Download Antithrombotic Therapy in Valvular Heart Disease

Antithrombotic Therapy in
Valvular Heart Disease
Herbert J. Levine, MD, FCCP, Chair;
and Mark H. Eckman, MD
Stephen G. Pauker, MD;
studies of less-intense regimens of warfarin
ported in recent
been reported that prothrombin times (PTs)
therapy. It has
performed with the commonly used commercial North
American thromboplastin, maintained in the range of 1.3 to
1.5 times normal
control (international normalized ratio
[INR], 2.0 to 3.0), retained effectiveness against recurrent
thromboembolism with a greatly reduced frequency
of bleeding complications.5 Of greater relevance to patients
with valvular heart disease is the report by Turpie et al,6
which suggests that a less-intensive regimen of warfarin
and is safer than standard an¬
therapy is "no less effective,
in
ticoagulant therapy patients with tissue heart valve
replacement." Similar findings have been reported in pa¬
tients with mechanical heart valves. Among 258 patients
randomized to regimens of moderate-intensity warfarin
therapy (PT ratio, 1.5; INR, 2.65) vs high-intensity therapy
(PT ratio, 2.5; INR, 9.0), thromboembolism occurred with
similar frequency in the two groups, while the risk of
bleeding was significantly lower in the moderate-intensity
venous
complications of valvular heart disease be
Few
devastating than systemic embolism. With little regard
for the
of the
valve
cerebral
can
severity
underlying
lesion, a
more
or
mesenteric embolus can, in a moment's time, cripple or kill
a previously asymptomatic patient. It is well recognized that
antithrombotic therapy can reduce, although not eliminate,
the likelihood of this catastrophe. If this therapy were risk
free, all patients with valvular heart disease should be
treated. Unfortunately, antithrombotic therapy, particularly
with warfarin derivatives or heparin, carries a substantial risk
of bleeding; that risk varies with the drug used, the intensity
of the anticoagulant effect, and the clinical circumstances in
individual patients. For example, risks of anticoagulant
are greater in patients with endocarditis, pregnancy,
therapy
and bleeding diatheses.
This review will examine the risks of thromboembolism in
various forms of valvular heart disease and attempt to
establish strategies for using antithrombotic drugs in each
disease. For the most part, these analyses and guidelines will
concern the long-term use of antithrombotic therapy in
ambulatory
patients.
Basic to these considerations is assessment of the risk of
bleeding. For example, it is appreciated that the rewards of
anticoagulant therapy will be greater in patients with a high
risk of thromboembolism than in those at low risk for this
event, but the benefits of anticoagulation may be offset by
the hemorrhagic complications of antithrombotic therapy. It
is also important to emphasize that the permanent conse¬
quences of a thromboembolic event are generally more se¬
rious than the ultimate outcome of a hemorrhagic compli¬
cation of anticoagulant therapy, and thus the rate of embolic
is not necessarily counterbalanced by an equal
phenomenon
event rate of bleeding.
Rahimtoola1 reported that the risk of major bleeding in
patients with prosthetic heart valves who received warfarin
was 1 to 2 %/yr, and in a careful analysis of ten reports of
anticoagulant therapy in patients with prosthetic valves cov¬
ering 215.5 patient centuries of follow-up, Edmunds2 found
the weighted mean rate of serious bleeding complications to
be 2.19%/yr, with fatalities due to bleeding in 0.17%/yr. In¬
terestingly,inthe same ratewithof serious
bleeding (2.11%/yr) was
atrial
fibrillation during 284
reported patients
patient-years of warfarin therapy.3 In a recent review of 46
studies of patients with mechanical heart valve prostheses
who had undergone anticoagulation with warfarin deriva¬
tives (53,647 patient-years of follow-up), the incidence of
major bleeding was 1.4%/yr 4
Another consideration that will influence greatly our as¬
sessment of the risk-benefit ratio of anticoagulant therapy
relates to the intensity of anticoagulation, particularly as reReprint
requests: Dr. Levine, 750 Washington St, Box 315, Boston,
MA 02111
360S
group.7
The
utility and safety of a lower intensity of warfarin ef¬
fect has also been shown in patients with mechanical heart
valves treated with concomitant antiplatelet therapy. Altman
et al8 found that among patients given aspirin (330 mg/d) and
dipyridamole (75 mg twice daily), those randomized to
warfarin therapy (INR, 2.0 to 3.0) had less
modest-intensity
than
those
bleeding
given higher-intensity warfarin (INR,
3.0 to 4.5), while the incidence of thromboembolism was
similar in the two groups.
Further evidence to support the use of lower-intensity
warfarin anticoagulation comes from five large, multicenter,
randomized studies of patients with nonvalvular atrial fibril¬
lation.9"13 In these studies, all of which showed a substantial
benefit of warfarin, the utility of the anticoagulant therapy
was independent of the target range of INR, which varied
from 1.4 to 2.813 to 2.8 to 4.2,9 suggesting a better risk-ben¬
efit ratio with the lower-dose range. It should be empha¬
sized, however, that the utility of lower-intensity anticoagu¬
lation in patients with nonvalvular atrial fibrillation should
not necessarily be extrapolated to patients with mitral valve
disease.
Rheumatic Mitral Valve Disease
The incidence of systemic embolism is greater in rheu¬
matic mitral valve disease than in any other common form
of heart disease. While the natural history of this disease has
been altered during the past 40 years by surgery and the
frequent use of long-term anticoagulant therapy, Wood14
cited a prevalence of systemic emboli of 9 to 14% in several
and in 1961, Ellis and
large early series of mitral27%stenosis,
of 1,500 patients undergoing
Harken15 reported that
mitral valvuloplasty had a history of clinically detectable
systemic emboli. Among 754 patients followed up for 5,833
patient-years, Szekely16 observed an incidence of emboli of
1.5%/yr, while the figure was found to vary from 1.5 to
4.7%/yr preoperatively in six reports of rheumatic mitral
valve disease.17 As a generalization, it is perhaps reasonable
to assume that a patient with rheumatic mitral valve disease
has at least one chance in five of having a clinically detect¬
able systemic embolus during the course of the disease.18
The incidence of systemic emboli increases dramatically
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of atrial fibrillation (AF). Szekely16
development
that
the
risk
of
embolism was seven times greater
reported
in patients with rheumatic mitral valve disease and AF than
in those with normal sinus rhythm, and among mitral
patients with AF, Hinton et al19 found a 41% prevalence of
systemic emboli at autopsy. Three quarters of the patients
with mitral stenosis and cerebral emboli described by Har¬
ris and Levine20 and by Wood14 had AF. Among 839 patients
with mitral valve disease described by Coulshed and associ¬
ates,21 emboli occurred in 8% of mitral stenosis patients with
normal sinus rhythm, 31.5% of those with AF, 7.7% of those
with dominant mitral regurgitation and normal sinus rhythm,
and 22% of those with mitral regurgitation and AF. Wood14
confirmed that emboli occur VA times as frequently in pa¬
tients with mitral stenosis as in patients with rheumatic mi¬
tral regurgitation.
The risk of systemic emboli in patients with rheumatic
mitral disease is greater in older patients22"25 and those with
lower cardiac indices22 but appears to correlate poorly with
mitral calcification,21 mitral valve area,22 or clinical classifi¬
cation.14'21'22,26 Indeed, several investigators have pointed
out that mitral patients with emboli frequently are found to
have minor valve disease, and Wood14 reported that in 12.4%
of cases, systemic embolization was the initial manifestation
of rheumatic mitral disease. The relationship between
thromboembolism and left atrial size remains unclear. In
earlier studies of rheumatic mitral valve disease, a poor cor¬
relation was observed,14,21,26 but more recent reports, pri¬
marily in patients with nonvalvular atrial fibrillation, suggest
that left atrial size is an independent risk factor for throm¬
with the
boembolism.27"29
Among patients with valvular disease who suffer a firstof
recurrent emboli occur in 30 to 65%
cases,14183031 of which 60 to 65% are within the first
year30,31 and the majority occur within 6 months. Mitral
embolus,
not appear to decrease the risk of throm¬
valvuloplasty doesThus
a successful mitral valvuloplasty does
boembolism.17,21
not eliminate the need for anticoagulation, and patients will
continue to require this therapy postoperatively.
There is good reason to believe that the frequency of sys¬
temic emboli due to rheumatic valve disease is decreasing,
while the number due to ischemic heart disease is on the rise.
This reduction in the number of systemic emboli due to
rheumatic heart disease is due both to a decrease in the ab¬
solute number of rheumatic heart disease patients and to the
widespread use of long-term anticoagulant therapy in these
patients.
Although never evaluated by randomized trial, there is
little doubt that long-term anticoagulant therapy is effective
in reducing the incidence of systemic emboli in patients with
rheumatic mitral valve disease. In a level IV study, the inci¬
dence of recurrent embolism in mitral valve patients who
received warfarin was 3.4%/yr, while in the nonanticoagulation group it was 9.6%/yr. Adams et al32 followed up 84
patients with mitral stenosis and cerebral emboli for up to 20
years, half ofwhom received no anticoagulant therapy (1949
to 1959), and half of whom received warfarin (1959 to 1969)
(level IV study). Using life table analyses, a significant
reduction in emboli was reported in the treated group, with
13 deaths from emboli in the untreated group and only 4
deaths in the treated group. Fleming and Bailey,26 in a level
IV study, found a 25% incidence of emboli among 500 un¬
patients with mitral valve disease, while in 217
patients treated with warfarin, only five embolic episodes
occurred with an incidence of thromboembolism of 0.8%/
patient-yr. In a retrospective study of 254 patients with AF
(level IV study), an embolic rate of 5.46%/yr was reported for
patients who did not receive anticoagulation vs 0.7%/yr for
those receiving long-term warfarin therapy.3
the strongest evidence to date supporting the
Perhaps
of
utility anticoagulation for the prevention of thromboem¬
treated
bolism in mitral valve disease comes from extrapolation of
the results of four, recent, large, randomized studies in pa¬
tients with nonvalvular atrial fibrillation.9"1113 Each of these
level I studies demonstrated that warfarin was effective in
reducing stroke in patients with nonvalvular AF. An addi¬
tional Canadian multicenter trial12 was terminated prema¬
a trend consistent with the
turely when its results developedtrials.
In one of these trials,10
data reported in the four earlier
rate of thromboem¬
to
the
decrease
was
also
found
aspirin
bolism in patients younger than 75 years of age.
In view of these data, as a general rule, all patients with
rheumatic mitral valve disease and AF (paroxysmal or
chronic) should be treated with long-term warfarin therapy.
include the
Exceptions that require detailed tradeoff analysis for
serious
risk
at
or
the
woman
patient high
pregnant
concomitant
to
established
due
whether
disease,
bleeding,
exposure to contact sports or trauma, or inability to control
the PT.
Despite the powerful thromboembolic potential of AF,
the rheumatic mitral valve disease patient in sinus rhythm
still has a substantial risk of systemic embolism and is,
therefore, a candidate for long-term warfarin therapy. Other
than age, there are no reliable clinical markers in such cases,
so the decision to treat is problematic. Because the risk of AF
is high in rheumatic mitral disease patients with a very large
atrium, it has been suggested that such patients in normal
sinus rhythm with a left atrial diameter greater than 55 mm
should receive anticoagulant therapy.33
With the advent of percutaneous balloon mitral valvulo¬
clinicians are faced with a small chance that the
plasty,
catheter will dislodge the left atrial clot during the proce¬
dure. Accordingly, some centers have made it a practice to
treat all such patients with warfarin, regardless of the pres¬
ence or absence of AF, for a minimum of 3 weeks before the
balloon valvuloplasty. An alternate strategy might be to per¬
form transesophageal echocardiography (TEE) just prior to
balloon mitral valvuloplasty and if the examination reveals no
left atrial clot, anticoagulation prior to the valvuloplasty can
be avoided.34,35 However, experience with patients under¬
going cardioversion of atrial fibrillation suggests that the
absence of atrial clot by TEE at the time of the procedure
does not preclude the need for prompt anticoagulation af¬
ter cardioversion to prevent thromboembofism. Therefore,
one can make a good case for providing anticoagulation
therapy for most patients after balloon mitral valvuloplasty
for at least 4 weeks.
Several studies have suggested that systemic embolism in
patients with valvular heart disease occurs more frequently
in those with shortened platelet survival times.36"40 Steele
and Rainwater41 reported that shortened platelet survival
was a sensitive index of past thromboembofism in patients
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with rheumatic valve disease, but the specificity of this
finding was low, since 78% of patients without thromboem¬
bolism also had shortened platelet survival. Although sulfin¬
pyrazone appeared to decrease the incidence ofthromboem¬
bolism in these patients with mitral stenosis, two thirds were
also taking warfarin, and efficacy of sulfinpyrazone as
monotherapy for the prevention of thromboembolism re¬
mains
unproved.42
It has also been shown that shortened platelet survival in
patients with prosthetic heart valves can be normalized by
sulfinpyrazone36 and by dipyridamole.3' Similar observa¬
tions have been made in patients with mitral stenosis treated
with sulfinpyrazone40,41 and in patients with arterial grafts
treated with dipyridamole.43 Furthermore, in a level I ran¬
domized study of patients with prosthetic heart valves, the
addition of dipyridamole to warfarin therapy proved effec¬
tive in reducing the incidence of systemic emboli.44 Similar
findings were reported in a level III study,45 and the com¬
bination of dipyridamole (450 mg/d) and aspirin (3.0 g/d) was
also observed to reduce the incidence of thromboembolism
in patients with prosthetic heart valves (level IV study).39
Dale and associates46 performed a randomized study of as¬
pirin (1.0 g/d) plus warfarin vs warfarin alone in 148 patients
with prosthetic heart valves and noted a significant reduction
of emboli in the aspirin-treated group. Intracranial bleeding
occurred with equal frequency in both groups, while GI
encountered more
complications, including bleeding, were
often in the patients taking aspirin. At the completion of the
were treated with aspirin alone and had
study, all patients
recently,
unsatisfactory control of embolic events. More
Turpie et al4' have reported that the addition of aspirin (100
to 4.5) reduced mortality and
mg/d) to warfarin (INR, 3.0
major thromboembolism in patients with mechanical heart
valves and in high-risk patients with bioprosthetic heart
valves with no significant increase in major bleeding. The
safety and effectiveness of combined warfarin and antiplate¬
let therapy have since been confirmed in a nonrandomized
prospective study of patients with St. Jude Medical Valve
prostheses.48
there is evidence that
dipyridamole and sulfinpyra¬
will normalize shortened platelet survival and reduce
the incidence of emboli in some patients with valvular heart
disease and that dipyridamole and/or aspirin added to war¬
farin therapy will reduce the incidence of thromboembofism
in patients with prosthetic valves. However, until these
findings are confirmed and the effectiveness of platelet-ac¬
tive drugs compared with that of warfarin in randomized
trials, patients with rheumatic mitral valve disease consid¬
ered to be at risk for thromboembolism should be given
warfarin unless the risk of bleeding is unusually high. If this
should fail, a platelet-active agent should be added;
therapy
or, if warfarin is contraindicated, antiplatelet therapy might
be a reasonable, albeit uncertain, alternative. The recom¬
mendation concerning the use of dipyridamole is to be re¬
as tentative as there is increasing evidence that the
gardedoffers
little beyond the effect of aspirin administered
drug
Thus,
zone
concomitantly.49
The relative
utility of warfarin vs aspirin as antithrombotic
fibrillation
monotherapy patients with nonvalvular atrial fifteen
been
addressed.50
Seven
hundred
pa¬
recently
tients aged 75 years or younger and 385 patients older than
in
has
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75 years were separately randomized to warfarin
to 4.5) or aspirin (325
mg/d) therapy;
mean
(INR, 2.0
follow-up was 3.1
and 2.0 years in the two age groups, respectively. The pri¬
mary event rate (ischemic stroke and systemic embolism)
was 1.3%/yr with warfarin and 1.9% with aspirin (p=0.24) in
the younger group, and 3.6% with warfarin vs 4.8% with as¬
pirin (p=0.39) in the older group. While it was concluded
that warfarin may be more effective than aspirin for
prevention of ischemic stroke, the absolute reduction in
stroke rate by warfarin was small and not statistically signif¬
icant. Furthermore, in the older age group, the rate of all
stroke with residual deficit (ischemic and hemorrhagic) was
4.6%/yr with warfarin and 4.3% with aspirin, and again this
difference was not statistically significant.
While these findings suggest that risk stratification of in¬
dividual patients with nonvalvular atrial fibrillation is rec¬
ommended when choosing warfarin or aspirin therapy to
prevent stroke and systemic emboli, extrapolation of these
results to patients with rheumatic mitral valve disease or to
those with significant nonrheumatic mitral disease is prob¬
lematic. Furthermore, an analysis of pooled data from five
randomized, controlled studies of antithrombotic therapy in
nonvalvular AF, the European Atrial Fibrillation Trial, and
the SPAF II study concludes that, "Patients with risk factors
are optimally protected from stroke with warfarin if they are
individuals
good candidates for anticoagulation. Unreliable
or those with other contraindications to anticoagulation
should be considered for aspirin therapy."51
Since to our knowledge randomized studies of the relative
warfarin vs aspirin have not been carried out in
utility ofwith
mitral valve disease, guidelines for antithrom¬
patients
botic therapy in this circumstance have been borrowed from
studies of patients with nonvalvular AF. Since rheumatic
mitral valve disease has long been associated with a high in¬
cidence of thromboembolism, extrapolation of the lessons
learned from patients with nonvalvular AF to patients with
mitral valve disease seems appropriate.
The decision to treat will remain difficult in many cases.
For example, should antithrombotic therapy be given to the
35-year-old,
physically active male with trivial mitral steno¬
sis and normal sinus rhythm or to the asymptomatic mitral
valve patient with AF and history of recurrent GI bleeding?
In some instances, decision analysis will help to clarify
whether to use antithrombotic therapy.52 In others, where
the merits of anticoagulant therapy are questionable, the
finding of a shortened platelet survival may lead the clinician
to recommend the use of platelet-active drugs. In these set¬
tings, the patient's preference may also be important. In all
cases, the risks of treatment will be influenced by the choice
and dose of the agent to be used.
Mitral Valve Prolapse
Mitral valve prolapse (MVP) is the most common form of
valve disease in adults.53 While generally innocuous, it is
sometimes annoying, and serious complications can occur.
During the past 20 years, embolic phenomena have been
several patients with MVP in whom no other
reportedforin emboli
could be found. In 1974, Barnett54
source
observed four patients with MVP who suffered cerebral is¬
chemic events. Two years later, a total of 12 patients were
described with recurrent transient ischemic attacks (TIAs)
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and partial nonprogressive strokes who had no evidence of
atherosclerotic disease, hypertension, or coagulation disor¬
ders.55 Similar observations have been made by other
and as many as nine such patients have
investigators,56"58
been described from a single center.58
Perhaps the most convincing evidence linking MVP to
stroke is provided by the case-control study of Barnett and
associates.59 Among 60 patients younger than 45 years who
had TIAs or partial stroke, MVP was detected in 40%, while
in 60 age-matched controls, the incidence was 6.8%
and in 42 stroke patients older than 45 years,
(p<0.001),
MVP was found in 5.7%, an incidence comparable to that in
the general population.59 However, in a recent preliminary
report of 244 patients younger than 45 years with stroke or
TIAs who were referred for transthoracic echocardiography
(TTE) in search of a source of embolus, only 1.2% had
MVP.60 The authors suggest that these results reflect the
recently validated two-dimensional echocardiographic cri¬
teria for MVP.
A pathologic basis for thromboembolism in MVP has been
suggested
by several investigators. Pomerance61 examined
the hearts of 35 patients with a ballooning deformity of the
mitral valve and found that 10 exhibited a "fibrinous
endocarditis" of the mitral valve. Guthrie and Edwards62
observed endothelial denudation of the mitral valve in
patients with myxomatous degeneration with deposits of fi¬
brin on the denuded surface of the valve, and mural throm¬
bus has been reported at the junction of a prolapsed mitral
leaflet and the atrial wall by Kostuk et al. While clinico¬
pathologic correlations have been lacking in most studies,
fibrin thrombi on a prolapsed valve with myxomatous
degeneration were demonstratedandin a patient who suffered
to brain, heart,
multiplethatemboli,
kidneys.64 It also seems
the
of
transmural
likely
myocardial in¬
phenomenon
farction in MVP patients with angiographic normal coronary
arteries may best be explained on the basis of coronary em¬
bolism65
Thus, although it appears that a small number of patients
with MVP are at risk for systemic thromboembolism,
consideration of denominators should temper our therapeu¬
tic approach to this problem. Assuming that 6% ofthe female
and 4% of the male population have MVP, the incidence of
thromboembolism in these more than 12 million Americans
must be extraordinarily low. Indeed, it has been estimated
that the risk of stroke in young adults with MVP is only
As suggested by Cheitlin,67 informing the
1/6,000/yr.66
with
MVP of this risk is not indicated, "nor is it
patients
reasonable to recommend prophylactic platelet-active drugs"
to all patients with MVP. However, it seems reasonable that
the MVP patient with convincing evidence of TIAs with no
other source of emboli should receive antithrombotic ther¬
apy. Because repeated ischemic episodes are not uncom¬
mon,56'59'62,64 long-term aspirin therapy appears indicated.68
To our knowledge, no studies of antithrombotic therapy in
this disease have been reported, so guidelines for therapy are
at best empiric and drawn from experience with other
thromboembolic conditions. Long-term warfarin therapy is
appropriate for those patients with AF and for those who
continue to have cerebral ischemic events despite aspirin
therapy.
The dilemma of
cost-effective antithrombotic therapy in
patients with MVP would best be solved by a reliable means
of identifying the small cohort of patients at high risk for
thromboembolism. In a retrospective study of 26 patients
with MVP, Steele et al69 reported that platelet survival time
was significantly shortened in all 5 patients with a history of
thromboembolism, but this abnormality was also observed in
one third of the patients without thromboembolism. Future
studies of the clinical and laboratory characteristics of MVP
patients may succeed in reducing the fraction at risk.
Because myxomatous degeneration and denudation of the
mitral endothelium are likely to be critical in the thrombogenic process, patients with "secondary" MVP,70 due solely
to a reduction in left ventricular dimensions, would not be
expected to be at risk. It would also be important to learn
whether the "click-only" or silent MVP patient can be
excluded from the risk of thromboembolism. However, past
observations indicate otherwise as most MVP patients with
cerebral ischemia are found to have a normal physical
examination.'1
study
valve on echocardiography constituted a subgroup of pa¬
tients at high risk for mitral regurgitation, infectious en¬
docarditis, sudden death, and cerebral embolic events. Most
ofthese observations were confirmed in a retrospective study
by Marks et al73 except that the risk of stroke was not cor¬
related with valve thickening. Thus, at this time, there
appears to be no clinical or echocardiographic marker that
clearly identifies the MVP patient at risk for cerebral
In a prospective
of 237 patients with MVP, Nishimura et al concluded that those with a redundant mitral
ischemic events.
Mitral Annular Calcification
The clinical syndrome of mitral annular calcification
(MAC), first clearly described in 1962,74 includes a strong
female preponderance and may be associated with mitral
stenosis and regurgitation, calcific aortic stenosis, conduction
disturbances, arrhythmias, embolic phenomena, and en¬
docarditis. It must be emphasized that radiographic evi¬
dence of calcium in the mitral annulus does not in itself
constitute the syndrome of MAC. While the true incidence
of systemic emboli in this condition is not known, embolic
events appear conspicuous with or without associated AF.74"79
Four ofthe 14 original patients described by Korn et al'4 had
cerebral emboli, and 5 of 80 patients described by Fulkerson et al76 had systemic emboli, only 2 of whom had AF. In
autopsy specimens, thrombi have been found on heavily
calcified annular tissue,80 and echogenic densities have been
described in the left ventricular outflow tract in this condi¬
tion among patients with cerebral ischemic events.7' Perhaps
the best estimate of the thromboembolic potential of MAC
comes from the Framingham Heart Study.'9 Among 1,159
of stroke at the index echocardio¬
subjects with no history
examination, the relative risk of stroke in those with
graphic
MAC was 2.10 times that without MAC (p=.006), indepen¬
dent of traditional risk factors for stroke. Even in those sub¬
jects without prevalent AF, the risk of stroke in subjects with
MAC was twice that of those without MAC.
In addition to embolization of fibrin clot, calcified spicules
may become dislodged from the ulcerated calcified annulus
and present as systemic emboli.76,78,81 While the relative
frequency of calcific emboli and thromboembolism is unCHEST /108 / 4 / OCTOBER, 1995 / Supplement
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363S
known, it is likely that the incidence of the former problem
has been underestimated, because this diagnosis can be es¬
tablished only by pathologic examination of the embolus or
by the rarely visualized calcified fragments in the retinal
circulation.76,82 Since there is little reason to believe that
therapy would be effective in preventing cal¬
anticoagulant
cific emboli, the rationale for using antithrombotic drugs in
patients with mitral annular calcification rests primarily on
the frequency of true thromboembolism. In the Framing¬
ham Study, the incidence of AF was 12 times greater in pa¬
tients with MAC than in those without this lesion,83 and 29%
of the patients with annular calcification described by Fulkerson et al76 had AF. In addition, left atrial enlargement is
not uncommon, even in those with normal sinus rhythm.
Thus, the many factors contributing to the risk of throm¬
boembofism in MAC include AF, the hemodynamic conse¬
quences of the mitral valve lesion itself (stenosis and regur¬
gitation), and fragmentation of calcific annular tissue. In light
of these observations, a good argument can be made for
prophylactic anticoagulant therapy in patients with AF or a
because most of these
history ofarean embolic event. However,
to
73
75
patients elderly (mean age,
years,72,76), the risks
of anticoagulation with warfarin will be increased. Therefore,
if the mitral lesion is mild or if an embolic event is clearly
identified as calcific rather than thrombotic, the risks from
outweigh the benefit of warfarin ther¬
anticoagulationthemayclinician
should be discouraged from ini¬
apy. Certainly
tiating anticoagulant therapy merely on the basis of radiographic evidence of MAC. Antiplatelet drugs might represent
an uncertain compromise for those with advanced lesions,
our knowledge, no studies indicate that this
althoughis toeffective
in preventing thromboembolism in pa¬
therapy
tients with MAC. For patients with repeated embolic events
despite warfarin therapy or in whom multiple calcific emboli
are recognized, valve replacement should be considered.
Aortic Valve Disease
Clinically detectable systemic emboli in patients with
isolated aortic valve disease are distinctly uncommon. How¬
ever, Stein et al84 emphasized the thromboembolic potential
of severe calcific aortic valve disease and demonstrated microthrombi in 10 of 19 calcified and stenotic aortic valves
studied histologically. In only one, however, was a thrombus
on the excised valve, and clinical evidence of
grossly visible
was not reported. Four cases of calcific
embolism
systemic
emboli to the retinal artery in patients with calcific aortic
stenosis were reported by Brockmeier et al,82 and four cases
of cerebral emboli were observed in patients with bicuspid
aortic valves in whom no other source of emboli could be
found.85 In the latter group, all four patients were treated
with aspirin, and no recurrences were observed. Perhaps the
most startling report of calcific emboli in a patient with cal¬
cific aortic stenosis is that of Holley et al. In this autopsy
study of 165 patients, systemic emboli were found in 31 pa¬
tients (19%); the heart and kidneys were the most common
sites of emboli, but again, clinically detectable events were
notably rare.
It appears, therefore, that calcific microemboli from
are not rare, but, be¬
heavily calcified, stenotic aorticarevalves
not readily detected unless
cause of their small size, they
they can be visualized in the retinal artery. Indeed, the small
364S
but consistent frequency of systemic emboli reported in
earlier studies of aortic valvular disease may best be ex¬
plained
by unrecognized mitral valvular or ischemic heart
disease or by coexisting AF. It is of interest in this regard that
of 194 patients with rheumatic valvular disease and systemic
emboli described by Daley et al,8' only 6 had isolated aortic
valve disease, and in each AF was also present. More
recently, the association of AF and aortic valve disease was
examined by Myler and Sanders.88 In 122 consecutive
patients with proved isolated severe aortic valve disease, only
1 had AF, and in that instance, advanced coronary heart
disease with infarction was present as well.
Thus, in the absence of associated mitral valve disease,
systemic embolism in patients with aortic valve disease is
uncommon, and long-term anticoagulation is not indicated.
However, a significant number of patients with severe cal¬
cific aortic valve disease do have microscopic calcific emboli,
although they are not often associated with clinical events or
evidence of infarction. Because the value of anticoagulant
es¬
therapy in preventing calcific microemboliarehas not been
tablished and their clinical consequences
few, the risks
of long-term anticoagulant therapy in patients with isolated
aortic valve disease apparently outweigh the potential use¬
fulness, unless there is a history consistent with prior
thromboembolism.
Patent Foramen Ovale and Atrial Septal
Aneurysm
of
The incidence paradoxical embolism is unknown. In
recent years, however, the role of developmental and
acquired disease of the interatrial septum as a cause of
cryptogenic stroke has received considerable attention.
Paradoxical embolism through a patent foramen ovale (PFO)
is well documented and thrombus on the arterial side of an
atrial septal aneurysm has been reported at autopsy, during
surgery, and by TEE.89 Much of the uncertainty about the
incidence of paradoxical embolism lies in the fact that 27 to
29% of normal hearts have demonstrable PFOs at autop¬
the specificity of this finding as a marker of
sy,90,91 and thus
embolism is low. However, the demonstration by
paradoxical
TTE that 10 to 18% of normal people exhibit right-to-left
shunting through a PFO during cough or Valsalva's maneu¬
ver,92,93 (by TEE the incidence approaches the anatomic
data98), and the observation that 57% of patients with PFOs
and suspected paradoxical embolism were found to have
venous thrombosis by venography,94 provides support for the
thesis that paradoxical embolism may be more common than
believed.
generally
A number of studies have demonstrated a strong associ¬
ation between PFO and stroke.9395"97 The evidence for this
association is particularly apparent in younger patients where
the likelihood of atherosclerotic embolic disease is less
in a thoughtful review of this
compelling. Nevertheless,
al98
that the role of "para¬
Movsowitz
et
conclude
subject,
doxical embolism through a PFO remains controversial." It
is generally agreed that contrast TEE is the diagnostic
technique of choice for demonstrating a PFO. However,
because the sensitivity of contrast TEE is greater than that
of contrast TTE, the question may be asked whether the
smaller PFOs identified only by TEE are likely to be clin¬
ically relevant to the true incidence of paradoxical embolism.
Fourth ACCP Consensus Conference on Antithrombotic Therapy
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A strong association between atrial septal aneurysm and
stroke has also been reported.89'99 The former condition has
been identified in 1% of autopsies and in 3 to 4% of
nonstroke patients examined by TEE.89,99 Because of a high
incidence of PFO in patients with atrial septal aneurysm (70
to 83%) and anecdotal reports of clot within the aneurysm,
there are two potential sources of systemic embolism in this
condition; namely paradoxical embolism and arterial throm¬
boembolism from the left side of the atrial septal aneurysm.
In both isolated PFO and in atrial septal aneurysm, the
indications for antithrombotic therapy remain problematic.
In patients with unexplained cerebral ischemia or stroke, the
demonstration of right-to-left shunting through a PFO war¬
rants a search for deep vein thrombosis. In this circumstance,
evidence for venous thrombosis (or pulmonary embolism)
together with systemic embolism and a PFO provides a
strong indication for long-term anticoagulation, venous
interruption, or in some cases closure of the PFO. In the
absence of evidence for venous thromboembolism, the
threshold for these interventions is higher and must be made
on a case-by-case basis. Certainly, long-term anticoagulation
would not be recommended for asymptomatic PFOs or atrial
aneurysms, although low-dose aspirin therapy would
septal
seem prudent therapy to reduce the likelihood of thrombo¬
sis on the arterial side of an atrial septal aneurysm. While
role of PFO in patients with
subsequent studies of thebroaden
the indications for longstroke
may
cryptogenic
term warfarin therapy, the low specificity of PFO shunting
as a risk factor for stroke and the known risks of long-term
apply cautionsus¬in
anticoagulation therapy mandate that we for
life-long anticoagulation patients
recommending
of paradoxical embolism, unless the diagnostic
pected
evidence is quite convincing or alternate causes for stroke in
themselves would justify this therapy. Decision analysis may
be helpful in guiding therapy in the more difficult cases.
Infective Endocarditis
With the advent of effective antimicrobial therapy, the
incidence of systemic emboli in patients with infective
endocarditis has decreased. In the preantibiotic era, clini¬
to 97% of patients
cally detectable emboli occurred in 70since
that time, the
with infective endocarditis,100 while,
Emboli
to
40%.101"106
to
be
12
has
been
reported
prevalence
occur more frequently in patients with acute endocarditis
than in those with subacute disease,107 and the incidence of
emboli in right-sided endocarditis is particularly
pulmonary Cerebral
emboli are considerably more common
high.103108
in patients with mitral valve endocarditis than in those with
infection of the aortic valve; interestingly, this observation is
not explained by the occurrence of AF.104 While embolic
rate (in terms of events per patient-week) has not been re¬
in endocarditis, considering the relatively short
ported
course of the disease, an unusually high event per unit time
may be inferred.
The use of anticoagulant therapy in patients with infective
endocarditis was initially introduced in the sulfonamide era,
not as a means of preventing thromboembolism but to im¬
prove the penetration of antibiotic into the infected vegeta¬
tions.109 While complications ofthis therapy were not always
encountered,110111 most workers reported an alarming
incidence of cerebral hemorrhage,112"114 and it was sug¬
gested
that the routine use of anticoagulant therapy in pa¬
tients with endocarditis be abandoned.113115,116 However,
the issue remained controversial. While reference to the
early adverse experience of anticoagulant therapy in patients
with endocarditis frequently has been made, Lerner and
Weinstein103 concluded that anticoagulants were "probably
contraindicated" in patients with infective endocarditis.
With the advent of echocardiography, means of identify¬
ing the patient at risk for embolization have been proposed,
and a high correlation between echocardiographically de¬
monstrable vegetations and embolism has been report¬
ed.108117"119 However, in a review of this subject, O'Brien
and Geiser120 report that 80% of patients with infective en¬
docarditis have vegetations detected by echocardiography
while only one third have systemic emboli. TEE has added
a further dimension to the diagnostic accuracy of endocardi¬
tis. Indeed, Popp121 concludes that "the current state of the
art in transesophageal echocardiographic imaging makes the
likelihood of endocarditis low in patients without demon¬
strated vegetations." However, the ability of these tech¬
niques to identify the patient at risk for embolism is low.
Further, there is no convincing evidence that prophylactic
of emboli in
therapy reduces the incidence
anticoagulant
it
is generally
and
valve
with
native
endocarditis,
patients
believed that the routine use of anticoagulant drugs is not
in this circumstance. In a study of the rate of cere¬
justified
bral embolic events in relation to antibiotic and anticoagu¬
lant therapy in patients with infective endocarditis, a prompt
reduction in emboli was observed soon after antibiotic
while the incidence of emboli was the
therapy was started,
same among those who did or did not receive anticoagulant
therapy.122 However, in the patient with a special indication,
eg, the patient with mitral valve disease and the recent on¬
set of AF, appropriate anticoagulant therapy should not be
withheld.
The patient with prosthetic valve endocarditis deserves
With the exception of those patients with
special comment.
sinus rhythm, patients with pros¬
in
normal
bioprostheses
thetic valves are at constant risk of thromboembolism and
there are important reasons not to interrupt anticoagulant
The risks of thromboembolic
therapy in this circumstance.
events in patients with prosthetic valve endocarditis are
than in those with native valve endocarditis; emboli
higherbeen
have
reported in 50 to 88% of patients with prosthetic
valve endocarditis.104"106123,124 However, opinion is divided
on the effectiveness of anticoagulation in reducing the
number of embolic events associated with prosthetic valve
endocarditis. Wilson et al124 reported CNS complications in
endocarditis who
only 3 of 38 patients with prosthetic valvewhile
events were
received adequate anticoagulant therapy,
observed in 10 to 14 patients who received either inadequate
or no anticoagulation (level IV). However, Yeh et al125 found
that adequate anticoagulation failed to control emboli dur¬
ing prosthetic valve endocarditis, and the risk of bleeding
appears to be greater among patients with infected prostheses (level IV).105 Pruitt and associates104 found that 23%
of the hemorrhagic events occurred in the 3% of patients
receiving anticoagulants and a 50% incidence of hemorrhage
was observed by Johnson126 in patients with prosthetic valve
endocarditis treated with anticoagulants. Other workers, too,
have reported a high incidence of intracranial hemorrhage
not
CHEST /108 / 4 / OCTOBER, 1995 / Supplement
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365S
ovale in young stroke patients. Lancet 1988; 2:11-12
RL, Gopal A, et al. Patent foramen ovale as
a risk factor for cryptogenic stroke. Ann Intern Med 1992;
117:461-65
DeBelder MA, Tourikis L, Leech G, et al. Risk of patent fora¬
men ovale for thromboembolic events in all age groups. Am J
Cardiol 1992; 69:1316-20
Movsowitz C, Podolsky LA, Meyerowitz CB, et al. Patent fora¬
men ovale: a nonfunctional embryological remnant or a poten¬
tial cause of significant pathology? J Am Soc Echocardiogr 1992;
5:257-70
Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneu¬
rysm and stroke: a transesophageal echocardiographic study. J
Am Coll Cardiol 1991; 18:1223-29
Weinstein L. Infective endocarditis. In: Braunwald E, ed. Heart
disease. Philadelphia: WB Saunders, 1984
Cates JE, Christie RV. Subacute bacterial endocarditis: a review
of 442 patients treated in 14 centers appointed by the penicillin
trials committee of the MRC. Q J Med 1951; 20:93
Brunson JG. Coronary embolism in bacterial endocarditis. Am
J Pathol 1953; 26:689
Lerner PI, Weinstein L. Infective endocarditis in the antibiotic
era. N Engl J Med 1966; 274:323-93
Pruitt AA, Rubin RH, Karchmer AW, et al. Neurologic compli¬
cations of bacterial endocarditis. Medicine 1978; 57:329-43
Carpenter JL, McAllister CK. Anticoagulation in prosthetic
valve endocarditis. South Med J 1983; 76:1372-75
Garvey CJ, Neu HC. Infective endocarditis: an evolving disease.
Medicine 1979; 57:105-26
Morgan WL, Bland EF. Bacterial endocarditis in the antibiotic
era. Circulation 1959; 19:753-59
Ginzton LE, Siegel RJ, Criley JM. Natural history of tricuspid
valve endocarditis: a two-dimensional echocardiographic study.
Am J Cardiol 1982; 49:1853-59
Friedman M, Katz LN, Howell K. Experimental endocarditis
due to streptococcal viridans. Arch Intern Med 1938; 61:95
Loewe L, Rosenblatt P, Greene HJ, et al. Combined penicillin
and heparin therapy of subacute bacterial endocarditis. JAMA
96 DiTullio M, Sacco
97
98
99
100
101
102
103
104
105
106
107
108
109
110
Roy P, Tajik AJ, Guiliani ER, et al. Spectrum of echocardio¬
graphic findings in bacterial endocarditis. Circulation 1976;
53:474-82
119 Stuart JA, Silimperi D, Harris P, et al. Echocardiographic doc¬
umentation of vegetative lesion in infective endocarditis: clinical
implications. Circulation 1980; 61:374-80
120 O'Brien JT, Geiser EA. Infective endocarditis and echocardi¬
ography. Am Heart J 1984; 108:386-94
121 Popp RL. Echocardiography. N Engl J Med 1990; 323:165-72
122 Paschalis C, Pugsley W, John R, et al. Rate of cerebral embolic
events in relation to antibiotic and anticoagulant therapy in pa¬
tients with bacterial endocarditis. Eur Neurol 1990; 30:87-9
123 Block PC, DeSanctis RW, Weinberg AN. Prosthetic valve en¬
docarditis. J Thorac Cardiovasc Surg 1970; 60:540-48
124 Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant
therapy and central nervous system complications in patients
with prosthetic valve endocarditis. Circulation 1978; 57:1004-07
125 Yeh TJ, Anabtaw I, Cornet VE, et al. Influence of rhythm and
anticoagulation upon the essence of embolization associated
with Starr-Edwards prostheses. Circulation 1967; 35:77-81
126 Johnson WD Jr. Prosthetic valve endocarditis. In: Kay E, ed.
118
Infective endocarditis. Baltimore:
129
127 Lieberman A, Hass WE, Pinto R, et al. Intracranial hemorrhage
and infarction in anticoagulated patients with prosthetic heart
valves. Stroke 1978; 9:18-24
128 Scott WR, New PFJ, Davis KR, et al. Computerized axial
tomography of intracerebral and intraventricular hemorrhage.
Radiology 1974; 112:73-80
129 Cerebral Embolism Study Group. Immediate anticoagulation of
embolic stroke: a randomized trial. Stroke 1983; 14:668-76
130 Cerebral Embolism Study Group. Immediate anticoagulation of
131
132
1944; 124:144-49
111 Thill CJ, Meyer OO. Experiences with penicillin and dicouma¬
rol in the treatment of subacute bacterial endocarditis. Am J
Med Sci 1947; 213:300
112 McLean J, Meyer BBM, Griffith JM. Heparin in subacute bac¬
terial endocarditis: report of a case and critical review of litera¬
ture. JAMA 1941; 117:1870-79
113 Katz LN, Elek SR. Combined
heparin and chemotherapy in
subacute bacterial endocarditis. JAMA 1944; 124:149-52
114 Kanis JA. The use of anticoagulants in bacterial endocarditis.
Postgrad Med J 1974; 50:312-13
115 Finland M. Current status of therapy in bacterial endocarditis.
JAMA 1959; 166:364-73
116 Priest WS, Smith JM, McGee CJ. The effect of anticoagulants
on the penicillin therapy and the pathologic lesion of subacute
bacterial endocarditis. N Engl J Med 1946; 235:699-706
117 Wann LS, Dillon JC, Weyman AE, et al. Echocardiography in
bacterial endocarditis. N Engl J Med 1976; 295:135
370S
University Park Press, 1979;
133
134
135
136
embolic stroke: brain hemorrhage and management options.
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low-up of patients undergoing porcine heart valve replacement.
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antibiotics, anticoagulation and stroke. Stroke 1990; 21:993-99
Lopez JA, Ross RS, Fishbein MC, et al. Non-bacterial throm¬
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Fourth ACCP Consensus Conference on Antithrombotic Therapy
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Recommendations
Rheumatic Mitral Valve Disease
1. It is strongly recommended that long-term warfarin
sufficient to prolong the INR to 2.0 to 3.0 be used
therapy
in patients with rheumatic mitral valve disease who have ei¬
ther a history of systemic embolism or who have paroxysmal
or chronic atrial fibrillation, This recommendation is based
on three level IV studies16,26,32 demonstrating efficacy in
patients with mitral valve disease and five level I studies
showing efficacy in subjects with nonvalvular atrial fibrilla¬
tory of thromboembolism or AF. This grade C recommen¬
dation is based on the relatively low incidence of throm¬
boembolism in patients with this common disorder.76,79
2. It is recommended that long-term warfarin therapy
(INR, 2.0 to 3.0) be considered in patients with rheumatic
Patent Foramen Ovale and Atrial Septal Aneurysm
1. It is strongly recommended that anticoagulant therapy
not be given to patients with asymptomatic PFOs or atrial
aneurysms. This grade C recommendation is made
septal
because of the high incidence of demonstrable PFOs in the
tion.9^
mitral valve disease and normal sinus rhythm, if the left atrial
diameter is in excess of 5.5 cm. This recommendation is
based on the belief that the likelihood of developing AF in
such cases will be high. Furthermore, since it is recognized
that the risk of thromboembolism may be substantial in some
patients with rheumatic mitral valve disease and normal si¬
nus rhythm, it is recommended that the decision to use
warfarin be adjudicated on the basis of comorbid risk factors,
left atrial size, age, and the hemodynamic
particularly
severity of the lesion. These grade C recommendations are
not based on published studies.
3. It is recommended that if recurrent systemic embolism
occurs despite adequate warfarin therapy, that the addition
of aspirin (80 to 100 mg/d) be considered,47 For those pa¬
tients unable to take aspirin, alternative strategies would be
to increase the warfarin dose sufficient to prolong the PT to
an INR of 2.5 to 3.5, add dipyridamole, 400 mg/d, or add
ticlopidine, 250 mg twice daily.
Aortic Valve Disease
1. It is strongly recommended that long-term antithrom¬
botic therapy not be given to patients with aortic valve dis¬
ease unless they also have concomitant mitral valve disease,
AF, or a history of systemic embolism. This grade C recom¬
mendation is made because of the low incidence of clinically
detectable systemic thromboembolism in these patients.
Mitral Valve Prolapse
1. It is strongly recommended that long-term antithrom¬
botic therapy not be given to patients with MVP who have
not
experienced systemic embolism, unexplained TIAs, or
AF. This grade C recommendation is based on the low in¬
cidence of systemic embolism in patients with this common
disorder.53,66
2. It is recommended that patients with MVP who have
documented but unexplained TIAs be treated with longterm low-dose aspirin therapy. The dose currently recom¬
mended is 160 to 325 mg/d (see article on cerebrovascular
disease by Sherman et al, pp 444S-456S in this supplement).
3. It is recommended that patients with MVP who have
(1) documented systemic embolism, (2) chronic or paroxys¬
mal AF, or (3) recurrent TIAs despite aspirin therapy be
treated with long-term warfarin therapy (INR, 2.0 to 3.0).
Mitral Annular Calcification
1. It is recommended that long-term antithrombotic
therapy not be given to patients with MAC who lack a his¬
2. It is recommended that patients with MAC compli¬
cated by (1) systemic embolism not documented to be cal¬
cific embolism or (2) associated AF be treated with longterm warfarin therapy (INR, 2.0 to 3.0). This grade A
recommendation is based on the high incidence of systemic
embolism in older AF patients and the demonstrated
efficacy of anticoagulant therapy in patients with nonvalvu¬
lar atrial fibrillation.9-13
at large.
population
2. It is strongly recommended that patients with unex¬
plained systemic embolism or TIAs and demonstrable
venous thrombosis or pulmonary embolism and either PFO
or atrial septal aneurysm be treated with long-term warfarin
or closure of the PFO is
therapy, unless venous interruption
considered preferable therapy. In the case of atrial septal
aneurysm, the possibility of both paradoxical embolism and
systemic embolism from the arterial side of the aneurysm
should be considered in choosing therapy.
Infective Endocarditis
1. It is strongly recommended that anticoagulant therapy
be given to patients in normal sinus rhythm with
endocarditis involving a native valve
uncomplicated infective
or a bioprosthetic valve. This grade C recommendation is
not
based on the increased incidence of hemorrhage in these
lack of demonstrated efficacy of an¬
patients112-114 and thein this
setting.122132
ticoagulant
therapy
2. It is recommended that long-term warfarin therapy be
continued when endocarditis occurs in patients with a me¬
chanical prosthetic valve unless there are specific contrain¬
dications. This grade C recommendation is based on the high
of systemic thromboembolism in these pa¬
frequency
tients.104"106123,125 However, it is to be noted that the risk of
intracranial hemorrhage is substantial.104105'127
3. The indications for anticoagulant therapy when sys¬
temic embolism occurs during the course of infective
endocarditis involving a native or bioprosthetic heart valve
are uncertain. The therapeutic decision should consider co¬
morbid factors, including AF, evidence of left atrial throm¬
bus, evidence and size of valvular vegetations, and particu¬
larly the success of antibiotic therapy in controlling the
infective endocarditis.
Nonbacterial Thrombotic Endocarditis
1. It is recommended that patients with NBTE and sys¬
temic
or
pulmonary emboli be treated with heparin. This
grade C recommendation is based on a strong association
between NBTE and disseminated intravascular coagulation
and uncontrolled studies demonstrating efficacy in hospi¬
talized patients.133135,136
2. It is recommended that heparin therapy be considered
for patients with disseminated cancer or debilitating disease
CHEST /108 / 4 / OCTOBER, 1995 / Supplement
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367S
who are found to have aseptic vegetations on echocardio¬
graphic study. This grade C recommendation is based on a
high incidence of systemic emboli in patients with
NBTE.133'135,136
disease and atrial fibrillation. Br Heart J 1983; 49:133-40
Hay WE, Levine SA. Age and atrial fibrillation as independent
factors in auricular mural thrombus formation. Am Heart J1942;
24:1-4
Daley R, Mattingly TW, Holt C et al. Systemic arterial embo¬
lism in rheumatic heart disease. Am Heart J 1951; 42:566-81
26 Fleming HA, Bailey SM. Mitral valve disease, systemic embo¬
lism and anticoagulants. Postgrad Med J 1971; 47:599-604
27 The Stroke Prevention in Atrial Fibrillation Investigators. Pre¬
dictors of thromboembolism in atrial fibrillation: II. Echocar¬
diographic features of patients at risk. Ann Intern Med 1992;
25
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