient population enrolled.8
These risks cannot be assumed to exist were the patient a younger individual without SHD given an antiarrhythmic drug to maintain sinus rhythm, such as a class IC antiarrhythmic drug. Consequently, AF patients who remain symptomatic despite rate control, patients without significant SHD who are young and have potentially decades of AF ahead of them, and some others as well, should still be treated with sinus rhythm as the goal. Depriving the younger group of patients the opportunity to hold sinus rhythm, at least for awhile, would likely result in irreversible adverse atrial remodeling and reduce the probability that they could achieve sinus rhythm in the future as newer therapeutic options become available.
Additionally, should such new antiarrhythmic drugs now under development reach the market, it cannot automatically be assumed that the same adverse profile offsetting the benefit of sinus rhythm as was seen in AFFIRM and the other recent pivotal trials will exist with their use, too. This may become particularly relevant if dronedarone, an amiodarone congener that so far has not shown pulmonary or thyroid toxicity in its pivotal trials, or if 'atrial-specific' agents with little or no ventricular electrophysiologic effects and therefore no ventricular proarrhythmic risk, receive regulatory agency approval.
Methods of Rate Control and/or Rhythm Control
As noted above, rate control may be a primary therapeutic option in some patients with AF and, in patients in whom rhythm control is selected as the primary therapy to be employed, rate control is almost always concomitantly utilized.9 In the overwhelming majority of patients, rate control can be achieved with the use of beta blockers, verapamil, diltiazem, and/or digitalis. Beta blockers and the two calcium channel blockers are generally the most effective choices for monotherapy. Digitalis, which works largely through vagomimetic effects on the atrioventricular (AV) node, is generally less effective as monotherapy in active individuals and is more apt to work when used as a single agent in the elderly patient or in the patient with heart failure (when beta blockade is also indicated for reasons other than rate control). The adequacy of rate control can be determined utilizing ambulatory monitoring, such that rates during AF approximate the rates seen during sinus rhythm at comparable levels of activity.
The challenge of rate control comes in the form of the occasional patient who does not respond to the aforementioned agents. In these individuals, the addition of a sympatholytic drug, such as clonidine, has occasionally been useful, while in most other refractory patients, the creation of AV block via AV nodal ablation, coupled with the implantation of a rate-responsive ventricular pacemaker, becomes the therapy that achieves the rate-control goal.9With such drugs and procedures, rate control should be achievable in 100% of AF patients. In contrast, the challenges involved in employing a rhythm control strategy are more difficult and complex.
Rhythm control requires the use of an antiarrhythmic strategy, which may entail an antiarrhythmic drug or sequence of antiarrhythmic drugs and/or an ablative intervention. Because antiarrhythmic drugs and procedures can carry with them the potential for life-threatening risk in the form of drug-induced organ toxicity or ventricular proarrhythmia, or in the form of an interventional complication, and because such risks may exceed the risks to the patient from adequately rate-controlled and anticoagulated AF, guidelines and algorithms have been formulated by the American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC)/Heart Rhythm Society (HRS).
These guidelines indicate which agents have the lowest risks, as stratified by the nature and severity of any underlying structural heart disease, the strata in which to consider them (first-line, second-line, third-line) and, similarly, at what point non-pharmacologic ablative therapy is reasonable to consider in those patients in whom it has been determined that sinus rhythm should be sought and maintained.10,11 Unfortunately, assessments of physician practice patterns and physician prescribing patterns indicates that these well-intentioned, data-driven, thoughtful, safety-first guidelines are frequently not being utilized by the practitioners caring for AF patients.12 These non-complying practices appear to occur for a variety of reasons, including lack of awareness of, lack of appreciation of, and/or lack of agreement with the guidelines; on-going old habits; inconveniences involved in hospitalization and/or follow-up requirements that are necessary with some specific agents and circumstances; financial conflicts of interest; concerns with the processes involved in defining SHD; and other reasons as were recently detailed by Reiffel and Naccarelli.12
One consequence of these concerns and patterns is the substantial excess use of amiodarone as a first-line therapeutic choice.12 Arguably, one of the largest challenges faced in improving the management of the patient with AF is to improve the compliance of practicing physicians with the sanctioned AF guidelines.11 These AF guidelines were first published in 2001 and were revised and republished in 2006. They continue to focus on patient safety as the prime consideration and, in general, this goal should take precedence over physician inconvenience, procedural reimbursement, old habits, anecdotal experience, and the like.
The challenge will be to better educate practitioners about this sanctioned strategy. Nonetheless, it needs to be recognized that even these guidelines have limitations that have challenged their implementation in all seemingly appropriate circumstances. For example, when there are several choices at the level of a first-line or second-line option, the guidelines do not provide certain guidance as to how to select among the options available. How do prior drug exposure and experience, specific heart disease, gender, and the like come into play when the selection process become more empiric than solidly data driven.13 The challenge is to continue to manage patients in the context of further clinical trials that are designed to address those areas for which important clinical questions remain. The challenge will also be to modify and adapt the recommendations made as drugs now under development, that are different to currently available agents in mechanism and/or safety/tolerance, become available and as improvements in ablational techniques evolve. Thus, fluidity will be required in practice patterns over then next five to ten years as these improved options become clinical practice realities. Hopefully, given the efficacy limitations of current drug and device therapies (40-70% in most observations), the future will also bring more effective as well as safer options. This is the challenge for pharmaceutical and non-pharmacologic industrial partners.
Definitions of Therapeutic Success
For many dysrhythmic conditions, therapeutic success is measured by the elimination of any recurrence of the condition. Pharmacologic treatment of sustained ventricular tachyarrhythmias or pacemaker therapy of complete heart block would both fall into this category. This approach, however, is neither essential nor realistic for other conditions, including AF. Complete elimination of all AF episodes in patients who have had AF unassociated with a reversible precipitant is highly unlikely with current therapeutic options.
Rather, the definition of successful rhythm-control therapy in the AF patient is best recognized as a reduction in the frequency, duration, and severity of events such that the patient's QOL is rendered adequate.14 For example, consider the patient who, prior to therapy, has episodes of paroxysmal AF (PAF) several times a month, lasting for up to 36 hours, and had two persistent AF events in the last two years that required cardioversion. If, on 1C antiarrhythmic drug therapy or following ablation, he then has three episodes of PAF of no greater than one hour during the next year, therapy should be considered as successful, rather than as a failure. Unless the patient was still substantially disturbed by the nature of the residual PAF pattern, the preventive drug regimen should be continued rather than changed, or repeat ablation not pursued. For physicians this would be analogous to recognizing that occasional, nitroglycerine- responsive angina is acceptable in most patients during chronic drug therapy and that coronary angiography and interventional therapy in hopes of eliminating any recurrent angina is not needed based solely on the presence of an occasional anginal episode.
The challenge is to change the perception of physicians from the pursuit of perfection to the pursuit of realistic goals in the suppression of AF in most patients.Moreover, if a change in therapy is felt necessary, practitioners should generally first increase the dose of the drug being employed, if possible, rather than change to another agent. Often, in clinical practice surveys, only low doses of a drug is tried before that agent is discarded as a failure, and this pattern substantially reduces the number of effective drug options that could be considered.
Anticoagulation is perhaps the largest challenge faced in the management of the patient with AF. As detailed in the ACC/AHA/ESC guidelines manuscripts10,11 and elsewhere:
- multiple studies have documented that stroke and other systemic emboli are significant complications in many AF patients;
- risk markers have been recognized and well categorized that, when present, may indicate an annual risk of as high as 4% to >10% but when absent indicate an annual risk of <1-2%;
- well-performed clinical trials have repeatedly taught us that in patients with a significant risk profile, anticoagulation with warfarin is highly effective in reducing the risk of embolism to almost the low risk present in the patient without risk markers.
Little debate exists any longer about the efficacy and benefit of warfarin anticoagulation in such patients and the guidelines indicate its use in AF patients in whom high-risk markers are present.10,11 No trial has ever shown that aspirin and/or another platelet inhibitor compares effectively with warfarin in such patients. Nonetheless, physicians appear to underutilize this life-saving and life-salvaging therapy in 40-60% of AF patients for whom it appears to be indicated.15,16 Reasons appear to include:
- fear of bleeding on warfarin;
- the patient is too old;
- difficulties in regulating the dose such that the international normalized ratio (INR) of the prothrombin time consistently remains in the therapeutic range, whether due to dietary variation, interaction with other drugs and supplements, genetic factors, or formulation substitution;
- over-enthusiasm for aspirin;
- substantial unreimbursed, time-consuming efforts required for anticoagulation management; and
- other factors.
In contrast to these excuses, recent well-performed clinical trials comparing warfarin with the investigational thrombin inhibitor ximelagatran have shown that the risk of bleeding with well-controlled warfarin therapy is quite low, including major hemorrhage <3%/year with intracerebral hemorrhage under 0.5%/year.17,18 Moreover, INR variability can be minimized with insistence upon dietary consistency week to week, avoidance of potentially interacting herbals and supplements, anticipatory dosing alterations when possible interactions of other drugs with warfarin are likely, insistence on formulation consistency with warfarin dosing (such as by using only a branded preparation),19 and utilization of a specialized anticoagulation clinic, nurse, or physician.Additionally, it needs to be recognized that older age (<75-80 years) is a far greater risk for embolism in the absence of warfarin than it is a risk for excessive bleeding in the patient given warfarin.
Accordingly, a major challenge in the management of patients with AF is to improve the utilization of warfarin anticoagulation in patients at increased risk for an embolic complication of their AF. Both better physician and patient education are required if this goal is ever to be achieved. Even if investigational anticoagulants now under study ultimately become available and even if they have a better perceived risk/benefit ratio, the under-recognition of embolic risk and over-perception of bleeding risk will still be factors that have to be eliminated through physician education in order for adequate anticoagulation to be employed.
Finally, and in addition, physicians will have to recognize that, contrary to their wishes, the restoration of sinus rhythm in AF patients with risk markers for embolism has not been demonstrated to reduce embolic risk sufficiently to allow discontinuation of anticoagulation. In both AFFIRM and RACE, for example, the incidence of embolic stroke was higher in the rhythm-control arms than in the rate-control arms, and was particularly associated with either the discontinuation of warfarin or with INR values below the therapeutic range of 2.0-3.0.6,7 Recurrence of unrecognized ('silent') AF, and/or residual risk from atrial mechanical dysfunction and/or persistence of a chemical thrombotic milieu in the setting of atrial disease despite electrical normality are likely contributors to this phenomenon. These issues would also be likely in patients who are treated with AF ablation and, in studies to date that have utilized ambulatory monitoring following ablation, a substantial incidence of residual, though 'silent' AF recurrence has been detected.20
In association with the underuse of warfarin anticoagulation, inappropriate discontinuation of previously utilized warfarin therapy, and/or under-recognition of the presence of or recurrence of AF (including 'silent AF'), it has been estimated that 60,000 to 105,000 embolic strokes occur per year in the US in AF patients.This devastating complication is clearly under physicians' control to reduce if adherence to anticoagulation guidelines were to occur! Perhaps some day, although not now a reality, earlier recognition of the presence of AF and earlier effective intervention will allow a cure for AF prior to the development of irreversible adverse atrial remodeling and the hope that in that era the elimination of AF will, indeed, carry with it the elimination of the need for on-going anticoagulation.
Use of 'Ancillary' Pharmacologic Agents—The Enticing Data for ACE Inhibitors, ARBs, Statins, and Fish Oil
In the past half decade or so a series of reports have appeared suggesting that in some AF patients the progression of AF (e.g. frequency of PAF events, development of persistent AF in patients with prior PAF, recurrence of AF subsequent to a cardioverted episode of persistent AF, and the like) can be reduced in the presence of/by the employment of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), statins and/or purified omega- 3 fish oil.21-30 The efficacy data for the ACE inhibitors and ARB agents appear strongest in patients who have hypertensive heart disease and/or systolic heart failure.21,22
Investigational data suggests they likely act by reducing the adverse atrial remodeling effects, including inflammation and fibrosis, that occur in these settings in response to the increased levels of angiotensin II commonly present in these conditions. Inflammation and fibrosis can produce electrophysiological changes in the atria that promote abnormal automaticity and/or conditions for re-entry. Similarly, statins appear likely to exert their beneficial effect in this arena via their anti-inflammatory actions, although this specific mechanism remains speculative rather than certain as regards their AF actions.
The mechanisms by which fish oils might exert antiarrhythmic actions are several as their electrophysiological effects are multifocal.31 To date, the precise electrophysiological actions by which omega- 3 fish oils can specifically make fibrillation in the atria more difficult to establish have not yet been adequately evaluated.
Despite an incomplete understanding of the ways in which these ancillary agents act, it is enticing that these ancillary therapies, not commonly thought of as antiarrhythmic agents, may have beneficial roles in the management of AF via actions that can alter the abnormal atrial milieu at the microarchitectural and electrophysiological level.The challenge going forward is to better understand the ways in which these agents may exert their AF suppressing effects and to learn to recognize those patients in whom they may have a role and those patients in whom they do not. For example, it has been reported that the incidence of AF is higher in patient populations with significant serum elevations of C reactive protein (CRP) than in patients in whom CRP values are normal.32,33 Is it possible that the efficacy of these agents can be predicted in a given patient by the level of this biomarker? This is a plausible hypothesis that screams to be tested.We already know that parasympatholytic agents may provide antiarrhythmic benefit in patients with vagally-mediated AF34 and hence the tailoring of ancillary therapy to a mechanistic biomarker also seems reasonable to pursue. In addition, the challenge with these agents is also to better characterize the magnitude of their effects in the presence, as well as the absence, of concomitant antiarrhythmic agents. The ARB irbesartan has been demonstrated in one trial to augment the effect of amiodarone35,36 in reducing recurrent AF following cardioversion, as has the ACE inhibitor enalapril in combination with amiodarone. This needs to be confirmed by additional study, and whether this holds true in the presence of an antiarrhythmic drug with a different mechanism of action to amiodarone, or with the use of an alternative ancillary agent, or in the setting of PAF remains to be tested. Similarly, we have no information as to whether or not the effects of these ancillary drugs are additive to each other as regards the suppression of AF. Much remains to be learned in this arena and that is one of the remaining challenges for us to confront in the management of AF.
So, stay tuned; the decade to come should be an exciting one for physicians who deal with the study of and/or management of patients with AF.