Indications For Anticoagulation In Atrial Fibrillation [jnl article] WW.PDF

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130 AMERICAN FAMILY PHYSICIAN VOLUME 58, NUMBER 1 / JULY 1998

women who were evaluated biennially for 22 years, showed that chronic AF developed in 49men and 49 women. The incidence of new-onset AF increased with age in both sexes. Formen and women aged 22 to 34,the rate was 2.6and 2.2 per 1,000, respectively. In the group 55to 64 years of age, however, the rate of AFincreased to 37.9 and 29.9 per 1,000 men andwomen, respectively. Patients with diabetes,hypertension, rheumatic heart disease, coro-nary artery disease and congestive heart failurehave a higher incidence of AF than patientswithout these disorders. 4

In another large study, 5 which included2,254 patients, AF was noted in 2 percent of the patients 65 to 75 years of age and in 5 per-cent of those older than 75 years of age.Again,the occurrence of AF was found to increasewith age, with 14 percent of those older than84 years of age having this dysrhythmia.In themore recently initiated Cardiovascular HealthStudy of Americans More Than 65 Years, theprevalence of AF on 24-hour Holter record-ings was approximately 5 percent. 4

Impact on MorbidityTable 23,6-8 lists the factors associated with

an increased risk of stroke in patients with AF.The risk ratio of stroke in patients with AF

Atrial fibrillation (AF),one of themost common dysrhythmias,has numerous causes (Table 1).When an underlying cause isnot identified, the condition is

called lone AF. Approximately 10 percent of patients with chronic AF have this type. 1

Management of AF requires assessment andtreatment of the underlying cause, control of the rate, consideration of pharmacologic orelectric cardioconversion and consideration of anticoagulation. This article discusses theissues involved in the risk of a thromboem-bolic event in association with AF and theindications for anticoagulation therapy.

Incidence of Atrial FibrillationThe incidence of AF increases with age and

with the presence of structural heart disease. 2

The Framingham Heart Study, 3 which in-cluded a cohort of 2,325 men and 2,866

Indications for Anticoagulation

in Atrial FibrillationWAHEED AKHTAR, M.D.,WILLIAM C. REEVES, M.D., and ASSAD MOVAHED, M.D.East Carolina University School of Medicine,Greenville, North Carolina

Factors associated with an increased risk of thromboembolic events in patients with atrial fibrillation (AF) include increasing age, rheumatic heart disease, poor left ventricular function, previous myocardial infarc-tion, hypertension and a past history of a thromboembolic event. Patientswith AF should be considered for anticoagulation or antiplatelet therapy based on the patients age, the presence of other risk factors for stroke and the risk of complications from anticoagulation. In general, patients withrisk factors for stroke should receive warfarin anticoagulation,regardless of their age. In patients who are under age 65 and have no other risk factors

for stroke, either aspirin therapy or no therapy at all is recommended. Aspirin or warfarin is recommended for use in patients between 65 and 75 years of age with no other risk factors, and warfarin is recommended for use in patients without risk factors who are older than 75 years of age.

This articleexemplifies the AAFP 1997-98 Annual Clinical Focus on preventionand management ofcardiovascular disease.

See editorialon page 39.

Factors associated with an increased risk of stroke in atrial fibrillation include increasing age, rheumatic heart disease,

poor left ventricular function, prior myocardial infarction,hypertension and a history of a thromboembolic event.


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and nonrheumatic heart disease has beenfound in various studies to range from 2.3during five years of follow-up 9 to 7.0 during14 years of follow-up. 10

A significant increase in the incidence of stroke was noted among participants with AFin the Framingham study. 3 Patients withrheumatic heart disease and AF had a 17-foldincrease in the incidence of stroke, whereaspatients with nonrheumatic AF had a fivefoldincrease in stroke. A fourfold increase instroke was found in patients with lone AF. 11

Most of these patients were older than 60 years of age. In the Stroke Prevention in AtrialFibrillation Investigators (SPAFI) study, 7

patients with lone AF who were younger than65 years of age had a stroke rate of 1 percentper year, compared with a stroke rate of 4.3percent per year in patients over 65 years of age. Data from this study highlight the por-tentous prognosis associated with lone AF inolder patients and underscore the need for

treatment. Approximately 25 percent of thestrokes in patients with lone AF occurred atthe onset of AF. Stroke recurrence in the firstsix months was twice as high in the AF group.

In the Olmsted county population in Min-nesota, 12 where patients were followed for 30 years, lone AF was identified in 97 (2.7 per-

AMERICAN FAMILY PHYSICIAN 131JULY 1998 / VOLUME 58, NUMBER 1

TABLE 1Etiology of Atrial Fibrillation

Coronary artery diseaseMyocardial infarction with congestive heart failureFollowing coronary bypass surgery

HypertensionValvular heart disease (especially mitral stenosis

and regurgitation)Cardiomyopathy (dilated, hypertrophic, restrictive)ThyrotoxicosisAlcohol

Metabolic disorders (hypokalemia, hypomagnesemia,hypercalcemia)Autonomic causes

Vagal stimulation (carotid sinus pressure)Nausea and vomitingNocturnal atrial fibrillation (preceded by bradycardia)Digoxin (Lanoxin)Sympathetic excess (pheochromocytoma,

hypoglycemia, psychologic stress)Physical causes (lightning, electric shock,

hypothermia, chest contusion)

TABLE 2Factors Increasing the Risk of Strokein Patients with Atrial Fibrillation

Increasing age3

Rheumatic heart disease3

Poor left ventricular function or recent congestiveheart failure6

Enlarged left atrium7

Previous myocardial infarction8

Hypertension7

History of previous thromboembolic events7

Information from references 3 and 6 through 8.

Iatrogenic causesElectrophysiologic testingCold fluids injected into right atriumLong-term ventricular pacingMagnet applied to a dual-chamber pacemakerAutomatic cardioverter-defibrillator (AICD) firing,

presence of AICDEndoscopyAnesthesia

Cardiotoxic drugs (e.g., anthracyclines)Drugs (ophthalmic atropine, digoxin, theophylline,

sympathomimetics, adenosine [Adenocard],antidepressants, nicotine gum)

Congenital heart disease (especially atrial septal defect)Intrathoracic infections and inflammation (pneumonia,

pericarditis, myocarditis, endocarditis)Malignancy (with atrial involvement)Sinus node dysfunctionLone atrial fibrillation


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cent) of 3,623 patients with AF. This study population differed from that of the Framing-ham study; in the Olmsted county study,patients older than 60 years of age wereexcluded at entry into the study. The incidenceof stroke was 0.35 per 100 person-years, withstroke occurring in 1.3 percent at 15 years. It isimportant to recognize that patients olderthan 60 years at entry and those with hyper-tension were excluded from the study.

Lone AF in younger patients without otherrisk factors for stroke carries the same risk of

stroke as that in the general population. Theimportance of AF in the general population isthat its appearance heralds a mortality ratedouble that of control subjects. Much of themorbidity and some of the mortality associ-ated with AF is due to stroke.While the risk of stroke is not due solely to AF, AF substantially increases the risk of stroke in the presence of other cardiovascular disorders (Table 3). Theattributable risk of stroke from AF is esti-mated to be 1.5 percent in the 50- to 59-year-old age group and to approach 30 percent inpersons 80 to 89 years of age. 13,14

Clinical Trials of Anticoagulationin Nonvalvular AF

General consensus has been reached regard-ing the recommendations for anticoagulationin patients with rheumatic AF. However, untilrecently, clear-cut recommendations have notbeen available for management of patientswith nonvalvular AF. Since 1989, many large,prospective, randomized trials have been con-ducted to evaluate the risks and benefits of warfarin (Coumadin) or aspirin therapy in theprevention of stroke. The results of these trialsprovide a strong foundation for recommenda-tions regarding the use of anticoagulationtherapy in patients with nonvalvular AF.

A reduction in the risk of thromboem-bolism with anticoagulation or antiplateletagents as compared with placebo was noted inthe following trials: the Copenhagen AtrialFibrillation Aspirin and AnticoagulationStudy (AFASAK),8 the Boston Area Anticoag-


TABLE 3Annual Rates of Stroke Based on Five RandomizedStudies of Patients with Nonrheumatic Atrial Fibrillation

Rate of stroke per year (%)*

Category Placebo Warfarin

Independent risk factorsAge 75 yearsNo other risk factors 3.5 1.7One or more additional risk factors 8.1 1.2

History of hypertension 5.6 1.9History of diabetes 8.6 2.8

History of prior stroke or transient 11.7 5.1ischemic attack

Risk factors in any of the 5 trials History of congestive heart failure 6.8 1.6History of angina pectoris 6.7 0.9History of myocardial infarction 8.2 3.3History of congestive heart failure, 6.1 1.6

angina pectoris and myocardialinfarction

OtherHistory of peripheral vascular disease 6.0 1.8Women 5.8 0.9Paroxysmal or intermittent AF 5.7 1.7

Atrial fibrillation duration >1 year 4.4 1.5

NOTE: The five studies are the Atrial Fibrillation, Aspirin, Anticoagulation Study from Copenhagen, Denmark (AFASAK), the Stroke Prevention in Atrial Fibrilla-tion Investigators (SPAFI) study, the Boston Area Anticoagulation Trial in Atrial Fibrillation (BAATAF), the Canadian Atrial Fibrillation Anticoagulation (CAFA)

study and the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrilla-tion (SPINAF) study.

*Rates of stroke are based on the pooled results of five randomized studiesthat included 3,691 patients with nonrheumatic AF. They received placebo or warfarin.In a separate randomized study of patients with AF who had a stroke or transient ischemic attack within 3 months before enrollment, the rate of strokewas 12 percent and 4 percent with placebo and warfarin, respectively (Lancet

1993;342:1255-62).Selection criteria differed somewhat for the randomized trials. These factorswere determined to be independent risk factors for stroke in any one of thefive randomized studies. The rates of stroke, however, are tabulated from the

pooled analysis.

Adapted with permission from Risk factors for stroke and efficacy of antithrom-botic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-57 [Published erratum in

Arch Intern Med 1994;154:2254] and EAFT (European Atrial Fibrillation Trial)Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet 1993;342:1255-62.


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ulation Trial in Atrial Fibrillation (BATAF), 15

the Canadian Atrial Fibrillation Anticoagula-tion Study (CAFA) 16 and the Stroke Preven-tion in Atrial Fibrillation (SPAF) trial. 6,7,17-19

Stroke Prevention in Atrial Fibrillation TrialThe SPAF III trial 18 included 1,044 patients

(mean age: 71 years) with nonrheumatic AFand underlying risk factors for stroke, includ-ing systemic embolism. Patients in the study were randomized to receive full-dose warfarin(International Normalized Ratio [INR]: 2.0 to

3.0) or 325 mg of aspirin plus low-dose war-farin (INR: 1.2 to 1.5). The risk factors forstroke in these patients included a history of hypertension (67 percent), congestive heartfailure (44 percent), diabetes (19 percent),myocardial infarction (19 percent) and amean left atrial size of 4.4 cm on two-dimen-sional echocardiography.

After approximately one year of follow-up,the trial was prematurely stopped because thestroke rate in the aspirin plus low-dose war-farin group was substantially higher than thatin the warfarin group (7.8 percent as opposedto 2.6 percent).The advantage of full-dose war-farin (INR: 2.0 to 3.0) in reducing stroke wasevident in the subgroup analysis of patientswith a history of stroke. The rate of stroke inthis subgroup was 3.4 percent in patientsreceiving full-dose warfarin, compared with arate of 11 percent in those receiving aspirin andlow-dose warfarin. In patients without a previ-ous stroke, the rate of stroke was 1.1 percent inthose receiving full-dose warfarin and 5.1 per-cent in those receiving low-dose warfarin andaspirin. The data clearly favor anticoagulationwith warfarin to an intended INR of 2.0 to 3.0in high-risk groups with AF.

Anticoagulation Before CardioversionIn hemodynamically compromised patients,

AF must be treated emergently with synchro-nized electric cardioversion. There are no con-trolled studies available to suggest recommen-dations regarding anticoagulation in thesepatients. In a nonrandomized trial of 437

patients (532 instances of cardioversion), 20 theincidence of an embolic event was 0.8 percentin the group receiving anticoagulant therapy,compared with 5.3 percent in the group notreceiving anticoagulant therapy. These results

are impressive because the number of patientswith congestive heart failure, hypertension andrheumatic heart disease was greater in the anti-coagulation group than in the group notreceiving anticoagulation.

The prevalence of intracardiac thrombi inpatients with AF has been investigated in sev-eral studies. 21-24 One study included 233patients with AF of more than 48 hours dura-tion who had not previously received anticoag-ulants. 22 A left atrial thrombus was found in 15percent of the patients. In all but one patient,the thrombi were located in the atrial appen-dage. In another study, 24 left atrial thrombiwere detected by transesophageal echocardiog-raphy in 13 percent of 113 patients with noacute embolic event, even though AF had beenpresent for fewer than three days. In 122patients with AF of three days duration orlonger and no embolic event, the prevalence of left atrial thrombi was 29 percent. 24

Based on these observations, it is generally recommended that anticoagulation be insti-tuted for three weeks before cardioversion isattempted in patients with AF of more thantwo days duration. To minimize thromboem-bolic complications, anticoagulants should becontinued for four weeks after cardioversion.This period is required for recovery of atrialmechanical contractility after conversion to asinus rhythm. Such a recommendation isbased more on tradition and theory than onfindings from controlled trials.

The time required for a clot to form in theatrium during AF is unknown. Once a clot is


Current evidence suggests that a target INR of 2.0 to 3.0reduces the risk of stroke in high-risk patients with atrialfibrillation.


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formed, the assumption is that a poorly adherent clot is more likely to dislodge at thetime of cardioversion. It has been estimatedthat the time needed for organization of the

newly formed clot is approximately twoweeks. Therefore, anticoagulation for fourweeks following cardioversion would coverthe time required for organization of a clot,adherence of any existing clot and preventionof a new clot. Continued anticoagulation aftercardioversion would theoretically protect thepatient from embolic events until atrialmechanical activity is restored, which can takeup to two weeks.

An alternate approach using transesoph-ageal echocardiography has been suggestedfor use in hospitalized patients with AF of more than 48 hours duration. 22 In one

prospective study, 22 intravenous heparin wasadministered for at least 12 hours and trans-esophageal echocardiography was used todetermine whether atrial thrombi were pre-sent. Patients without atrial thrombi under-went electrical or pharmacologic cardiover-sion, followed by warfarin therapy for fourweeks after cardioversion. No clinicalembolic events occurred in this group.Patients with atrial thrombi identified ontransesophageal echocardiography receivedwarfarin therapy for three weeks before car-

dioversion was attempted and for four weeksafter cardioversion.The need for anticoagulation before car-

dioversion in patients with AF of short dura-tion (less than 48 hours) is less clear. Thesepatients can harbor left atrial thrombi and sys-temic emboli. Intravenous administration of heparin before cardioversion, followed by warfarin therapy for four weeks after car-dioversion, may be beneficial but supportivedata are not available.

Risk of Bleeding with

Antithrombotic TherapyIn pooled data from five randomized trials

(mean age of patients was 69 years), the rate of intracranial hemorrhage in warfarin-treatedpatients (therapeutic target range varied) was0.3 percent per year. 25 In the subgroup of elderly patients (mean age: 80 years) in SPAFII,17 the rate of intracranial hemorrhage was1.8 percent in those who received warfarin(INR: 2.0 to 4.5) and 0.8 percent in those whoreceived aspirin. One explanation for thehigher rate of intracranial hemorrhage in thiselderly subgroup is that the selection of patients for enrollment was less restrictivethan that used in the five trials. Elderly patients overall would be expected to have arate of warfarin-associated intracranial hem-orrhage higher than 0.3 percent per year,which was reported in collaborative AF trialsanalysis.25

In addition to increasing age of the patient,the strongest risk factors for warfarin-associ-

Anticoagulation


If atrial fibrillation has been present for more than two days,the patient should receive anticoagulant therapy for threeweeks before cardioversion and for four weeks after cardioversion.

The AuthorsWAHEED AKHTAR, M.D., is currently in private practice in Mount Olive, N.C. He for-merly was a clinical instructor of medicine and a fellow in cardiology at East CarolinaUniversity School of Medicine, Greenville, N.C. A graduate of King Edward MedicalCollege, Lahore, Pakistan, Dr. Akhtar completed a residency in internal medicine at St.Marys Hospital, University of Rochester (N.Y.) School of Medicine and Dentistry.

WILLIAM C. REEVES, M.D., is professor of medicine at East Carolina University Schoolof Medicine. Dr. Reeves received a medical degree from the University of Texas Med-ical Branch at Galveston and completed a residency in internal medicine at MontefioreHospital, Pittsburgh, Pa., and a fellowship in cardiology at Strong Memorial Hospital,Rochester, N.Y.

ASSAD MOVAHED, M.D., is director of nuclear cardiology and professor of medicineand radiology at East Carolina University School of Medicine. Dr. Movahed received amedical degree from Jondi ShaPour Medical School, Ahwaz, Iran. He completed a res-idency in internal medicine at Wayne State University, Detroit, Mich., and a fellowshipin cardiology at Cleveland (Ohio) Metropolitan General Hospital and a fellowship innuclear medicine at Johns Hopkins Medical Center, Baltimore.

Address correspondence to Waheed Akhtar, M.D., Mount Olive Family Medicine Cen-ter, 238 Smith Chapel Rd., Mount Olive, NC 28365. Reprints are not available fromthe authors.


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ated intracranial hemorrhage are poorly con-trolled hypertension, excessive anticoagula-tion and a history of cerebrovascular disease.

Final CommentAnticoagulation with warfarin (INR: 2.0 to

3.0) is clearly beneficial in patients with non-rheumatic AF who are at moderate risk forstroke and have a low risk of bleeding as aresult of anticoagulation (Table 4). 26,27 Antico-agulation with warfarin should also be insti-tuted in patients with a high risk of emboli

unless the risk of bleeding is very high.Patients with lone AF who are under 60

years of age with no other risk factors forstroke are at low risk for systemic embolismand stroke. The risks of anticoagulation inthese patients outweigh the potential benefits.Patients over 60 years of age are at intermedi-ate risk of stroke and will benefit from antico-agulation.Younger patients without heart fail-ure or cardiac chamber dilatation who are athigh risk for atherosclerosis may take aspirinin a dosage of 325 mg per day.

A decision to initiate anticoagulation mustbe individualized, with the physician carefully weighing the risk of bleeding against thepotential reduction in embolic risks. Currentrecommendations for antithrombotic therapy for AF necessitate individualization of therapy after an integrated clinical assessment thatevaluates thromboembolic risk due to AFalone, other potential indications for antico-agulation, hemorrhagic risk and nonmedicalfactors related to compliance, the patientsability to follow through with INR monitor-ing, the patients gait stability, the risk of othertrauma and the patients preferences. 26

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TABLE 4Recommendations for Anticoagulationof Patients in Atrial Fibrillation

Other risk factorsAge of patient for stroke No other risk factors for stroke

< 65 years Warfarin (Coumadin) Aspirin or no anticoagulant therapy

65 to 75 years Warfarin Aspirin or warfarin

> 75 years Warfarin Warfarin

Information from references 26 and 27.


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