Atrial Fibrillation Medication
- Author: Lawrence Rosenthal, MD, PhD, FACC, FHRS; Chief Editor: Jeffrey N Rottman, MD more...
The goals of medical therapy for patients with atrial fibrillation are to maintain sinus rhythm, avoid the risk of complications (eg, stroke), and minimize symptoms. Warfarin represents the cornerstone of anticoagulant therapy for patients at moderate to high risk of thromboembolic events. Some patients may not be able to take anticoagulants because of contraindications or comorbidities.
Warfarin is associated with approximately 30% of reported anticoagulant-related errors. In an effort to improve patient safety, Schillig et al implemented an inpatient Pharmacist-Directed Anticoagulation Service (PDAS) to help patients reduce the risks associated with initiation of Coumadin when transitioning from the inpatient to the outpatient setting. This included appropriate enrollment in the anticoagulation clinic, documented inpatient-to-outpatient provider contact, documented inpatient provider-to-anticoagulation clinic communication, and patient follow-up with the anticoagulation clinic within 5 days of discharge. The results suggest PDAS may improve quality of care.
In patients unable to take warfarin, the addition of clopidogrel to aspirin was shown to reduce the risk of major vascular events, especially stroke, when compared with placebo and aspirin in the ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) trial; however, increased risk for major hemorrhage was more prevalent in the clopidogrel plus aspirin group than the placebo and aspirin group. The ACTIVE trial studied 7554 patients with AF with the intent to determine whether adding clopidogrel to aspirin therapy would reduce the risk for acute vascular events (ie, stroke, MI, non-CNS systemic embolism, or death from vascular event).
In another study, among AF patients treated with concomitant aspirin and oral anticoagulation, there was also a significantly increased risk for bleeding. Hospitalizations for bleeding events were also increased in those receiving this treatment combination.
Clopidogrel has been suggested to be less effective in reducing the rate of cardiovascular events in individuals who carry the loss-of-function CYP2C19 alleles. However, a 2010 study concluded that patients with acute coronary syndromes or AF respond well to clopidogrel, regardless of CYP2C19 loss-of-function carrier status.
The goal of antiarrhythmic drug therapy is to reduce the duration and frequency of atrial fibrillation episodes, thus improving patient quality of life and symptoms. If successful, rhythm control can eliminate or delay the need for long-term anticoagulation with warfarin in some patients.
Several antiarrhythmic drugs are commonly used to prevent atrial fibrillation recurrence, such as quinidine, flecainide, propafenone, sotalol, and dofetilide. Other antiarrhythmic agents, such as amiodarone, are used in an off-label fashion with great clinical efficacy. Use of antiarrhythmic drugs requires caution because they are proarrhythmic. These agents can exacerbate preexisting arrhythmias and generate arrhythmia de novo. Tachyarrhythmias and bradyarrhythmias generated by these agents can be of ventricular or atrial origin. Drug-drug interactions and extracardiac side effects are common. Consultation with a cardiac electrophysiologist or knowledgeable clinician is recommended prior to antiarrhythmic drug initiation.
If maintenance of sinus rhythm is the goal, the ACA/AHA/ECC have jointly developed guidelines for the long-term antiarrhythmic treatment in the maintenance of sinus rhythm. These guidelines are intended to help clinicians tailor antiarrhythmic therapy on an individual basis for their patients.
The following algorithm incorporates clinical trial data on the safety and efficacy of antiarrhythmic agents:
For patients with no evidence of structural heart disease, flecainide, propafenone and sotalol should be considered first-line agents, and amiodarone and dofetilide can be considered as alternative agents. Amiodarone is considered a reasonable first-line agent for patients with substantial LVH. Dofetilide and sotalol are first-line therapy for patients with CAD, and amiodarone is considered a second-line agent in this population. For patients with heart failure, amiodarone and dofetilide are first-line agents.
The Atrial arrhythmia Conversion Trial (ACT) I and the open-label ACT IV trials suggest that intravenous vernakalant hydrochloride can quickly convert recent-onset AF to sinus rhythm. This is potentially an important therapeutic option for the treatment of patients with AF seen in the emergency department, as the treatment was well tolerated.
Current practice constraints mandate that clinicians carefully consider patient populations at low and acceptable risks for outpatient antiarrhythmic drug initiation. Proarrhythmia is the most common adverse effect of antiarrhythmics during the loading phase. While the proarrhythmic effect of these drugs extends into the maintenance phase, a monitored inpatient setting is generally recommended for drug initiation, especially for those patients with structural heart disease or substantial comorbidities. Nevertheless, certain antiarrhythmic drugs have established and acceptable safety profiles when used in outpatients without structural heart disease or other risk factors.
Schmidt et al found that the use of non-aspirin NSAIDs is associated with an increased risk of AF or flutter, suggesting a need to add this caution when prescribing this course of medication.
Calcium Channel blockers
Calcium channel blockers are more effective than digoxin when given orally for long-term rate control and should be the initial drug of choice. They reduce the rate of AV nodal conduction and control ventricular response. Intravenous formulations control severe symptoms related to rapid ventricular rates in emergent situations.
Diltiazem is the drug of choice for rate control in many cases. During depolarization, it inhibits calcium ions from entering the slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
Verapamil can diminish PVCs associated with perfusion therapy and can decrease the risk of ventricular fibrillation and ventricular tachycardia. During depolarization, verapamil inhibits calcium ions from entering the slow channels or voltage-sensitive areas of vascular smooth muscle and myocardium.
Beta-adrenergic Receptor Blockers
These agents slow the sinus rate and decrease AV nodal conduction. Beta-blockers now have more of a secondary role in AF rate control. Carefully monitor blood pressure.
Esmolol is an ultra–short-acting beta-adrenergic receptor blocker. It selectively blocks beta-1 receptors, with little or no effect on beta-2 receptor types. It is particularly useful in patients with elevated arterial pressure, especially if surgery is planned. It has been shown to reduce episodes of chest pain and clinical cardiac events compared with placebo. It can be discontinued abruptly if necessary. It is useful in patients at risk for experiencing complications from beta-blockade, particularly those with reactive airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease. A short half-life of 8 min allows for titration to the desired effect and quick discontinuation if needed.
Propranolol is a nonselective beta-adrenergic receptor blocker as well as a class II antiarrhythmic, with membrane-stabilizing activity that decreases the automaticity of contractions.
Atenolol selectively blocks beta-1 receptors, with little or no effect on beta-2 types. Atenolol is excellent for use in patients at risk for experiencing complications from beta-blockade, particularly those with reactive airway disease, mild-to-moderate LV dysfunction, and/or peripheral vascular disease.
Metoprolol is a selective beta-1 adrenergic receptor blocker that decreases the automaticity of contractions. During intravenous administration, carefully monitor blood pressure, heart rate, and ECG.
These drugs slow AV nodal conduction primarily by increasing vagal tone. They are used primarily in the setting of AF with CHF.
Digoxin slows the sinus node and AV node via vagomimetic effects and is not very effective if sympathetic tone is increased. It is generally not recommended unless depressed LV function is present. Digoxin can be effective in sedentary patients (especially in those with heart failure) but requires close monitoring of drug levels and renal function. Combinations of rate-control medications (eg, a beta-blocker and digoxin) may be superior to individual agents in some patients.
Antiarrhythmics, class IA
Quinidine, procainamide, and disopyramide are class IA antiarrhythmic agents used to maintain sinus rhythm. Generally, start administration in the hospital because of the high risk of adverse effects. All patients treated with class IA agents should be treated concomitantly with AV nodal blocking agents. Some patients demonstrate a slowing in the atrial rate and an increase in AV conduction, with rapid ventricular rates, when treated with class IA agents alone. They are fading as first-line drugs for AF.
Of Vaughn-Williams class IA agents, only quinidine is FDA approved for atrial fibrillation. As with all class IA agents, QRS and QTc prolongation are the main ECG manifestations. It should not be used in patients with a prolonged QTc baseline (>460 milliseconds). Quinidine has generally fallen out of favor as a first- or second-line agent for the treatment of atrial fibrillation.
Procainamide is not FDA approved for the treatment of atrial fibrillation; however, many use this agent for acute cardioversion (eg, postoperatively) and because it can be administered intravenously. Intravenous administration is useful for acute conversion, and it can subsequently be converted to an oral dose. It is a negative inotropic agent and vasodilator, and care must be taken when administering to patients with reduced LV function. It is generally considered a second-line agent.
Disopyramide is not commonly used to treat atrial fibrillation because it has adverse anticholinergic effects and because it is a strongly negative inotropic agent, which may precipitate CHF and cardiogenic shock in patients with reduced LV function. It may be useful in vagally mediated syncope.
Antiarrhythmics, class IC
These agents are indicated for patients with AF and supraventricular tachycardia without structural heart disease. Given the results of the CAST I and II trials (increased mortality), class IC agents are generally not used in patients with concomitant LV dysfunction and/or CAD. The applicability of the CAST results to other populations (eg, patients without recent MI) is uncertain. Many specialists initiate class IC antiarrhythmic agents in an outpatient setting for patients with paroxysmal AF and no associated structural heart disease. Regardless, close patient follow-up is mandated, with frequent ECG monitoring or via transtelephonic monitoring for potential signs of proarrhythmia.
It is indicated for documented life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia. It appears to be effective in the treatment of supraventricular tachycardias, including atrial fibrillation and flutter. It is not recommended in patients with less severe ventricular arrhythmias, even if symptomatic. Use it in conjunction with AV nodal blocking agents when administered to patients in atrial fibrillation, because conversion to AFL with 1:1 conduction (producing fast ventricular rates) has been noted.
It is indicated for the treatment of paroxysmal atrial fibrillation/flutter associated with disabling symptoms and paroxysmal supraventricular tachycardias, including AV nodal reentrant tachycardia, AV reentrant tachycardia, and other supraventricular tachycardias of unspecified mechanism associated with disabling symptoms in patients without structural heart disease. It is also indicated for the prevention of documented life-threatening ventricular arrhythmias (eg, sustained ventricular tachycardia). It is not recommended in less severe ventricular arrhythmias even if patients are symptomatic. Use flecainide in conjunction with AV nodal blocking agents when given to patients in atrial fibrillation, because conversion to AFL with 1:1 conduction (producing fast ventricular rates) can occur.
Antiarrhythmics, class III
Currently, the class III antiarrhythmic agents sotalol and dofetilide are FDA approved for use in treating atrial arrhythmias; however, amiodarone is also used widely for maintenance of sinus rhythm in patients with AF. Dofetilide must be initiated in an inpatient setting. Sotalol is also initiated in an inpatient setting.
Amiodarone has antiarrhythmic effects that overlap all 4 Vaughn-Williams antiarrhythmic classes. It has a low risk of proarrhythmia, and any proarrhythmic reactions generally are delayed. It is used in patients with structural heart disease. Most clinicians are comfortable with inpatient or outpatient loading with 400 mg PO tid for 1 wk because of low proarrhythmic effect, followed by weekly reductions, with a goal of the lowest dose with desired therapeutic benefit (usual maintenance dose for atrial fibrillation is 200 mg/d). During loading, patients must be monitored for bradyarrhythmias.
Sotalol is a class III agent with beta-blocking effects. It is effective in the maintenance of sinus rhythm, even in patients with underlying structural heart disease. Inpatient loading is FDA mandated.
Dofetilide is approved by the FDA for maintenance of sinus rhythm, as well as for the conversion of atrial fibrillation to sinus rhythm (approximately 50%) in patients with persistent atrial fibrillation. It has no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate CHF, angina, and either normal or reduced LVEF. It has not shown evidence of any negative inotropic effects.
Ibutilide is indicated for conversion of recent-onset atrial fibrillation or atrial flutter (3 h to 90 d). It prolongs repolarization by increasing the slow inward sodium current and by blocking the delayed rectifier current with rapid onset.
Antiarrhythmic Agent, Miscellaneous
Dronedarone is an antiarrhythmic agent with properties belonging to all 4 Vaughn-Williams antiarrhythmic classes.
It is indicated to reduce the risk for cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter, with a recent episode of atrial fibrillation/atrial flutter and associated cardiovascular risk factors (ie, age >70 y, hypertension, diabetes, history of CVA, LAD >50 mm or LVEF < 40%) who are in sinus rhythm or who will be cardioverted.
Important to note, however, is that dronedarone was found to be associated with increased mortality in patients with permanent atrial fibrillation. A recent randomized, double-blind, phase III trial, the Permanent Atrial fibriLLation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS) study, was halted following a preliminary review that revealed that dronedarone was associated with a 2-fold rise in risk of death. Two-fold increases in 2 other endpoints, stroke and hospitalization for heart failure, were also noted when compared with placebo. Healthcare professionals are advised by the FDA not to prescribe dronedarone to patients with permanent atrial fibrillation. The FDA is currently analyzing whether the PALLAS results apply to patients taking dronedarone for paroxysmal or persistent atrial fibrillation and atrial flutter. The study results are considered preliminary at this time because the data have not undergone quality assurance procedures and have not been completely adjudicated.
Anticoagulants are used to prevent thromboembolic complications.
Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.
Enoxaparin is a low molecular weight heparin. It augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. It does not actively lyse but is able to inhibit further thrombogenesis. It prevents reaccumulation of clot after spontaneous fibrinolysis.
Warfarin interferes with the hepatic synthesis of vitamin K–dependent coagulation factors. It is used for the prophylaxis and treatment of venous thrombosis, pulmonary embolism, and thromboembolic disorders. Tailor the dose to maintain an INR of 2-3.
Competitive, direct thrombin inhibitor. Thrombin enables fibrinogen conversion to fibrin during the coagulation cascade, thereby preventing thrombus development. Inhibits both free and clot-bound thrombin and thrombin-induced platelet aggregation. Indicated for prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation.
Factor Xa inhibitor indicated reduce risk of stroke and systemic embolism with nonvalvular atrial fibrillation. Dose is adjusted according to estimated creatinine clearance.
Apixaban is a Factor Xa inhibitor that inhibits platelet activation by selectively and reversibly blocking the active site of Factor Xa without requiring a cofactor (eg, antithrombin III) for activity. It inhibits free and clot-bound Factor Xa, and prothrombinase activity. Although this agent has no direct effect on platelet aggregation, it does indirectly inhibit platelet aggregation induced by thrombin. Apixaban is indicated to reduce risk of stroke and systemic embolism associated with nonvalvular atrial fibrillation.
Some patients may not be able to take anticoagulants such as warfarin because of contraindications or comorbidities. In patients unable to take warfarin, the addition of clopidogrel to aspirin has been shown to reduce the risk of major vascular events.
Clopidogrel selectively inhibits adenosine diphosphate (ADP) binding to the platelet receptor and subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. It is indicated for reduction of atherothrombotic events following recent stroke.
Aspirin irreversibly inhibits platelet aggregation by inhibiting platelet cyclooxygenase. This, in turn, inhibits conversion of arachidonic acid to PGI2 (potent vasodilator and inhibitor of platelet activation) and thromboxane A2 (potent vasoconstrictor and platelet aggregate). Platelet-inhibition lasts for the life of the cell (approximately 10 d). It may be used at a low dose to inhibit platelet aggregation and improve complications of venous stases and thrombosis. It reduces the likelihood of myocardial infarction. It is also very effective in reducing the risk of stroke. Anticoagulation with either aspirin or warfarin should be initiated for all individuals with AF, except those with lone AF or contraindications.
Zimetbaum P, Reynolds MR, Ho KK, et al. Impact of a practice guideline for patients with atrial fibrillation on medical resource utilization and costs. Am J Cardiol. 2003 Sep 15. 92(6):677-81. [Medline].
Fuster V, Rydn LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006 Aug 15. 114(7):e257-354. [Medline]. [Full Text].
[Guideline] Wann LS, Curtis AB, January CT, et al. 2011 ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation (updating the 2006 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 Jan 4. 123(1):104-23. [Medline].
[Guideline] Wann LS, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation (Update on Dabigatran): A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 Feb 14. [Medline].
Singh BN, Singh SN, Reda DJ, Tang XC, Lopez B, Harris CL, et al. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med. 2005 May 5. 352(18):1861-72. [Medline].
Fuster V, Rydén LE, Asinger RW, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation: Executive Summary A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines and Policy Conferences (Committee to Develop Guidelines for the Management of Patients With Atrial Fibrillation) Developed in Collaboration With the North American Society of Pacing and Electrophysiology. Circulation. 2001 Oct 23. 104(17):2118-50. [Full Text].
[Guideline] Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation-executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients with Atrial Fibrillation). Eur Heart J. 2006 Aug. 27(16):1979-2030. [Medline]. [Full Text].
Kannel WB, Wolf PA, Benjamin EJ, Levy D. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol. 1998 Oct 16. 82(8A):2N-9N. [Medline].
Ferrari R, Bertini M, Blomstrom-Lundqvist C, et al. An update on atrial fibrillation in 2014: From pathophysiology to treatment. Int J Cardiol. 2016 Jan 15. 203:22-9. [Medline].
Nakao K, Seto S, Ueyama C, Matsuo K, Komiya N, Isomoto S, et al. Extended distribution of prolonged and fractionated right atrial electrograms predicts development of chronic atrial fibrillation in patients with idiopathic paroxysmal atrial fibrillation. J Cardiovasc Electrophysiol. 2002 Oct. 13(10):996-1002. [Medline].
Akyürek O, Sayin T, Dinçer I, Karaoguz R, Güldal M, Oral D. Lengthening of intraatrial conduction time in atrial fibrillation and its relation with early recurrence of atrial fibrillation. Jpn Heart J. 2001 Sep. 42(5):575-84. [Medline].
Fox CS, Parise H, D'Agostino RB Sr, Lloyd-Jones DM, Vasan RS, Wang TJ, et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA. 2004 Jun 16. 291(23):2851-5. [Medline].
Lubitz SA, Yin X, Fontes JD, Magnani JW, Rienstra M, Pai M, et al. Association between familial atrial fibrillation and risk of new-onset atrial fibrillation. JAMA. 2010 Nov 24. 304(20):2263-9. [Medline].
Xu DZ, Murakoshi N, Sairenchi T, et al. Anemia and reduced kidney function as risk factors for new onset of atrial fibrillation (from the Ibaraki Prefectural Health Study) [abstract]. Am J Cardiol. Nov 11, 2014. [Full Text].
Harrison P. Anemia and CKD associated with new-onset AF. Heartwire. November 17, 2014. [Full Text].
Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004 Aug 31. 110(9):1042-6. [Medline].
Abdel Latif A, Messinger-Rapport BJ. Should nursing home residents with atrial fibrillation be anticoagulated?. Cleve Clin J Med. 2004 Jan. 71(1):40-4. [Medline].
Alonso A, Lopez FL, Matsushita K, et al. Chronic Kidney Disease Is Associated With the Incidence of Atrial Fibrillation: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation. 2011 Jun 28. 123(25):2946-53. [Medline].
Stöllberger C, Chnupa P, Abzieher C, Länger T, Finsterer J, Klem I, et al. Mortality and rate of stroke or embolism in atrial fibrillation during long-term follow-up in the embolism in left atrial thrombi (ELAT) study. Clin Cardiol. 2004 Jan. 27(1):40-6. [Medline].
Rathore SS, Berger AK, Weinfurt KP, Schulman KA, Oetgen WJ, Gersh BJ, et al. Acute myocardial infarction complicated by atrial fibrillation in the elderly: prevalence and outcomes. Circulation. 2000 Mar 7. 101(9):969-74. [Medline].
Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Behlouli H, Pilote L. Sex differences in stroke risk among older patients with recently diagnosed atrial fibrillation. JAMA. 2012 May 9. 307(18):1952-8. [Medline].
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991 Aug. 22(8):983-8. [Medline].
Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002 Dec 5. 347(23):1825-33. [Medline].
Kotecha D, Chudasama R, Lane DA, Kirchhof P, Lip GY. Atrial fibrillation and heart failure due to reduced versus preserved ejection fraction: A systematic review and meta-analysis of death and adverse outcomes. Int J Cardiol. 2016 Jan 15. 203:660-6. [Medline].
Hobbs FD, Roalfe AK, Lip GY, et al. Performance of stroke risk scores in older people with atrial fibrillation not taking warfarin: comparative cohort study from BAFTA trial. BMJ. 2011 Jun 23. 342:d3653. [Medline].
Welles CC, Whooley MA, Na B, et al. The CHADS(2) score predicts ischemic stroke in the absence of atrial fibrillation among subjects with coronary heart disease: Data from the Heart and Soul Study. Am Heart J. 2011 Sep. 162(3):555-61. [Medline].
Gerth A, Nabauer M, Oeff M, et al. Stroke events in patients with CHADS2 scores 0 and 1 in a contemporary population of patients with atrial fibrillation: results from the German AFNET registry [abstract 4381]. Presented at: European Society of Cardiology (ESC) Congress 2013; September 3, 2013; Amsterdam, The Netherlands. Eur Heart J. 2013. 34 (suppl):808. [Full Text].
Hughes S. CHA2DS2-VASc score best for stroke risk assessment in AF. Medscape Medical News. September 19, 2013. [Full Text].
Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J, et al. Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ. 2012 Feb 27. [Medline].
Jabre P, Roger VL, Murad MH, et al. Mortality associated with atrial fibrillation in patients with myocardial infarction: a systematic review and meta-analysis. Circulation. 2011 Apr 19. 123(15):1587-93. [Medline].
van Diepen S, Bakal JA, McAlister FA, Ezekowitz JA. Mortality and readmission of patients with heart failure, atrial fibrillation, or coronary artery disease undergoing noncardiac surgery: an analysis of 38 047 patients. Circulation. 2011 Jul 19. 124(3):289-96. [Medline].
Michael JA, Stiell IG, Agarwal S, Mandavia DP. Cardioversion of paroxysmal atrial fibrillation in the emergency department. Ann Emerg Med. 1999 Apr. 33(4):379-87. [Medline].
Page RL, Wilkinson WE, Clair WK, McCarthy EA, Pritchett EL. Asymptomatic arrhythmias in patients with symptomatic paroxysmal atrial fibrillation and paroxysmal supraventricular tachycardia. Circulation. 1994 Jan. 89(1):224-7. [Medline].
van den Bos EJ, Constantinescu AA, van Domburg RT, Akin S, Jordaens LJ, Kofflard MJ. Minor elevations in troponin I are associated with mortality and adverse cardiac events in patients with atrial fibrillation. Eur Heart J. 2011 Mar. 32(5):611-7. [Medline].
Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, et al. Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med. 2001 May 10. 344(19):1411-20. [Medline].
Marrouche N. Delayed Enhancement - MRI determinant of successful Catheter Ablation of Atrial Fibrillation (DECAAF): analysis of post ablation scar and outcome. Presented at: The European Society of Cardiology (ESC) Congress 2013; September 1, 2013; Amsterdam, The Netherlands. [Full Text].
O'Riordan M. DECAAF: Targeting MRI-identified fibrosis during ablation improves outcomes. Heartwire. September 1, 2013. [Full Text].
Fang MC, Go AS, Chang Y, Borowsky LH, Pomernacki NK, Udaltsova N, et al. Thirty-Day Mortality After Ischemic Stroke and Intracranial Hemorrhage in Patients With Atrial Fibrillation On and Off Anticoagulants. Stroke. 2012 Apr 26. [Medline].
Steinberg BA, Kim S, Piccini JP, Fonarow GC, Lopes RD, Thomas L, et al. Use and Associated Risks of Concomitant Aspirin Therapy with Oral Anticoagulation in Patients with Atrial Fibrillation: Insights from the ORBIT-AF Registry. Circulation. 2013 Jul 16. [Medline].
van Walraven C, Hart RG, Wells GA, Petersen P, Koudstaal PJ, Gullov AL. A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin. Arch Intern Med. 2003 Apr 28. 163(8):936-43. [Medline].
Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen J, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. BMJ. 2011 Jan 31. 342:d124. [Medline]. [Full Text].
January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Mar 28. [Medline].
[Guideline] Busko M. New AF Guideline Includes Four Key Changes. Heartwire. March 28 2014. [Full Text].
[Guideline] Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012 Nov. 33(21):2719-47. [Medline]. [Full Text].
Hagens VE, Ranchor AV, Van Sonderen E, Bosker HA, Kamp O, Tijssen JG, et al. Effect of rate or rhythm control on quality of life in persistent atrial fibrillation. Results from the Rate Control Versus Electrical Cardioversion (RACE) Study. J Am Coll Cardiol. 2004 Jan 21. 43(2):241-7. [Medline].
Busko M. Fatal Foxglove: Digoxin in Early AF Ups Mortality Risk. Medscape. Aug 11 2014. [Full Text].
Turakhia MP, Santangeli P, Winkelmayer WC, et al. Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation: Findings From the TREAT-AF Study. J Am Coll Cardiol. 2014 Aug 19. 64(7):660-8. [Medline].
McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med. 2003 Dec 16. 139(12):1018-33. [Medline].
Fang MC, Go AS, Chang Y, et al. A New Risk Scheme to Predict Warfarin-Associated Hemorrhage The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol. 2011 Jul 19. 58(4):395-401. [Medline].
FDA. FDA approves Xarelto to prevent stroke in people with common type of abnormal heart rhythm. US Food and Drug Administration. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm278646.htm. Accessed: November 4, 2011.
Bayer Schering Pharma AG. Xarelto: Summary of Product Characteristics. Available at http://www.xarelto.com/scripts/pages/en/information-on-xarelto/summary_of_product_characteristics/index.php. Accessed: 2008.
Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8. 365(10):883-91. [Medline].
Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010 Sep 18. 376(9745):975-83. [Medline].
O’Riordan M. Consistent benefit of apixaban, even in patients at highest risk of bleeding: ARISTOTLE. Medscape Medical News. Available at http://www.medscape.com/viewarticle/772080. Accessed: October 15, 2012.
Lopes RD, Al-Khatib SM, Wallentin L, et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet. 2012 Oct 1. [Medline].
O’Riordan M. FDA approves apixaban to prevent stroke in nonvalvular AF. Medscape Medical News. Dec 28, 2012. [Full Text].
Lowes R. FDA Okays Kcentra to Reverse Anticoagulation, Stop Bleeding. Medscape Medical News. Available at http://www.medscape.com/viewarticle/803321. Accessed: May 8, 2013.
O'Shea SI, Arcasoy MO, Samsa G, Cummings SE, Thames EH, Surwit RS, et al. Direct-to-patient expert system and home INR monitoring improves control of oral anticoagulation. J Thromb Thrombolysis. 2008 Aug. 26(1):14-21. [Medline].
van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD, et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke. 2009 Apr. 40(4):1410-6. [Medline].
Gage BF, Yan Y, Milligan PE, Waterman AD, Culverhouse R, Rich MW, et al. Clinical classification schemes for predicting hemorrhage: results from the National Registry of Atrial Fibrillation (NRAF). Am Heart J. 2006 Mar. 151(3):713-9. [Medline].
Larsen TB, Lip GY. Warfarin or novel oral anticoagulants for atrial fibrillation?. Lancet. 2013 Dec 3. [Medline].
Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28. 369(22):2093-104. [Medline].
Stiles S. New' Oral Anticoagulant Stroke-Protection Benefits in AF Cut Across Subgroups in Meta-Analysis. Medscape Medical News. Available at http://www.medscape.com/viewarticle/815453. Accessed: December 17, 2013.
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2013 Dec 3. [Medline].
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Sep 17. 361(12):1139-51. [Medline].
Uchino K, Hernandez AV. Dabigatran Association With Higher Risk of Acute Coronary Events: Meta-analysis of Noninferiority Randomized Controlled Trials. Arch Intern Med. 2012 Jan 9. [Medline].
Stiles S. Major Bleeds Less Daunting With Dabigatran Than Warfarin in Meta-Analysis. Medscape. Oct 4 2013. [Full Text].
Majeed A, Hwang HG, Connolly SJ, Eikelboom JW, Ezekowitz MD, Wallentin L, et al. Management and outcomes of major bleeding during treatment with dabigatran or warfarin. Circulation. 2013 Sep 30. [Medline].
Imazio M, Brucato A, Ferrazzi P, Rovere ME, Gandino A, Cemin R, et al. Colchicine Reduces Postoperative Atrial Fibrillation: Results of the Colchicine for the Prevention of the Postpericardiotomy Syndrome (COPPS) Atrial Fibrillation Substudy. Circulation. 2011 Nov 22. 124(21):2290-2295. [Medline].
O’Riordan M. Colchicine postablation reduces early AF recurrences. Medscape Medical News. Available at http://www.medscape.com/viewarticle/772079. Accessed: October 15, 2012.
Deftereos S, Giannopoulos G, Kossyvakis C, et al. Colchicine for prevention of early atrial fibrillation recurrence after pulmonary vein isolation: a randomized controlled study. J Am Coll Cardiol. 2012 Sep 22. [Medline]. [Full Text].
Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010 Sep 13. 170(16):1433-41. [Medline].
[Guideline] Hughes S. New AAN Guidelines on Stroke Prevention in AF. Medscape Medical News. Feb 24 2014. [Full Text].
[Guideline] Culebras A, Messe SR, Chaturvedi S, et al. Summary of evidence-based guideline update: Prevention of stroke in nonvalvular atrial fibrillation: Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014 Feb 25. 82(8):716-24. [Medline].
Kowey PR, Reiffel JA, Ellenbogen KA, Naccarelli GV, Pratt CM. Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial. JAMA. 2010 Dec 1. 304(21):2363-72. [Medline].
Liu T, Korantzopoulos P, Shehata M, Li G, Wang X, Kaul S. Prevention of atrial fibrillation with omega-3 fatty acids: a meta-analysis of randomised clinical trials. Heart. 2011 Jul. 97(13):1034-40. [Medline].
Shi y, Li D, Tardif JC, Nattel S. Enalapril effects on atrial remodeling and atrial fibrillation in experimental congestive heart failure. Cardiovasc Res. 2002. 54:456-61.
Moreno I, Caballero R, Gonzalez T et al. Effects of irbesartan on cloned potassium channels involved in human cardiac repolarization. J Pharmacol Exp Ther. 2003. 304:862-873.
Gerdts E, Wachtell K, Omvik, P et al. Left atrial size and risk of major cardiovascular events during antihypertensive treatment: Losartan Intervention for Endpoint Reduction in Hypertension trial. Hypertension. 2007. 49:311-316.
Yusuf S, Healey JS, Pogue J, Chrolavicius S, Flather M, Hart RG, et al. Irbesartan in patients with atrial fibrillation. N Engl J Med. 2011 Mar 10. 364(10):928-38. [Medline].
Roy D, Talajic M, Dorian P, Connolly S, Eisenberg MJ, Green M, et al. Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators. N Engl J Med. 2000 Mar 30. 342(13):913-20. [Medline].
FDA drug safety communication: Multaq (dronedarone) and increased risk of death and serious cardiovascular adverse events. July 21, 2011. U.S. Food and Drug Administration. Available at http://www.fda.gov/Drugs/DrugSafety/ucm264059.htm. Accessed: July 26, 2011.
Connolly SJ, Camm AJ, Halperin JL, et al. Dronedarone in High-Risk Permanent Atrial Fibrillation. N Engl J Med. 2011 Nov 14. [Medline].
Goodier R. Dofetilide cardioversion may increase proarrhythmia risk. Medscape Medical News. June 3, 2013. [Full Text].
Brumberg G, Gera N, Pray C, Adelstein E, Barrington W, Bazaz R, et al. Frequency of Toxicity With Chemical Conversion of Atrial Fibrillation With Dofetilide. Am J Cardiol. 2013 May 22. [Medline].
Echt DS, Liebson PR, Mitchell LB, Peters RW, Obias-Manno D, Barker AH, et al. Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991 Mar 21. 324(12):781-8. [Medline].
Hoyt H, Bhonsale A, Chilukuri K, Alhumaid F, Needleman M, Edwards D, et al. Complications arising from catheter ablation of atrial fibrillation: Temporal trends and predictors. Heart Rhythm. 2011 Dec. 8(12):1869-74. [Medline].
Boersma LV, Castella M, van Boven W, et al. Atrial Fibrillation Catheter Ablation Versus Surgical Ablation Treatment (FAST): A 2-Center Randomized Clinical Trial. Circulation. 2012 Jan 3. 125(1):23-30. [Medline].
Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005 Jun 7. 45(11):1832-9. [Medline].
Fauchier L, Pierre B, de Labriolle A, Grimard C, Zannad N, Babuty D. Antiarrhythmic effect of statin therapy and atrial fibrillation a meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2008 Feb 26. 51(8):828-35. [Medline].
Vermes E, Tardif JC, Bourassa MG, Racine N, Levesque S, White M, et al. Enalapril decreases the incidence of atrial fibrillation in patients with left ventricular dysfunction: insight from the Studies Of Left Ventricular Dysfunction (SOLVD) trials. Circulation. 2003 Jun 17. 107(23):2926-31. [Medline].
Pedersen OD, Bagger H, Kober L, Torp-Pedersen C. Trandolapril reduces the incidence of atrial fibrillation after acute myocardial infarction in patients with left ventricular dysfunction. Circulation. 1999 Jul 27. 100(4):376-80. [Medline].
Alboni P, Botto GL, Baldi N, Luzi M, Russo V, Gianfranchi L, et al. Outpatient treatment of recent-onset atrial fibrillation with the "pill-in-the-pocket" approach. N Engl J Med. 2004 Dec 2. 351(23):2384-91. [Medline].
Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. [ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation--excutive summary]. Rev Port Cardiol. 2007 Apr. 26(4):383-446. [Medline].
[Guideline] Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, et al. Guidelines for the Primary Prevention of Stroke. A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2010 Dec 6. [Medline].
Bradley D, Creswell LL, Hogue CW Jr, Epstein AE, Prystowsky EN, Daoud EG. Pharmacologic prophylaxis: American College of Chest Physicians guidelines for the prevention and management of postoperative atrial fibrillation after cardiac surgery. Chest. 2005 Aug. 128(2 Suppl):39S-47S. [Medline].
Sezai A, Minami K, Nakai T, et al. Landiolol hydrochloride for prevention of atrial fibrillation after coronary artery bypass grafting: New evidence from the PASCAL trial. J Thorac Cardiovasc Surg. 2011 Jun. 141(6):1478-87. [Medline].
Anselme F, Saoudi N, Cribier A. Pacing in prevention of atrial fibrillation: the PIPAF studies. J Interv Card Electrophysiol. 2000 Jan. 4 Suppl 1:177-84. [Medline].
Roux JF, Zado E, Callans DJ, Garcia F, Lin D, Marchlinski FE, et al. Antiarrhythmics After Ablation of Atrial Fibrillation (5A Study). Circulation. 2009 Sep 22. 120(12):1036-40. [Medline].
Hussein AA, Wazni OM, Harb S, et al. Radiofrequency ablation of atrial fibrillation in patients with mechanical mitral valve prostheses safety, feasibility, electrophysiologic findings, and outcomes. J Am Coll Cardiol. 2011 Aug 2. 58(6):596-602. [Medline].
Onorati F, Mariscalco G, Rubino AS, Serraino F, Santini F, Musazzi A, et al. Impact of lesion sets on mid-term results of surgical ablation procedure for atrial fibrillation. J Am Coll Cardiol. 2011 Feb 22. 57(8):931-40. [Medline].
Haïssaguerre M, Shah DC, Jaïs P, Hocini M, Yamane T, Deisenhofer I, et al. Electrophysiological breakthroughs from the left atrium to the pulmonary veins. Circulation. 2000 Nov 14. 102(20):2463-5. [Medline].
Jaïs P, Shah DC, Haïssaguerre M, Hocini M, Garrigue S, Clémenty J. Atrial fibrillation: role of arrhythmogenic foci. J Interv Card Electrophysiol. 2000 Jan. 4 Suppl 1:29-37. [Medline].
Santangeli P, Di Biase L, Santoro F, et al. Pulmonary Vein Antrum Isolation in Patients With Paroxysmal Atrial Fibrillation: A Decade of Follow-Up. Nov 18 2013. [Full Text].
Soga Y, Okabayashi H, Arai Y, et al. Up to 6-year follow-up after pulmonary vein isolation for persistent/permanent atrial fibrillation: Importance of sinus node function. J Thorac Cardiovasc Surg. 2011 Jun. 141(6):1455-60. [Medline].
O'Neill MD, Jaïs P, Hocini M, Sacher F, Klein GJ, Clémenty J, et al. Catheter ablation for atrial fibrillation. Circulation. 2007 Sep 25. 116(13):1515-23. [Medline].
Winkle RA, Mead RH, Engel G, Patrawala RA. Long-term results of atrial fibrillation ablation: The importance of all initial ablation failures undergoing a repeat ablation. Am Heart J. 2011 Jul. 162(1):193-200. [Medline].
Stiles S. Repeat Ablation Wins Out Over Antiarrhythmic Agents for Recurrent Paroxysmal. Medscape. May 13 2013. [Full Text].
Progression of Atrial Fibrillation After a Failed Initial Ablation Procedure in Patients With Paroxysmal Atrial Fibrillation: A Randomized Comparison of the Drug Therapy Versus Re-Ablation. ClinicalTrials.gov. [Full Text].
Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, et al. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol. 2005 Nov. 16(11):1160-5. [Medline].
Natale A, Zimerman L, Tomassoni G, Newby K, Leonelli F, Fanelli R, et al. AV node ablation and pacemaker implantation after withdrawal of effective rate-control medications for chronic atrial fibrillation: effect on quality of life and exercise performance. Pacing Clin Electrophysiol. 1999 Nov. 22(11):1634-9. [Medline].
Holmes DR, Reddy VY, Turi ZG, Doshi SK, Sievert H, Buchbinder M, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet. 2009 Aug 15. 374(9689):534-42. [Medline].
Pappone C, Rosanio S, Oreto G, Tocchi M, Gugliotta F, Vicedomini G, et al. Circumferential radiofrequency ablation of pulmonary vein ostia: A new anatomic approach for curing atrial fibrillation. Circulation. 2000 Nov 21. 102(21):2619-28. [Medline].
Damiano RJ Jr, Lawrance CP, Saint LL, et al. Detection of atrial fibrillation after surgical ablation: conventional versus continuous monitoring. Ann Thorac Surg. 2016 Jan. 101 (1):42-8. [Medline].
Schillig J, Kaatz S, Hudson M, et al. Clinical and safety impact of an inpatient Pharmacist-Directed anticoagulation service. J Hosp Med. 2011 Jul. 6(6):322-8. [Medline].
Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius S, et al. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009 May 14. 360(20):2066-78. [Medline].
Paré G, Mehta SR, Yusuf S, Anand SS, Connolly SJ, Hirsh J, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010 Oct 28. 363(18):1704-14. [Medline].
Stiell IG, Dickinson G, Butterfield NN, Clement CM, Perry JJ, Vaillancourt C, et al. Vernakalant Hydrochloride: A NovelAtrial-selective Agent for the Cardioversionof Recent-onset Atrial Fibrillation in the Emergency Department. Acad Emerg Med. Nov 2, 2010. 17(11):1175-1182.
Schmidt M, Christiansen CF, Mehnert F, Rothman KJ, Sorensen HT. Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study. BMJ. 2011 Jul 4. 343:d3450. [Medline].
Everett BM, Cook NR, Conen D, Chasman DI, Ridker PM, Albert CM. Novel genetic markers improve measures of atrial fibrillation risk prediction. Eur Heart J. 2013 Feb 26. [Medline].
Hughes S. CRYSTAL-AF: Monitor Detects AF in Cryptogenic Stroke. Medscape [serial online]. Available at http://www.medscape.com/viewarticle/820686. Accessed: February 24, 2014.
Nagy-Baló E, Tint D, Clemens M, Beke I, Kovács KR, Csiba L, et al. Transcranial Measurement of Cerebral Microembolic Signals during Pulmonary Vein Isolation: A Comparison of Two Ablation Techniques. Circ Arrhythm Electrophysiol. 2013 Apr 11. [Medline].
Vassiliou VS, Flynn PD. Apixaban in atrial fibrillation: does predicted risk matter?. Lancet. 2012 Oct 1. [Medline].
Verberk WJ, Omboni S, Kollias A, Stergiou GS. Screening for atrial fibrillation with automated blood pressure measurement: Research evidence and practice recommendations. Int J Cardiol. 2016 Jan 15. 203:465-73. [Medline].
|Risk Factors||Relative Risk|
|Prior stroke or TIA||2.5|
|History of hypertension||1.6|
|Heart failure and/or reduced left ventricular function||1.4|
|Coronary artery disease||1.5|
|CHADS2 Score||Adjusted Stroke Rate (%/y)|
|Risk Category||Recommended Therapy|
|No risk factors||Aspirin 81-325 mg daily|
|One moderate-risk factor||Aspirin 81-325 mg daily or warfarin (INR 2-3)|
|Any high-risk factor or more than 1 moderate-risk factor||Warfarin (INR 2-3)|