The Medical Letter on Drugs and Therapeutics
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1580
Drugs for Atrial Fibrillation
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 Select a term to see related articles  Amiodarone   andexanet alfa   Anticoagulants   apixaban   Atenolol   Atrial fibrillation   Beta blockers   Betapace   Bisoprolol   Brevibloc   Calan   Calcium-channel blockers   Cardizem   Cartia   Carvedilol   Coreg   Corgard   Coumadin   Dabigatran   Digitek   Digox   Digoxin   Diltiazem   Disopyramide   DOAC   Dofetilide   Dronedarone   edoxaban   Eliquis   Esmolol   Flecainide   idarucizumab   Inderal   Innopran   Isoptin   Kapspargo Sprinkle   Lanoxin   Lixiana   Lopressor   Mephyton   Metoprolol   Multaq   Nadolol   NOAC   Norpace   Pacerone   Pradaxa   Praxbind   Propafenone   Propranolol   Rivaroxaban   Rythmol   Savaysa   Sotalol   Taztia   Tenormin   Tiazac   Tikosyn   Toprol   Verapamil   Verelan   Vitamin K   Warfarin   Weight loss   Xarelto 
Summary: Drugs for Atrial Fibrillation

Anticoagulation
  • Oral anticoagulant therapy to reduce the risk of thromboembolic stroke in patients with nonvalvular atrial fibrillation is recommended in men with a CHA2DS2-VASc score ≥2 and women with a score ≥3. It can be considered in men with a score of 1 and women with a score of 2, and may be omitted in men with a score of 0 and women with a score of 1.
  • NOACs (non-vitamin K oral anticoagulants) are preferred over warfarin for patients with nonvalvular atrial fibrillation.
  • Patients with atrial fibrillation who have a mechanical valve or moderate-to-severe mitral stenosis should take warfarin.
Rate Control
  • Ventricular rate control is now widely accepted as an alternative to rhythm control for first-line management of chronic atrial fibrillation.
  • Lenient rate control (resting heart rate <110 bpm) appears to be as effective as strict control (resting heart rate <80 bpm).
  • A beta blocker is preferred for rate control in patients with coronary artery disease or systolic dysfunction. Verapamil or diltiazem may be preferred over beta blockers in patients with asthma. Amiodarone may be effective when other drugs have failed to control ventricular rate.
Rhythm Control
  • Antiarrhythmic drugs, particularly amiodarone, can be used to restore and maintain normal sinus rhythm.
  • The treatment of choice for urgent conversion of unstable atrial fibrillation is DC cardioversion.

 

Treatment of atrial fibrillation includes anticoagulation, rate control, and rhythm control. US guidelines were recently updated.1

ANTICOAGULATION

Anticoagulant therapy reduces the risk of thromboembolic stroke in patients with atrial fibrillation, but it can cause intracranial and other serious bleeding. The decision to use an oral anticoagulant in patients with nonvalvular atrial fibrillation (atrial fibrillation without moderate-to-severe mitral stenosis or a mechanical valve) should be based on the patient's CHA2DS2-VASc score. For men with a score of ≥2 and women with a score of ≥3, treatment with an oral anticoagulant is recommended. Use of an oral anticoagulant can be considered in men with a score of 1 and women with a score of 2, and may be omitted in men with a score of 0 and women with a score of 1. All patients with atrial fibrillation who have moderate-to-severe mitral stenosis or a mechanical valve should be anticoagulated.

CHOICE OF AN ANTICOAGULANT — The non-vitamin K oral anticoagulants (NOACs; dabigatran, rivaroxaban, apixaban, and edoxaban), also known as direct oral anticoagulants (DOACs), are now recommended over the vitamin K antagonist warfarin (Coumadin, and others) in patients with nonvalvular atrial fibrillation. Patients with moderate-to-severe mitral stenosis or a mechanical valve should take warfarin.

WARFARIN — Warfarin inhibits the vitamin K-dependent synthesis of clotting factors II, VII, IX, and X.

Dosing – Warfarin requires close monitoring and dosage adjustment to keep the international normalized ratio (INR) between 2 and 3; the INR should generally be measured weekly during treatment initiation and monthly once it is stable. Dosing algorithms based on weight and age are available at www.warfarindosing.org.

Reversibility – Vitamin K (Mephyton, and others) can reverse the anticoagulant effect of warfarin.

Drug Interactions – Maintaining the INR within the desired range can be made more difficult by warfarin's numerous interactions with vitamin K-containing foods (see Table 2) and with other drugs (see Table 3). Warfarin is a substrate of CYP2C9, 2C19, 3A4, and 1A2; inhibitors and inducers of these enzymes can significantly alter its anticoagulant effect.2 Coadministration of warfarin and amiodarone significantly increases warfarin's anticoagulant effect; the dosage of warfarin should be reduced by one-third to one-half in patients taking both drugs.

NOACs — The direct thrombin inhibitor dabigatran (Pradaxa) and the direct factor Xa inhibitors rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Savaysa) are all FDA-approved for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In clinical trials in patients with atrial fibrillation, all four NOACs were at least as effective as warfarin in preventing stroke or systemic embolism (the primary endpoint) and were associated with lower rates of hemorrhagic stroke or intracranial bleeding.3-6

NOACs do not require routine INR-type monitoring or adherence to dietary restrictions. Renal and hepatic function should be evaluated before starting a NOAC and at least annually thereafter. Data on the use of NOACs in severely obese patients (BMI >35 or weight >120 kg) are limited.

DABIGATRAN — Efficacy – In the RE-LY trial, dabigatran etexilate 150 mg twice daily was superior to warfarin in preventing stroke or systemic embolism (1.11% vs 1.69% per year) with significantly lower rates of both hemorrhagic stroke (0.10% vs 0.38% per year) and ischemic stroke (0.92% vs 1.20% per year). Dabigatran is the only NOAC that has been shown to be superior to warfarin in reducing the risk of ischemic stroke.7

Bleeding Risk – There have been multiple reports of spontaneous, severe, sometimes fatal bleeding with dabigatran. In a postmarketing study conducted by the FDA in >134,000 patients ≥65 years old, the risk of intracranial bleeding was lower with dabigatran than with warfarin, but the risk of major GI bleeding was higher with dabigatran.8,9

Administration – Dabigatran is primarily cleared renally. Dosage adjustments are recommended in patients with renal impairment (CrCl <30 mL/min, or <50 mL/min in patients concomitantly taking the P-glycoprotein inhibitors dronedarone or ketoconazole).

Drug Interactions – Dabigatran is a substrate of the efflux transporter P-glycoprotein (P-gp). P-gp inducers, such as rifampin, could reduce serum concentrations of dabigatran and possibly its efficacy; coadministration is not recommended. P-gp inhibitors, such as ketoconazole, may increase serum concentrations of dabigatran.2

Reversibility – Idarucizumab (Praxbind) is FDA-approved to reverse the effect of dabigatran in the event of life-threatening bleeding or an urgent invasive procedure.10 Dabigatran is dialyzable.

RIVAROXABAN — Efficacy – In the ROCKET-AF trial, once-daily rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism (2.1% vs 2.4% per year), but did not achieve superiority in the intention-to-treat population.4,11

Administration – Rivaroxaban should not be used in patients with moderate or severe hepatic impairment (Child-Pugh B or C). The dose should be adjusted in patients with a CrCl ≤50 mL/min.

Drug Interactions – Rivaroxaban is a substrate of CYP3A4 and P-gp. Drugs that are combined P-gp and strong CYP3A4 inhibitors, such as ketoconazole, may increase serum concentrations of rivaroxaban and the risk of bleeding; coadministration should be avoided. Drugs that are combined P-gp and strong CYP3A4 inducers, such as rifampin, phenytoin, phenobarbital, and carbamazepine, can decrease serum concentrations of rivaroxaban and its efficacy; coadministration should also be avoided.2

Reversibility – Andexanet alfa (recombinant factor Xa; Andexxa) is a genetically modified variant of human factor Xa that is FDA-approved to reverse the effect of rivaroxaban in the event of life-threatening bleeding.12 Rivaroxaban is highly bound to protein in plasma and is not dialyzable.13

APIXABAN — Efficacy – In the ARISTOTLE trial, apixaban was superior to warfarin in preventing stroke or systemic embolism (1.27% vs 1.60% per year). Unlike dabigatran and rivaroxaban, apixaban was also superior to warfarin in preventing death from any cause (3.52% vs 3.94% per year) and caused significantly less major bleeding (2.13% vs 3.09% per year), but the trials were conducted in somewhat different populations and used slightly different definitions of major bleeding.5,14

Administration – Apixaban should not be used in patients with severe hepatic impairment (Child-Pugh C). The dosage should be reduced in patients who have ≥2 of the following: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.

Reversibility – Andexanet alfa is FDA-approved to reverse the effect of apixaban in the event of life-threatening bleeding.12 Apixaban is highly bound to protein in plasma and is not significantly dialyzable.15

Drug Interactions – Apixaban is a substrate of CYP3A4 and P-gp. In patients taking combined P-gp and strong CYP3A4 inhibitors, such as ketoconazole, the dosage of apixaban should be reduced to 2.5 mg twice daily and coadministration should be avoided if the patient is already taking 2.5 mg twice daily.9 Drugs that are combined P-gp and strong CYP3A4 inducers, such as rifampin, can decrease serum concentrations of apixaban and its efficacy; coadministration should be avoided.2

EDOXABAN — Efficacy – In the ENGAGE AF-TIMI 48 trial, edoxaban 60 mg once daily was noninferior to warfarin in preventing stroke and systemic embolism (1.57% vs 1.80% per year) and had a significantly lower rate of major bleeding (2.75% vs 3.43% per year).6

Administration – Edoxaban is 50% renally excreted and is not recommended for use in patients who have end-stage renal disease or are on dialysis. It should also not be used in patients with atrial fibrillation who have a CrCl >95 mL/min because of an increased risk of ischemic stroke compared to warfarin.16

Reversibility – The anticoagulant effect of edoxaban persists for about 24 hours after the last dose. There is no FDA-approved reversal agent for edoxaban, but limited data suggest that andexanet alfa may be effective.17,18 Edoxaban is not dialyzable.

LEFT ATRIAL APPENDAGEAL OCCLUSION – The left atrial appendage (LAA) is the source of most thromboemboli in patients with atrial fibrillation. In patients undergoing cardiac surgery, occlusion of the LAA can lower the risk of thromboembolism. A percutaneous implant (the Watchman device) that closes off the LAA may be considered for nonsurgical patients with atrial fibrillation at increased risk of stroke who have contraindications to long-term anticoagulation.19

RATE CONTROL

Ventricular rate control is now widely accepted as an alternative to rhythm control for first-line management of chronic atrial fibrillation. Antiarrhythmic drugs have considerable toxicity, and rhythm control with these drugs has not been shown to be more effective in preventing serious complications than rate control alone.20 Lenient rate control (resting heart rate <110 bpm), particularly in patients with a structurally normal heart and no heart failure, is easier to achieve and appears to be as effective as strict rate control (resting heart rate <80 bpm).21 The drugs most commonly used for rate control in atrial fibrillation are listed in Table 5. In some patients, rate control is achieved by AV nodal ablation and permanent ventricular pacing.

BETA-ADRENERGIC BLOCKERS — A beta blocker such as metoprolol or esmolol given intravenously can acutely control the ventricular rate in atrial fibrillation or flutter. Oral beta blockers are often used for long-term rate control. Beta blockers are preferred over calcium channel blockers in patients with coronary artery disease or systolic dysfunction. They should be used cautiously in patients with asthma or decompensated heart failure.

CALCIUM CHANNEL BLOCKERS — The nondihydropyridine calcium channel blockers diltiazem and verapamil are effective in slowing the ventricular rate in atrial fibrillation or flutter. IV use of these drugs can be complicated by hypotension or bradycardia in patients with underlying heart disease, especially with concurrent use of other cardiodepressant drugs such as beta blockers. Diltiazem and verapamil may be preferred over beta blockers for long-term use in patients with asthma. They should not be used in patients with decompensated heart failure or Wolff-Parkinson-White syndrome.

Unlike diltiazem and verapamil, dihydropyridine calcium channel blockers (all the other calcium channel blockers available in the US) generally have no rate-controlling activity.

AMIODARONE — More often used as a rhythm control agent, IV amiodarone has also been used for ventricular rate control in critically ill patients, and oral amiodarone has been used when other drugs have failed to control heart rate.

DIGOXIN — Generally used only as an adjunctive agent, digoxin can help control ventricular response in atrial fibrillation or flutter, but other drugs are more effective. Digoxin, like verapamil and diltiazem, should not be used in patients with Wolff-Parkinson-White syndrome.

RHYTHM CONTROL

The treatment of choice for urgent conversion of symptomatic unstable atrial fibrillation is DC cardioversion. Antiarrhythmic drugs, particularly amiodarone, are also used to restore and maintain normal sinus rhythm.

ANTIARRYTHMIC DRUGS — The antiarrhythmic drugs most commonly used now to prevent episodes of paroxysmal atrial fibrillation and to maintain sinus rhythm after cardioversion are listed in Table 7.

Amiodarone is the most effective antiarrhythmic drug for maintenance of sinus rhythm, but it has many adverse effects, including GI upset, CNS effects such as fatigue and ataxia, QT interval prolongation, optic neuropathy/neuritis, photosensitivity, and serious, potentially fatal pulmonary toxicity, hepatotoxicity, and exacerbation of arrhythmia. It has a long, variable half-life (usually 40-55 days) and interacts with many other drugs (see Table 6).

Dronedarone, a non-iodinated analog of amiodarone, has been less effective than amiodarone and has been associated with severe adverse effects, including increased mortality in patients with persistent atrial fibrillation.22

Propafenone and flecainide are generally reserved for patients with structurally normal hearts; they should only be used with a beta blocker, verapamil, or diltiazem. Sotalol, a nonselective beta blocker, can prolong the QT interval and can cause torsades de pointes; it should be avoided in patients who have baseline QT interval prolongation or are receiving other drugs that prolong the QT interval.23 Disopyramide is now only rarely used to maintain normal sinus rhythm in patients with vagally-induced atrial fibrillation. Dofetilide has been effective in patients with compromised left ventricular function, but it requires in-hospital dose titration and causes torsades de pointes in ~1% of patients24; it should not be used in patients with baseline QT interval prolongation or concomitantly with other QT interval-prolonging drugs.23

CATHETER ABLATION — Radiofrequency catheter ablation can restore sinus rhythm and may be superior to antiarrhythmic drugs in maintaining sinus rhythm and improving symptoms, exercise capacity, and quality of life. Complications are rare but can be fatal. In symptomatic patients with heart failure and a reduced ejection fraction, catheter ablation may reduce heart failure hospitalizations and mortality.25

WEIGHT LOSS

Obesity is a risk factor for atrial fibrillation. In a randomized trail in 150 patients with symptomatic atrial fibrillation and a BMI >27, a structured weight management program decreased the number, severity, and duration of atrial fibrillation episodes compared to lifestyle advice alone.26

REFERENCES

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