I a. Importance of early diagnosis

AF is an independent risk factor associated with mortality, increasing it twice in men and 1.5 times in women;¹ mortality due to embolic events can decrease with oral anticoagulation but other causes of cardiovascular death such as heart failure or sudden death continue to be frequent despite adequate treatment, that is the reason why an early diagnosis is of utmost importance since AF can be asymptomatic (silent AF), and patients have it inadvertently, delaying proper treatment. The diagnosis of AF requires an event lasting at least 30 s and to be observed on an ECG, rhythm strip, or cardiac monitor, characteristically with the irregularity of RR intervals without clearly identifiable P waves or with visible «f» waves of fibrillation. An early electrocardiographic recording is cost-effective for documenting chronic forms of AF particularly in populations older than 65 years with a prevalence of up to 2.3%, obtaining a «necessary to treat number» of 70 to find one person with AF.¹ As for paroxysmal AF, the longer the record, the more likely it is to find silent events. Now the technology has evolved, so in Mexico, we already have 48-hour recorders and implantable loop recorders whose duration is up to three years. The more we use these devices in high-risk patients, more likely to find AF and being able to start appropriate treatment earlier.⁴

II a. Recent onset atrial fibrillation: conversion to sinus rhythm in an unstable patient

If the AF paroxysm is associated with «angina pectoris», pulmonary edema, low blood pressure or shock, urgent electrical cardioversion should be practiced. It is recommended that the shock should be administered with the highest available energy: 200 joules biphasic or 360 joules monophasic. It is not suggested to proceed in stages by increasing from lower energies. The reason for this is to reduce the number of shocks, use a lower cumulative dose of energy, and reduce the anesthetic time. For thromboembolic prophylaxis, unfractionated heparin (bolus according to body weight followed by infusion) should be administered, followed by oral anticoagulation.¹ Although embolism risk might be increased because of the emergency nature of the condition.

II b. Stable patient

Assuming that the corresponding thromboembolic prevention measures have been taken and that the heart rate is controlled with the isolated or combined use of beta-blockers, calcium channel blockers or digoxin, the clinician should assess whether it is reasonable to administer any antiarrhythmic drug to restore sinus rhythm. It is known that up to 50% of AF paroxysms may spontaneously remit within 24-48 hours.⁷ If AF persists after this period, pharmacological cardioversion with amiodarone (oral or preferably intravenous), propafenone or flecainide is indicated. Intravenous amiodarone is given at a loading dose of 5 to 7 mg/kg in 30-60 minutes, followed by a maintenance dose of 1.2 to 1.8 g/day until ten g¹ completed. The oral dose of propafenone is 600 mg in a single dose, and that of flecainide is 300 mg in a single dose. Sinus rhythm conversion occurs in 80-90% of cases within the first few hours.⁸ It should be emphasized that sotalol, dronedarone, and digoxin are not indicated for conversion to sinus rhythm. If the episode becomes persistent despite the use of antiarrhythmics, electrical CV is indicated, preceded by a transesophageal echocardiogram to rule out intracavitary thrombus.¹,⁹

II c. Maintaining sinus rhythm

Once the conversion to sinus rhythm has been achieved, the clinician should assess whether it is appropriate to use an antiarrhythmic daily for the maintenance of sinus rhythm or whether it is preferable not to give preventive antiarrhythmic and choose to treat the episode with the «pill in your pocket» strategy.¹,¹⁰ For the maintenance of sinus rhythm it is indicated to use one of the following antiarrhythmics: propafenone, flecainide, sotalol, dronedarone or amiodarone. In the absence of structural heart disease, the use of propafenone or flecainide is recommended.¹⁰ Sotalol may be used in the presence of ischemic heart disease. Dronedarone is indicated only for cases of paroxysmal AF, in the absence of heart disease and with preserved left ventricular ejection fraction. Amiodarone is considered a second-line drug due to its side effects; however, it is the most effective alternative for maintaining sinus rhythm.¹ In the case of heart failure, the use of amiodarone is recommended. For the last three drugs (sotalol, dronedarone, and amiodarone), the duration of the QT interval should be monitored.¹¹ A single dose of 600 mg propafenone or 300 mg flecainide is recommended for the «pill in your pocket» strategy.¹,⁸,¹⁰ Caution should be exercised due to the possibility that these two drugs may unmask the electrocardiographic signs of Brugada syndrome or convert atrial fibrillation into an atrial flutter with a paradoxical increase in ventricular response (less than 1% of cases).¹²

II d. Recurrent atrial fibrillation (paroxysmal, persistent)

Unlike the first episode approach (or very sporadic recurrent cases), for recurrent cases of paroxysmal and persistent presentation, it is indicated to use antiarrhythmics for prevention. The therapeutic options are propafenone, flecainide, sotalol, dronedarone, and amiodarone. It should be emphasized that dronedarone is only indicated to prevent recurrence of paroxysmal or persistent AF that has lasted less than six months of evolution, in the absence of heart disease and with preserved left ventricular ejection fraction. AF ablation (radiofrequency or cryoballoon energy) should be considered as a first-line alternative for drug-refractory or symptomatic cases (at least one antiarrhythmic class Ic or III).¹,¹³

II e. Persistent atrial fibrillation (lasting more than a year)

This category was established to identify patients who may not benefit from a rhythm control strategy because AF is permanent, from those with a chance to convert to sinus rhythm. There are two therapeutic options: 1) facilitated electrical cardioversion with prior use of antiarrhythmics¹⁴ and 2) AF ablation.¹ It is reasonable to proceed with facilitated electrical cardioversion with antiarrhythmic drugs as the first measure because if successful, although with early relapse, it demonstrates that the patient can maintain sinus rhythm and would be a suitable candidate for catheter ablation.¹,¹³,¹⁴

II f. Immediate post-cardioversion recurrence

Electrical cardioversion is one of the cornerstones for rhythm control in AF. However, immediate recurrence or therapeutic failure, described in up to 26% of cases, limits its clinical application.¹⁵ To increase the response rate, antiarrhythmics must be given before the electric shock.¹³,¹⁴ The use of verapamil, amiodarone, or sotalol has been reported to decrease the incidence of immediate recurrence.¹³-¹⁶ Other drugs such as ibutilide (not widely available in Mexico), vernakalant (not available in Mexico), and ranolazine (available in our country) have also shown benefit in this area.¹,¹⁷

II g. Delayed cardioversion (facilitated by antiarrhythmic)

It is indicated for persistent AF, mainly when the temporal progression is unknown or when a high probability of immediate recurrence is assumed. Amiodarone 600 mg per day administered for one month (total dose 16.8 g) is indicated for a better outcome. Pharmacological cardioversion has been observed to occur during loading dose in 16-18% of cases.¹ The success of electrical cardioversion is 88%. Besides, if cardioversion does not occur, the ventricular response of the heart rate during AF could be reduced (from 100 ± 25 to 87 ± 27.5 beats per minute [p ≤ 0.001]) by a negative dromotropic effect on the atrioventricular node.¹⁸

III a. Permanent (chronic) AF

Permanent AF is the one in which recovery of sinus rhythm is not possible.¹,¹⁹ The distinguishing feature of this phase of AF is the uncontrollable variability of the ventricular rate. It depends on the AV conduction and not on the sinus node function; it is the autonomic nervous system (sympathetic and vagal) that determines the AV conduction velocity and thus the ventricular frequency.²⁵ It is common to consider ventricular frequency analysis only with a resting electrocardiogram (EKG) record, however this is not quite right because of the circadian heart rate variations. On the other hand, vagal tone during the early morning hours can delay AV conduction and cause considerable and sufficient ventricular pauses to cause low brain perfusion with its consequences. The therapeutic possibilities are: pharmacological and interventional.²⁶,²⁷

III b. Pharmacological treatment

The main limitation of drugs comes from their AV node conduction slowing properties, thus inducing severe bradycardias without avoiding abnormally fast rates.²⁸ Antiarrhythmic drugs such as amiodarone are ineffective, as, by definition, sinus rhythm is not intended to be restored.²⁹ Beta-adrenergic blockers may delay AV conduction, but decrease the force of ventricular contraction.¹

III c. Interventional treatment

Once it has been demonstrated that the patient has a very high ventricular rate variability and maintains a heart rate above 140/min, heart failure is an imminent threat,¹,³⁰ Ablation of the AV junction and placement of a variable frequency ventricular pacemaker (VVIR) is the indicated option. The use of anticoagulants is imperative even in patients who have regained sinus rhythm after isolating the pulmonary veins, so there is no argument to avoid it.³¹,³² Radiofrequency thermal injury of the AV junction causes an irreversible blockage. The injured tissue can be the AV node or the His bundle, and can be achieved either from the tricuspid ring or from the left ventricle.¹ The success of this procedure is very close to 100%, and the possibility of recurrence is practically null. The placement of a ventricular pacemaker is a routine procedure in any institution, with low risk and ventricular function improved by obtaining regularity of rate.¹

In a series of patients from the Department of Experimental Medicine and Arrhythmias (UNAM) in the General Hospital of Mexico, 177 ablations of the AV junction with placement of a ventricular pacemaker have been carried out. All patients showed a ventricular rate variability greater than 140 bpm, when the normal is above 100 bpm. Many of them, during the 6-min walk test (6MWT), could not perform more than 250 meters. In 159 of the patients, ablation of the AV junction was achieved from the right atrium, and in 17 (10%) it had to be done from the left ventricle. In no case, there was a recovery of AV conduction. (unpublished data). This study concludes that ablation of the AV node is affordable and feasible in cases of permanent AF. Isolation of pulmonary veins should not be performed as an attempt to recover sinus rhythm, even if other options have been exhausted. Anticoagulation is mandatory in almost all patients with AF, regardless of its type.

V a. AF is a cause of stroke

The presence of AF has long been associated with the development of cerebral and systemic (pulmonary, limb, coronary, renal and visceral) embolism.⁴⁰ Initially, only AF secondary to valvular disease, usually rheumatic heart disease, was considered thrombogenic,⁴¹ but since the Framingham study, AF of non-rheumatic origin is also recognized as a cause of embolism.⁴²

V b. The prevention of embolisms in «valvular» AF should be performed with vitamin K antagonists (VKA)

For embolic risk purposes, «valvular» AF is considered to be the one associated with moderate or severe mitral stenosis or in the presence of a mechanical valve prosthesis.⁴³ Although acetylsalicylic acid (ASA) was initially used in patients with rheumatic heart disease,⁴⁴ subjects with valvular AF should now be anti-coagulated with VKA, either acenocoumarin or warfarin.¹,⁴⁵ The dose is that necessary to achieve an INR between 2.0 and 3.0, except for patients with mechanical valve prostheses that require INR between 2.5 and 3.5. Direct oral anticoagulants (DOAC) should not be used in valvular AF until the results of studies supporting this practice are available.⁴⁶ To improve the time in therapeutic intervals it is recommended to: 1) establish anticoagulation clinics⁴⁷ and 2) self-monitoring of the INR with portable devices.⁴⁸

V c. CHA2DS2-VASc score and options for prevention of embolisms in «non-valvular» AF

For patients with AF not associated with mitral stenosis or a mechanical valve prosthesis, a choice can be made between antiplatelet drugs, VKA or DOAC. Antiplatelet agents have the weakest effect in preventing embolism.⁴⁹ In a meta-analysis of randomized studies (Hart RG et al), the relative risk reduction of stroke with ASA compared to placebo was calculated at 19% while with VKA was 64%.⁵⁰ It is important to note that based on the results of the ACTIVE-W study, dual antiagreggation therapy (e.g. ASA and clopidogrel) is not recommended over oral anticoagulation.⁵¹

The decision of which drug should be used in the prevention of cerebral infarction can be based on the use of the CHA₂DS₂-VASc¹,⁵² score (Table 1). For individuals with no points, (no risk factors, considered «low risk» by not observing any embolic event in a follow-up year) it is possible to choose: not to give treatment; in those with a score of 1 («intermediate risk» of 0.6% of an embolic event per year) if it is male or 2 if it is female, they benefit more with oral anticoagulation with VKA or DOAC.¹ The HAS- BLED or ATRIA scales can be used to assess the risk of bleeding (Table 1).⁵³

For individuals scoring 2 or more on the CHA₂DS₂-VASc scale («high risk», 3% embolic event per year) there is no doubt that formal anticoagulation with VKA or DOAC is required. There are currently three DOACs available in Mexico: dabigatran, rivaroxaban, and apixaban. Their mechanism of action is inhibition of thrombin (dabigatran) or inhibition of factor Xa (rivaroxaban and apixaban).⁵⁴

Each has a different dosage, which varies with the individual’s age (in the case of apixaban) and kidney function (all). None can be used in cases of renal failure with creatinine clearance less than 15 mL/min. For a complete review of DOAC including dosages, how to start them, switching from VKA to DOAC, drug interactions, and bleeding management, the clinical practice guidelines of the European Heart Rhythm Association are highly recommended.⁵⁵

V d. Left atrial appendage occluders (LAAO)

LAAO is an interventional option for the prevention of embolism that so far is only indicated for patients with high embolic risk and who have some contraindication to receive VKA or DOAC.⁵⁶

Outside of this select group of patients, implanting these devices as substitutes for anticoagulation does not yet have sufficient evidence. The most recent results on cost-benefit analysis using dedicated statistical models (e.g. Markov’s stochastic decision model) have yielded contradictory results.⁵⁷ However, several studies are ongoing and are expected to produce positive results for occluders.⁵⁸ Like any invasive procedure, its efficacy in preventing stoke should be weighed against possible complications of its implant.