Ten Pearls for the Use of Antiarrhythmic Drugs for Atrial Fibrillation

1) Does the patient need antiarrhythmic drug (AAD) 1,2 therapy for AF?

The first question to address when considering an antiarrhythmic drug (AAD) for any patient with atrial fibrillation (AF) is: does the patient need one?3 The major purpose for AAD therapy in AF is to reduce symptoms associated with AF so as to improve quality of life of the patient. No trial, including AFFIRM,4 has shown that AADs prolong the life of patients with AF aside, perhaps from a trend in the ATHENA5 trial with dronedarone in a particular subpopulation of AF patients. In ATHENA, dronedarone did reduce AF related hospitalizations, but this has not been shown to occur with other AADs and has not been shown to occur across the entire spectrum of AF patients.

  1. Is the patient symptomatic despite adequate (monitor-verified) rate control?
  2. Prior to initiating an AAD to reduce AF symptomatology, one should first assess rate-control. If rapid rates may be the underpinning of the patient's symptoms, then rate control with a reassessment thereafter should occur before considering the addition of an AAD. Importantly, rate control should be assessed with ambulatory monitoring during daily activity. A normal apical pulse (the radial pulse during AF is not an accurate assessment of ventricular rate) with the patient on the exam table or at rest for an ECG does not provide adequate assessment of sufficient rate control – it can only tell if rate control has not yet occurred. In my experience, optimally, the rates attained will approximate the rates appropriate for sinus rhythm at the same level of activities. Many symptoms associated with AF will lessen with adequate rate control, especially, in my experience, chest discomfort, dizziness, and dyspnea. In contrast, fatigue almost always requires restoration of normal sinus rhythm for adequate relief.

  3. If asymptomatic, does the patient have a progressive concomitant disorder, or family history thereof, or risk factors for one later in life during which AF may no longer be tolerated?
  4. There are patients who may be entirely asymptomatic or have minimally bothersome symptoms – even at a young age. However, if they develop ventricular dysfunction, ventricular hypertrophy, valve disease, or the like later in life, tolerance of the rapid atrial rates with loss of atrial mechanical function and AV synchrony may no longer occur. Thus, when assessing the need for an AAD, one must consider the likely future course of the patient, not only the present status. If AF is allowed to persist for long periods (e.g., years), return to sinus rhythm if the patient becomes symptomatic later in life may no longer prove feasible due to extensive adverse atrial remodeling.

2) When should an AAD be started?

If one is considering initiating an AAD for AF, a decision has to be made as to when to start it.6-8

  1. Not with the first episode unless severe hemodynamic or heart failure symptoms were associated with it.
  2. In general, AADs should not be started during/following the first AF episode, unless the symptoms are so dramatic that a recurrence could threaten mortality or rapid hospitalization.6-7 Rather, it is preferable to establish a sense of the patient's AF pattern. Infrequent episodes may be better treated with intermittent cardioversion (especially "pill-in-the-pocket" pharmacologic cardioversion, see below) than with the burden of taking a daily AAD or with the risks associated with both drug therapy and with ablation. The frequency with which such intermittent episodes are best treated with this approach versus the frequency with which the patient should be switched to daily prophylactic therapy should be determined by the patient. It is his/her life-style satisfaction that should underlie this decision.

3) What to consider when selecting an AAD.1,2,6-8

As a general philosophy, the guidelines and algorithms that have been promulgated by the ACC/AHA/ HRS and the ESC have focused upon minimizing the risks from antiarrhythmic therapy (drug or ablative) over maximizing efficacy in so far as the selection sequence of therapy goes. AF, once rate controlled and adequately anticoagulated, should under most circumstances no longer be associated with a substantial risk for mortality or major morbidity. Thus, "the treatment should not be worse than the disease."

  1. Minimize organ toxic risk and minimize ventricular proarrhythmic risk – follow the algorithm (ACC/AHA/HRS).
  2. The ACC/AHA/HRS algorithm (updated in 2011) which focuses upon categories of heart disease lists the AADs in each heart disease category in an order (first choice options, second choice options, third choice options) meant to minimize the likelihood of ventricular proarrhythmia and organ toxicity. When there is more than one choice as a first or second or third line agent, the selection process among the AADs at any one level should focus upon minimization of these same risks, as well as upon the considerations listed below. For example, when there is no or minimal heart disease and the first line agents are considered to be dronedarone, flecainide, propafenone, and sotalol: if the patient is a female, I would avoid sotalol if possible as its proarrhythmic risk (torsade de pointes, TdP) is twice as high in women as men; or, I would not likely choose a IC drug next if another had been tried and was inefficacious. If the patient has hypertension, the selection choices are the same as for no or minimal heart disease except in the presence of significant LVH where the proarrhythmic risk of all AADs appears likely to be enhanced, other than perhaps for amiodarone. Of note, patients with hypertension should have a stress test or similar ischemia work-up since, in hypertension, coronary disease is common and if positive, they would move into the coronary artery disease section of the algorithm flow chart.

  3. Are there sinus node, AV node, or His-Purkinje disease or inotropic considerations that could alter the choice?
  4. While the ACC/AHA/HRS algorithm as charted focus attention on the minimization of organ toxic and proarrhythmic risk, the selection of an AAD must also take into consideration other concomitant considerations, such as the presence or absence of sinus node and/or conduction system disease and/or heart failure or hypertrophic cardiomyopathy. Why would one choose sotalol, for example, in the presence of sinus node or AV nodal dysfunction, or a sodium channel blocker in the presence of His-Purkinje dysfunction, when these agents could worsen such conditions respectively; rather, dofetilide could be selected. Dofetilide does not appear to possess significant risk to the sinus node, the AV or His-Purkinje system, or to inotropy. However, it has multiple drug interactions, complicated renal-based dosing,9 and significant proarrhythmic risk that make it less ideal of a choice in other circumstances. Similarly, in the presence of impaired ventricular systolic function, class IC agents and dronedarone must be avoided. Sotalol can be used if the patient tolerates beta blockade and has adequate renal function, so long as it's other cautions are followed. Hence, it is not a low LVEF that precludes sotalol; it is symptomatic failure intolerant of or inappropriate for beta blockade. Similarly, dofetilide can be used with LV dysfunction so long as renal clearance is not impaired.

  5. Are there QT issues that could alter the choice?
  6. Yes, the corrected QT interval requires assessment prior to initiating an AAD. QT prolongation, and with it the risk of TdP, can be increased by agents that prolong repolarization (the QT minus the QRS duration is the interval to focus upon). Class IC agents can prolong the QT interval but they do so by prolonging the QRS rather than repolarization itself to any significant degree, whereas potassium channel blockers and ibutilide (mixed repolarization-prolonging actions) pose the major risk for TdP. Amiodarone can cause TdP but it appears to do so with a much lower risk. In very rare patients, the QT interval is short; some data suggests that its associated risk for VF can be reduced with quinidine – which may also lessen AF and might be the preferred choice in this circumstance. If patients are given AADs that prolong the QT interval, in general, the QT should not be allowed to prolong to beyond 500 msec, and, hypokalemia, hypomagnesemia, bradycardia, and the concomitant administration of any other drug that might lengthen the QT must be avoided. Simultaneous administration of eplerinone, sprionolactone, ameloride, or dyrenium may be of assistance in this regard if necessary.

  7. What dose should I choose?
  8. When choosing the initial dose of an antiarrhythmic drug, generally, the lowest possibly effective dose is chosen first, followed by dose escalation if needed in response to AF recurrence patterns following attainment of the steady state of the previous dose. Some agents, such as amiodarone, require a loading period rather than simply initiation of the first maintenance dose level. Importantly, there are exceptions to this general statement. Sotalol (d, l-sotalol) has two different dose response curves for its beta blocker and its class III actions. In the presence of normal renal function, sotalol's class III effects only begin at doses of 80 mg bid and increase linearly thereafter. Accordingly, beginning at 40 mg bid is really only testing it as a beta blocker in such circumstances. Its beta blocker effects tend to plateau after reaching a total daily dose of 240 mg. Dofetilide, which must be started in-hospital, is dosed according to a detailed renal and QT-response dependent algorithm that starts at 500 mcg bid (assuming normal renal function) and then may move to lower doses depending upon the QT behavior.9 Unfortunately, many physicians appear to give up on an AAD drug after it fails at its lowest dose, rather than dose-escalate appropriately.

  9. Are there drug interactions that might influence the choice?
  10. As with any other type of drug, an AAD may have important interactions with selected co-administered prescription drugs and non-prescription agents. If more than one AAD is a reasonable choice for the patient at hand, it would usually be best to choose the one with the least likelihood of untoward interaction potential, if possible. Examples of such considerations follow: The AADs with the greatest number of potential drug interactions are amiodarone and dofetilide; each of which can interact with numerous drugs by multiple mechanisms. I usually assume when I start amiodarone, that it will interact with almost every other drug the patient may be taking, and I modify their doses accordingly. Verapamil, and to a lesser degree, diltiazem can raise dofetilide levels. Importantly, when dealing with AF, AAD interactions with anticoagulants should never be overlooked. Amiodarone predictably increases the effect of warfarin, and serum concentrations of dabigatran and the factor Xa inhibitors. Dronedarone can increase warfarin effects (indirectly) and does increase the serum concentrations of dabigatran and the factor Xa inhibitors. Propafenone can increase warfarin's effects; in contrast, this is not expected with flecainide. Sotalol is not known to interact with any of the currently used anticoagulants and dofetilide has not yet been tested in combination with dabigatran or factor Xa inhibitors so far as I know. Also, when using a class III AAD, one must anticipate electrolyte effects and possible TdP risks if a diuretic is co-administered with it. Additionally, interactions that cause an increase in the serum level of digoxin can occur with amiodarone, propafenone, dronedarone, and quinidine. Finally, the above interactions are all pharmacokinetic in type. The prescriber must also keep in mind potential pharmacodynamic interactions, such as additive depressant effects on the sinus and AV nodes by combining any rate control agent with amiodarone, dronedarone, sotalol, and possibly propafenone.

4) Antiarrhythmic drug history:

When starting an AAD, consideration of the response to any prior AAD(s) may be important. In general, the response rate to any AAD for any arrhythmia tends to be higher if it is the first drug tried than it is if it is tried subsequent to a prior AAD failure due to inefficacy. While this is not so universally true that trying drugs serially is of little value, it is one underpinning of the positioning of ablation in the ablation guidelines. That is, ablation may be considered after failure of 1 or more AADs (not only after the failure of multiple AAD trials).

  1. Has the patient tried an AAD previously?
    • Was it efficacious or not?
      In my experience, if a drug within the same drug class (e.g., IA, IC, III) has been effective, but was stopped due to intolerance, in general, choosing another drug within the same drug class is appropriate.
    • Was it tolerated or not?
      Conversely, if a prior drug produced a proarrhythmic TdP event, I would rarely try another drug with the same anticipated risk. However, if the intolerance was due to a nuisance side effect rather than proarrhythmia (e.g., nausea, diarrhea, constipation, rash, etc.), then it is reasonable to try another agent within the same AAD drug class. For example: disopyramide may work (major side effect is constipation) in a patient who did not tolerate quinidine due to diarrhea, or propafenone may work in a patient who stopped flecainide due to tremor.

5) Consider "novel" antiarrhythmics.

In patients where an AAD is needed for AF and traditional AADs have failed or have not been tried due to specific medical concerns about their risks, use of other available drugs that have antiarrhythmic actions but for which such use would be "off-label" may be considered. Recently, this has been seen with increasing experience with ranolazine.

  1. Ranolazine10-13
  2. Ranolazine is an antianginal drug whose major mechanism of action is blockade of the late sodium current. It also has weaker effects on Ikr. In its pivotal trials for approval for angina, ranolazine was found to reduce ventricular and atrial arrhythmias in patients with acute coronary syndrome.10 Ranolazine's major side effects are constipation and dizziness, but it has been devoid of organ toxicity and proarrhythmia. In fact, ranolazine has inhibited the development of TdP in multiple models, and TdP has not been reported in association with its use despite a small anticipated increase (<10 msec) in QT interval. Over the last 4 years,11-13 the literature has revealed the successful use of ranolazine as "pill-in-the-pocket" therapy (see below) to produce pharmacologic cardioversion; as preventative therapy for post cardiac surgery AF; and as chronic prevention for AF with a daily maintenance regimen, including in patients who have "broken through" other previously effective AADs, using the same doses as are used for angina (500-1000 mg bid).

6) Consider "hybrid" therapy:

There may be times when therapy with an AAD for AF is ineffective, but a "hybrid" approach may work. Such hybrids may include the use of medication combinations, AADs combined with implantation of a pacemaker or a defibrillator, or AADs retried following an attempt at an ablative cure.

  1. Anticholinergic plus AAD:
  2. In some circumstances, AF may be triggered by parasympathetic activation. Most typically, this is seen in younger patients with apparently "lone" AF that appears in association with sleep, or with bending, or the post-prandial state, or other periods of high vagal tone. In my experience, combining an AAD with an anticholinergic agent may improve efficacy as compared with the AAD alone. Rarely, simply the use of the anticholinergic agent alone, such as just before bedtime in patients with nocturnal (but not sleep-apnea triggered) AF may be sufficient for good rhythm control. Similarly, I have used disopyramide (a class I AAD that also possesses potent anticholinergic effects) as monotherapy, but only given at bedtime, rather than in its typical bid schedule.

  3. Sympatholytic plus AAD:
  4. In other circumstances, AF may be triggered by periods of high sympathetic tone – such as if it is consistently triggered by physical or emotional stress. In these circumstances, beta blockers alone may suffice, or, they may be effective when added to an AAD that had previously failed when used alone. And, as noted earlier in this discussion, one may have to dose-range the beta blocker just as one may have to do with the AAD in order to optimize the regimen. At this point I should also point out that in many circumstances, catecholeamines can reverse the antiarrhythmic actions of an AAD, including those on conduction, repolarization, and refractoriness. Accordingly, combining a beta blocker with an AAD may enhance the efficacy of the AAD even if the history is not clearly suggestive of a sympathetic nervous system trigger. Similarly, verapamil may do the same via its inhibitory effects on sympathetic ganglia – an action that is not seen with diltiazem. Notably, when reviewing clinical trials of an AAD, in considering the outcomes, one should accordingly note whether the use of beta blockers is similar or not across the limbs of the trial.

  5. AAD combinations:
  6. Not tried frequently, combinations of AADs have been reported to be effective and tolerated when one AAD alone has failed. While this approach has been more common in the therapy of ventricular tachyarrhythmias, the literature (as well as my own experience) does contain reports of AAD combinations for AF, including, for example: amiodarone plus quinidine, propafenone, disopyramide, ranolazine; sotalol plus propafenone; dronedarone plus ranolazine; and others. When trying such combinations, one must consider both the potential pharmacokinetic interactions between the drugs as well as their combined pharmacodynamic interactions. Hence, for example, when amiodarone is tried in combination with another AAD, appropriate caution would suggest that the second drug be given in low to intermediate dose but never full dose; or, extremely cautious monitoring of the QT interval would be needed if amiodarone were to be combined with a class IA or III AAD.

  7. AAD plus a pacemaker or a defibrillator:
  8. In patients in whom an AAD is needed but a sinus node or conduction system disorder is present prior to or is precipitated by the AAD, pacemaker implantation followed by use of the AAD may be a reasonable alternative to consider. In a similar vein, patients with ICDs may also have AF episodes that require initiation of an AAD. There is no specific algorithm for AAD selection in such circumstances. However, in both of these cases consideration must be given to the effects by which AADs may interact adversely with the device. AADs may increase pacing or defibrillation thresholds. As a general comment, this is seen predominantly with class I agents and amiodarone, whereas sotalol, dofetilide, and dronedarone have not resulted in such changes. Also, amiodarone and potent class I AADs can alter ventricular tachycardia rates (slow them), or can alter the slew rates on their electrograms such that these ventricular arrhythmias are no longer recognized by the device unless retesting and reprogramming has been undertaken.

  9. AAD after AF ablation:
  10. Ablation for AF is often ineffective as monotherapy and reinitiation of an AAD may be necessary to provide satisfactory relief of AF for the patient. There is no specific algorithm for AAD selection in this circumstance and there have been no large-scale prospective comparison trials of AAD efficacy in the post-ablation patient. Hence, AAD selection should generally follow the same process it does in the absence of ablation. Notably, following ablation, success may be seen with the same AAD that failed prior to the ablation, due to an alteration in atrial substrate that then becomes responsive to the drug's actions.

  11. Flutter ablation plus AAD for AF:
  12. Atrial fibrillation and atrial flutter often present in the same patient. The flutter may be an independent primary arrhythmia, or flutter may occur as a result of the actions of an AAD that were insufficient to prevent atrial arrhythmias altogether but were sufficient to alter the atrial substrate such that fibrillation cannot be maintained but rather that it is converted to atrial flutter with its slower atrial rate and larger single reentrant loop. This is most commonly seen with class I AADs and amiodarone. It would not be anticipated with sotalol or dofetilide which do not directly alter atrial conduction. In such circumstances, one option to the managing physician is to ablate the flutter, and then continue the AAD for the suppression of AF.

7) Verify efficacy:

As with any drug, verification of efficacy is an appropriate part of the follow up of the patient. The commonly used endpoint in clinical trials14 is the time to first recurrence of AF. However, this is an inappropriate measurement standard to use in clinical practice.

  1. What is the definition of effective therapy?
  2. For the patient with AF, the goal should be the reduction in the frequency, duration, and severity of episodes; it is not necessarily the abolition of all AF. This is akin to the treatment approach to angina. For example, for a patient who has had persistent AF that has required repeated DC cardioversions, but now has only infrequent PAF, the AAD should be considered a success. Similarly, for the patient with frequent PAF, lasting many hours to a couple of days prior to AAD therapy who now has only occasional and relatively brief PAF (i.e., a reduction in overall AF burden), the AAD therapy should be considered successful, even if the first event were at no longer an interval that was typical for the patient's previous inter-event intervals. It is the patient who should provide to the physician the guide as to whether the pattern is now tolerable or remains intolerable, such that for the latter, a dose-escalation or a change in therapy may be appropriate. Importantly, however, for specific clinical trials with specific goals, the definition of success for a therapy may differ from the above patient-specific consideration. In a clinical trial, for example, the outcome being studied might specifically include the time to first AF recurrence, the time to first symptomatic AF recurrence, a specific degree of reduction in total AF burden or length of episodes, or the like. These should not be confused with the appropriate goal in the individual patient. Also notable with respect to the definition of AAD efficacy, even in patients with AF, monitoring trials have shown a relatively poor correlation between symptoms sensed by the patient (including palpitations) and the presence or absence of AF. Thus, in some patients, the patient can accurately tell whether his/her AF is gone whereas in others, one might have to use electrocardiographic ambulatory monitoring verification.

8) AADs to facilitate direct current cardioversion.1,2,15

Electrical direct current (DC) cardioversion is commonly employed to terminate persistent AF. In some patients, however, even using biphasic devices, DC cardioversion is unsuccessful in terminating the AF. In these circumstances, selected AADs may be used to facilitate a repeat attempt at DC cardioversion as they can reduce the energy needed to defibrillate. These include ibutilide, dofetilide, azimilide (an investigational class III AD), and ranolazine.

9) AADs to produce pharmacologic cardioversion / reduce PAF duration.1,2,15

For some patients, DC cardioversion may be unwanted or inconvenient. They may not have ready access to a facility performing the procedure, for example, or their physician may be unavailable. They may not want to undergo the sedation that is required or the discomfort that may follow the procedure. For such patients, especially if the AF episode has begun only recently (hours or 1-2 days), cardioversion may be successfully attained pharmacologically, thus avoiding the need for a DC shock. Pharmacologic cardioversion using an intravenous agent, such as ibutilide, can be effective, but it still requires administration in a monitored setting. Thus, of growing interest has been the use of oral AADs specifically administered to produce pharmacologic cardioversion of persistent AF (or shortening the duration of a symptomatic episode of longer-lasting PAF). These include immediate-release propafenone (600 mg as a single dose) or flecainide (300 mg as a single dose) in patients without significant structural heart disease. Some experience also exists for ranolazine, 2000 mg as a single dose (or two 1000 mg doses within 4 hours of each other), in patients with or without structural heart disease. For propafenone or flecainide, if needed, the single dose may be followed once by a half dose 8 hrs later. These doses all assume that the patient is not already on an AAD. If the patient is already taking an AAD, these "pill-in-the-pocket" regimens are not appropriate as there is no significant experience in such circumstances – with one exception. If a patient is taking propafenone, but not at the maximal daily dose (which would be 900 mg/d of the immediate release formulation), one can give the difference between the patient's regular daily dose and the 900 mg maximal dose as a single "pill-in-the-pocket" dose. Hence, if the patient were taking 150 mg tid of immediate release propafenone, one could give an additional 450 mg single dose. [Note: if the patient were taking sustained release propafenone, one would have to compute its dose equivalent into an immediate release dose amount. The conversion is not 1:1 but rather approximates a 3:2 equivalency ratio for sustained release to immediate release doses.] Similarly, if the patient were taking daily flecainide but less than its full dose of 400 mg/d, one could give a single oral dose in the amount equal to 400 mg minus the patient's usual total daily dose. If there is any concern about safety/tolerance, the initial time should be under observation, where a successful experience can then proceed to at-home/at-work use in the future. The average time to conversion with the IC agents is just under 4 hours; it is slightly longer with ranolazine.

10) "Upstream therapies":

Finally, it should not be forgotten that in many if not most patients with AF, there are contributing factors from underlying cardiac conditions or associated disorders, such as hypertension. Treatments aimed at reducing the effects of such circumstances have been termed "upstream therapies." Experience with them has been variable, with both success and failure reported for ACE inhibitors, angiotensin receptor blockers (ARBs), omega-3 fish oil, statins, and aldosterone antagonists and eplerinone. The most consistent results have been seen with ACE inhibitors and ARBs in patients with hypertension or heart failure.16 While experience is being gained in clinical trials with hopes of elucidating more clearly which types of patients may respond to such therapies, clinicians may avail themselves of their potential effects as "hybrid" therapy given with an AAD if there is an apparent need for increased drug efficacy and no likely harmful effects in the patient at hand.


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  9. Dofetilide package insert
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Keywords: Anti-Arrhythmia Agents, Atrial Fibrillation, Atrial Flutter, Dizziness, Drug Interactions, Heart Failure, Hypertension, Potassium Channel Blockers, Sympathetic Nervous System, Ventricular Dysfunction

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