Epidemiologic Assessment of Chronic Atrial Troke

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Article ab st ra ct Ch ro ni c atrial fibrillation AF) as a precursor of stroke was assessed o ver 24 yea rs offollow-up ofthe general population sample at Framing ham, Massachusetts. Persons with chronic established AF ith or withoutrheumatic heart disease RHD),are at greatl y increased risk of stroke , and th e stro ke is probably du e to embolism.Chronic AF in t he ab sence of RHD is associated with more tha n a fivefold increase in s troke incidence, while AF withRHD has a 17-fold increase. Stro ke occurrence increased as duration of A F increased, with no evidence of aparticularly vulnerable period. Chronic idiopathic A F is an imp orta nt precursor of cerebral embolism. Controlledtrials of anticoagulants or antiarrh ythmic agents in persons with chronic AF may demonstrate if strokes can beprevented in this highly susceptible group.

NEUROLOGY 28: 973-977, October 1978

Epidemiologic assessment ofchronic atrial fibrillation and riskof stroke: The fiamingham StudyPhilip A. Wolf, M.D, Thomas R. Dawber, M.D., M.P.H., H. Emerson Thoma s, Jr ., M.D., and William B.

Ka nne l, M.D., M.P.H.

Atri al fibrillation (AF) in rhe umatic hea rt disease(RHD), particularly with mitral stenosis, is ac-cepted as a factor th at predisposes to systemic em-bolism.' Embolism from the left at ri um occurs fre-quently an d cerebral infarction is a common causeof dea th among RHD pa t ien ts wi th mi t ra lstenosis.' There is no such agre ement about r isk ofcerebral embolism in persons with chronic AFwithout rheumatic valvular disease. Beer andGhi tma n3 ound only one stroke among 50 patientswith AF d ue to ischemic heart disease, a ra te ofcerebral embolism not appreciably different thanthe 2 percent occurring in ischemic he ar t diseasepatients without this arrhythmia. However,others have found systemic embolism to be ascommon in chronic AF with coronary and hyper-tensive heart disease as in RHD. .

Since it is likely that progress will come fromprevention rather than from improved medicalman age men t of completed embolic str oke s, it isimportant to determine if chronic AF predisposesto stroke. The le ast distorted view of the re lation-shi p of AF to stro ke can be obtained thr oug h pro-spective epidemiologic study of a gener al popula-tion which is free of the biases of selection thatexist i n clinical an d autopsy populations. We hav e

studied th e development of stro ke in a populationfollowed prospectively since 1950, an d we hav erelated stroke incidence to antecedent cardiacrhythm and disease.

Methods. We evaluate d the development of strokei n 5184 men a nd women, aged 30 to 62, and free ofstroke at ent ry, followed for 24 years. Samplingprocedure, criteria, and methods of examinationhave been described e l~ e wh e re .~ ,~ ubjects wereexamined every 2 years. Follow-up was good, with81 percent taking all possible examinations andless than 5 percent of the original cohort lost tomor tal ity follow-up.

On each of the 13 biennial examinations, thesubject was routinely questioned by a physicianconcerning habits, medications, and illnesses dur -ing t he preceding 2 years. Physical examinationand laboratory studies were made, a nd details sur-rounding all interim illnesses were sought. Forstroke, including transient ischemic at tacks(TIAs), surveillance was maint ained by daily mon-itoring of all admiss ions to the only gener al hospi-ta l in town. If a strok e was suspected, the pat ien twas seen in t he hospital by th e stud y neurologist.Neurologic symptoms or signs noted by t he st udy

From the Dep artment of Neurology Dr.Wolf ; and th e Section on Preventive Medicine of th e Division of Medicine (Drs. Dawber and Thomas , BostonUniversity School o f Medicine, Boston, Massachusetts; an d the Hea rt Disease Epidemiology Study (Dr. Kannel , National Heart and Lung Institute,Framingham, Massachusetts.

Presented in part a t the twenty-eighth an nual meeting of the American Academy of Neurology, April 29, 1976, Toronto, Canada.

Supported in part by Research Grant N S 09695-05 from the National Institutes of Health.

Accepted for publication September 12, 1977.

Reprint requests should be addressed to Dr. Wolf, Departmen t of Neurology, Boston Un iversity School of Medicine, 80 Eas t Concord Street , Boston,MA 02118.

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Atrial fibrillation and stroke

physician at biennial examination were followedby a detailed evaluation in the neurology clinic.The circumstances surrounding all illnesses andth e dea th of each stud y subject were also soug ht byscrutiny of all avai labl e medical information, in-cluding hospital and physician records and post-mortem da ta . Prospectively, for all illnesses und er

study and upon the de ath of each subject, all d at awere reviewed by a panel of physicians to deter-mine if minimal criteria were met for the diagnosisof the diseases under study and to determine theunderlying cause of de ath . A neurologist ha s par-ticipated in reviews of suspected stroke cases forthe past 17 years.

Determination th at a stroke has occurred canusually be made accurately if the neurologist canreview the historic details of the event with thepatie nt and his family, and can examine t he pa-tient in the hospital within a day or two of theictus. During the past 10 years, most subjects havebeen admitted to the hospital by their personal

physicians when stroke or TIA was suspected.Most had lum bar puncture, brain scan, EEG, andskull radiographs. Cerebral arteriography wasperformed on a minority of patients with stroke,but it was usually done in those suspected of sub-arachnoid hemorrhage . Genera l pos tmor temexaminations were performed in 40 percent of1305 decedents in the cohort, including 195 per-sons with stroke; complete neuropathologicexamination was made in half of the autopsies.Nevertheless, i t is often clinically difficult to dis-tinguish thrombotic from embolic stroke and tocorrectly identify small intracerebral hemor-rhages. It is not always clear whether a cerebralinfarct is secondary to occlusive disease of thelarge arte ries supplying the brai n or due to lacu-nar infarction as a consequence of occlusion of asmall penetrating vessel.

To elucidate the relationship of atrial fibrilla-tion to ris k of embolic stroke , it seemed most re a-sonable to compare the incidence of stroke of all

types, combined, in persons with and wi thout th isarr hyt hmi a. This approach should circumvent anylack of precision in diagnostic categorization ofstrok e by type, in relation to antecedent AF whereembolism is almost automatically diagnosed. Inci-dence of stroke (all types combined), was deter-mined in the 4969 men and women free of AF a nd

in the two subgroups of persons with AF on bien-nial examination-those with RHD and those withidiopathic AF. The du rat ion of AF to risk of stro kemay be impor tant a nd, by utilizing person-years ofobservation, duration of the arrhythmia can beaccounted for. We excluded subjects with strokeprior t o th e onset of AF. Perso ns found to be in AFfor the first time when hospitalized for strok e wereexcluded, as were those with known paroxysmalfibrill ation. I n order to provide a clear a nd prospec-tiv e picture of th e development of str oke in AF, weincluded only subjects who were fibrillating onbiennial examination.

To adjust for t he effect of ag e an d blood pressur e

on stroke incidence, an expected rate was calcu-lat ed in each sex for each a ge decade and for nor-mal, borderline, and hypertensive subjects; thisgave a n observed-to-expected ra tio, which correctsfor age and blood pressure in each sex.

Results. After 24 years of follow-up, 345 strokesoccurred; 168 in men an d 177 in women (tab le 1).Bra in infarction secondary to atherosclerotic andthrombotic disease, designated atherothromboticbrai n infarction (ABI), was t he most common typeof stroke, occurring in 97 men an d 107 women an daccounting for 59 percent of all strokes. Cerebralembolus, usually with a demonstrated source of

emboli, occurred in 14 percent. S trok e was due toother causes in 3 percent , a nd TIA only accountedfor 9 percent. I ntrac rani al hemorrha ge occurred in15 percent of the cases; subarachnoid hemorrhagein 10 percent, a nd intra cerebral hemorrhage in 5percent.

D u r i n g 481 per son -ye ars of fol low-up of

Table 1. Incidence of stroke by type-24-year followup

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Table 2 Age-sex hypertensive status adjusted rat e of stroke per 1000 person-years, based on 24-yearfollowup

idiopathic AF, there were 20 instances of stroke,10 in men a nd 10 in women (table 2). This r at e of41.4811000 person-years was 5.6 times as frequentas th at in men and women of the same age andblood pressure dist ribu tion who were fre e of AF. Inthe group with AF and RHD, the age and bloodpressure-adjusted risk of stroke was increasedabout 18-fold in both sexes. These differences werehighly significant 0.01) for persons wit h AF,with o r without RHD. St rok es among persons withchronic persistent AF occurred in direct rela tio n todurat ion of AF (table 3). The median duration ofAF prior to str oke was 39.5 months, with a distri -bution of inte rve nin g tim e from weeks to moretha n 10 years. Coronary h ea rt disease (CHD) wasfre que nt among persons with chronic AF, whetheror not a strok e occurred (tab le 4 . Congestive hea rtfailure (CHF) was also strongly associated withAF and occurred in half of those patients withchronic AF who developed st roke, and in a simila rproportion of non-stroke patients with AF. CHFoften occurred at th e onset of AF, and digitalis wasadministered uniformly. CHD or CHF did notseem to be the cause of these strokes, since thesecardiac abnormalities were equally frequent inchronic fibrillators without stroke.

It was difficult to determine the mechanism ofstroke in all cases. In persons with A F and RHD,there is ample reason to believe the stro ke was duet o cerebral embolus, the source of the embolusbeing the left atr iu m. Review of the clinical even tssuggested th at most of th e 20 strokes occurring inthe idiopathic AF group were also due to em-bolism. One patient ha d an intracerebral hemor-rhage related to antic oagulant therapy t ha t hadbeen given to pre ven t furt he r embolization follow-ing embolectomy from the left femoral artery 3months before. The other 19 patients had th e ab-rupt onset, often while active, of focal neurologicdysfunction, reaching its maximum in momentsand often clearing completely in days. None of the20 persons had a n antecedent tr ans ien t ischemicattack. Eleven of these 20 died and postmortemexamination was performed in eight; the brainwas examined in six of these eight necropsies. Inthese six, a cerebral infarct corresponded in loca-

Table 3. Duration of chronic AF prior to stroke

tion a nd age to th e clinical event. Infarction wasmultiple in one case and associated with atrialthrombus and an old splenic infarct in another.The art erie s were pa ten t in two cases, and in one ofthe se th e infarct wa s hemorrhagic. Th e absence ofRHD was confirmed in all eight autopsied cases.

Discussion. There is little doubt that patientswith RHD and AF, and particularly those withmitral stenosis, are at heightened risk of arterialembolization. The infarc tion is frequently solely inthe brain; visceral or limb arterial embolism isboth infrequent an d often overlooked in compari-son to cerebral embolism, which accounts for abouthalf of the emboli. The mode of exitus of thesepatie nts is frequently th e initi al embolism, and in65 percent, the s ite is the brain. Among survivors,more tha n half die of fur th er cerebral emboli, oftenwithout clinical evidence of renal, mesenteric,splenic, or limb embolism.’ Systemic art eri al em-bolism from the heart in rheumatic valvular dis-ease may occur soon after conversion from sinusrhyt hm to AF, or aft er spontaneous, drug, or elec-

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Atrial fibrillation and stroke

Table 4. The frequency of coronary heart disease or congestive heart failure among nonrheumatic atrialfibrillators, men and women

trical reversion to a sinus mechanism from AF.2Embolism also occurs dur ing t he course of chronicAF in RHD, usually in p atien ts with establishedAF.4.8

Evidence is accumulating tha t idiopathic AF isalso frequently followed by systemic arterial em-bolization, and t ha t cerebral infarction, secondary

to embolism from the heart, is a major factor instroke occurrence. The evidence comes fromepidemiologic, clinical, an d pathologic studies. I na prospective epidemiologic study of precursors ofstrok e among members of a ret ire men t commu-nity, AF was more freq uent among strok e cases,19.7 percent versus 3.4 percent, and about one-fifth of all str oke s occurred i n persons wit h AF.9

Among persons with chronic AF, cerebral in-farction may be the initia l and sole manif estat ionof systemic embolism. ', In a clinica l st ud y ofchronic sinoatrial disorder, stroke occurred sixtimes more frequently among those with chronicAF th an in matched controls. Embolism occurs

durin g paroxysmal AF even i n th e absence of or-ganic heart disease.':' In pathologic studies em-bolism is aow recognized as a f requent an d impor-tant mechanism in cerebral infar~tion. '~, '~ n theabsence of occlusive disease of th e carotid a rt er y,infarction in the territory of the middle cerebrala r t e r y i s usually due to embolism from theheart,' commonly ari sing within th e fibr illat ingatr ium. Hinton and colleagues studied 333 con-secutively autopsied patients who have docu-mented AF. Embolism was nea rly a s common inAF without RHD (35 percent) as in those withmitral valve disease (41 percent) ; lef t atr ialthrombus was present in 20 percent of non-

rheumatic patients with AF. Embolic infarctionwas solely in t he brain in 53 percent, and 90 per-cent of the pati ent s were functional and ambu la-tory prior t o the stroke. Death was directly att rib-uted to embolism in 26 percent of the cases.

The strokes occurring i n chronic fibrillators inthe Fr amingha m cohort had the clinical featu resof embolism in 19 of t he 20 events. T here w as th eab ru pt onset of deficit with maximal involvementat onset, absence of an teced ent TIAs, an d rapi dreversal of the neurologic signs. Pathologic sup-

por t for embolism as th e mechanism of stroke waspresent in 6 of the 12 who died.

Preventive implications Persons with chronicAF, idiopathic or rheumatic in origin, are atgreatly increased risk of embolic stroke. ChronicAF is not ra re i n the elderly, particulary amongthose with other risk factors for stroke-CHF,

CHD, hypertension, and LVH revealed by elec-trocardiogram (ECG). There is sufficient evidenceth at AF predisposes to stroke and efforts a t pre-vention are certainly war rante d. Attempts to re-store sinus rhyth m or to prevent left atri al throm-bus formation, including controlled trials of an-ticoa gulant s in chronic fibrillators without RHD,may reduce de ath a nd disability from embolism inthi s stroke-prone group.

Acknowledgments

The authors wish to acknowledge the cooperation and assis-tance of Dr. Theodore Colton, Miss Patricia M. McNamara,Miss Rita Nickerson, and Mr. Jeremy Pool in the data handl ingand analysis.

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2. Askey JM , Berstein S: The management ofrheumatic hear tdisease in relation t o systemic arter ial embolism. Prog Car-diovasc Dis 3:220-232 1960-1961

3. Beer DT, Ghitman B: Embolization from the atria in ar-teriosclerotic h ear t disease. JAMA 17728 7-291 , 1961

4 Hurst JW, Paulk EA, Proctor H, et al: Management ofpatients with atrial fibrillation. Am J Med 37:728-741,1968

5 Vost A, Wolochow DA, Howell DA: Incidence of infarcts ofthe brain in heart disease. J Pathol Bacteriol 88:463-470,1964

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7. Shurtleff, D: In Kann el WB, Gordon T (Edito rs): TheFramingham Study: An Epidemiological Investigation ofCardiovascu lar Disease. Section 30. Washington, D C, T SGovernment Printing Office, 1974

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9. Fried man GD, Loveland DB, Ehrlich SP: Relationship ofstroke to other cardiova scular disease. Circulation 38:533-541, 1968

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10. Fisher C M : Treat ment of chronic atr ial fibrillation. Lancet1:1284, 1972

11 Hinton RC Kistler JP , Fallon JT , et al: The influence ofetiology of atr ia l fibrilla tion on th e incidence of system icembolism. Am J Cardiol 4050 9-513, 1977

12. Fairfax AJ , Lambe rt CD, Lea tham A: Systemic embolismin chronic sinoatrial disorder . N Engl J Med 295:190-192,1976

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DOI 10.1212/WNL.28.10.9731978;28;973 Neurology

Philip A. Wolf, Thomas R. Dawber, H. Emerson Thomas, Jr., et al.Study

Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: The fiamingham

This information is current as of October 1, 1978

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Epidemiologic Assessment of Chronic Atrial Troke