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Antithrombotic Treatment and the Incidence of Angina Pectoris
Christine Knottenbelt, MB, ChB;
Patrick J. Brennan, MSc;
Tom W. Meade, DM, FRS;
for the Medical Research Council's General Practice Research Framework
Arch Intern Med. 2002;162:881-886.
ABSTRACT
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Background In primary prevention, anticoagulation with warfarin sodium to an international
normalized ratio of 1.5 and 75 mg of aspirin per day each reduced the incidence
of coronary heart disease (CHD). Effects on the development of angina pectoris
and total CHD (resulting from angina, myocardial infarction, and coronary
death) have been assessed, particularly in light of recent evidence that warfarin
may have a "durable effect" on CHD through effects on the pathologic condition
of the vessel walls involved.
Methods The Thrombosis Prevention Trial was carried out in 5499 men aged 45
through 69 years who were at increased risk of CHD. The trial was factorial,
with 1 group taking active warfarin and active aspirin, 1 taking active warfarin
and placebo aspirin, 1 taking placebo warfarin and active aspirin, and 1 taking
double placebo treatment. In addition to those with myocardial infarction
and coronary death, men developing angina pectoris after entry to the trial
were identified.
Results Warfarin appeared to reduce the incidence of stable angina by 16% (95%
confidence interval [CI], –14 to 38), although not significantly (P = .26), while aspirin increased the incidence by 39%
(95% CI, 0 to 91) (P = .05). The incidence of stable
angina was 37% (95% CI, –1 to 60) less in those taking warfarin than
in those taking aspirin (P = .05). Warfarin reduced
total CHD by 18% (95% CI, 4 to 30) (P = .01), while
the reduction due to aspirin was 8% (95% CI, –10 to 22) (P = .36).
Conclusions The results are compatible with the concept of a durable effect of warfarin
on the chronic pathologic conditions underlying angina, although this has
not been established with certainty. Further research is needed to confirm
or refute our findings, because they carry potentially important implications
for the primary prevention of CHD with the use of antithrombotic agents.
INTRODUCTION
THE THROMBOSIS Prevention Trial (TPT) was primarily concerned with the
value of low-dose antithrombotic treatment in the primary prevention of major
episodes of coronary heart disease (CHD), ie, myocardial infarction and coronary
death, in middle-aged men at increased risk. We showed1
that both low-intensity oral anticoagulation with warfarin sodium to an international
normalized ratio of about 1.5 and 75 mg of aspirin per day in a controlled-release
formulation each reduced the incidence of CHD by about 20%. Warfarin achieved
this benefit almost entirely through a reduction in fatal episodes by 39%,
while aspirin reduced nonfatal episodes by 32%. Combined treatment with warfarin
and aspirin reduced all major CHD, fatal or nonfatal, by 34%. Major episodes
are often the first clinical manifestation of CHD, but are frequently preceded
by gradual changes in the vessel walls, to which thrombosis and atherogenesis
may contribute and which lead to angina pectoris. Results from the Post Coronary
Artery Bypass Graft Trial2-3 indicate
that low-dose warfarin may have a "durable effect" on the long-term processes
underlying the eventual development of major events, because significant treatment
effects with warfarin not seen during the trial treatment phase emerged on
long-term follow-up—a 35% reduction in mortality (P = .008) and a 31% reduction in myocardial infarction (P = .003). Any such durable effect could be, at least partly, through
an effect of warfarin delaying the progression of atheroma, which, in turn,
would contribute to a delayed onset of angina and eventually to a reduction
in major episodes.
Although the onset of angina was not a primary end point in our trial,
we now describe the effects of the TPT treatments on its development, with
results that may have implications for aspirin and warfarin use. In addition,
many trials now include the onset of angina and the use of interventions as
outcomes, partly because angina represents a clinical development indicating
a high risk of major events later and because interventions for angina may
delay major episodes that might otherwise have occurred.
PARTICIPANTS AND METHODS
A detailed description of participants and methods has been given elsewhere,1, 4 along with CONSORT guidelines.5
PARTICIPANTS
The trial was carried out through 108 group practices in the British
Medical Research Council's General Practice Research Framework in men aged
45 through 69 years who were at an increased risk of CHD. At the screening,
attended by 61 422 (66%) of the 93 446 invited, smoking history
and family history of premature CHD were elicited, body mass index was calculated,
blood pressure was measured, and blood was taken for total cholesterol, plasma
fibrinogen, and plasma factor VII coagulant activity testing. These variables
were weighted according to their association with CHD in the Northwick Park
Heart Study.6 Family history had not been recorded
in this study, so a positive history given by entrants to the trial was assumed
to increase risk by 50%. A score for each man was then calculated. Within
each practice, those men in the top 20% of the risk score distribution, or
in the top 25% in regions with particularly high CHD mortality rates, were
considered to be eligible for the trial. Of the 10 557 men at increased
risk and eligible for the treatment phase, 5499 (52%) entered the trial.
TRIAL TREATMENT
The trial, which was double-blind and placebo-controlled, began as a
randomized comparison of warfarin and placebo (prefactorial), which accounts
(see "Results" section) for the slightly larger number of men in the analyses
following warfarin treatment than in the analyses following aspirin treatment.1 The full trial was factorial in design, resulting
in 4 treatment groups, ie, active warfarin and active aspirin, active warfarin
and placebo aspirin, placebo warfarin and active aspirin, and placebo warfarin
and placebo aspirin. Warfarin sodium was started at 2.5 mg/d and adjusted
by increments or decreases of 0.5 mg/d or 1.0 mg/d at monthly intervals until
the international normalized ratio was about 1.5. Dosage changes were matched
in men taking placebo warfarin. Aspirin was given as 75 mg/d in a controlled-release
formulation.
INCIDENT ANGINA
Men were followed up for a median of 6.8 years for major outcomes (myocardial
infarction or coronary death), including those who withdrew from treatment
while the trial was in progress. Incident angina was routinely ascertained
while men were receiving trial treatment, but they were not followed up for
angina if they withdrew. The median follow-up for systematic inquiry about
angina was 5.0 years and virtually the same in all 4 treatment groups. A previous
history of angina was elicited at screening, and those with angina at recruitment
were excluded. Possible cases of incident angina were identified in several
ways. First, the annual medical examination included a question about the
onset of angina, and the research nurses in the practices reported cases as
they arose in between annual examinations by the physician. In addition, and
following the initial report of the Antiplatelet Trialists' Collaboration,7 practices had been advised to initiate treatment of
angina with (nontrial) aspirin, which meant patients had to withdraw from
trial treatment, so that these withdrawals were a further source of information
about new cases. Second, the clinical notes of men withdrawn from the trial
because of coronary artery bypass grafting or angioplasty were reviewed to
identify those in whom angina was the indication and who had not already been
ascertained. Third, the clinical notes of all 410 men who had experienced
major CHD end points were reviewed to identify those who might have developed
angina beforehand and who had not already been notified as having done so.
Information was then collected about the basis for diagnosing angina in each
patient, either from the general practitioner's notes or from hospital records.
In all, 219 cases of apparent incident angina were identified, and these were
classified as definite, probable, or doubtful, these decisions being made
without knowledge of each man's trial treatment group. Criteria to be satisfied
for the 3 categories are shown in Table
1, 128 cases (58%) being definite, 76 (35%) probable, and 15 (7%)
doubtful (often, in this last group, only because of missing details required
for inclusion in the definite or probable groups). Patients were also classified
according to a physician's diagnosis as stable (161 [74%]), stable later becoming
unstable (11 [5%]), unstable (9 [4%]), or unclassifiable (38 [17%]). The onset
of angina occurred within less than 2 months of trial entry in 4 men (2%),
between 2 and 6 months in 12 (5%), between 6 and 12 months in 17 (8%), and
after more than 12 months in 186 (85%).
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Table 1. Criteria for Diagnosis of Incident Angina*
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The combination of coronary deaths, nonfatal myocardial infarction,
and incident angina is described as total CHD. Five
men developed angina during the prefactorial phase of the trial and subsequently
entered the factorial phase, 3 of whom later had nonfatal myocardial infarcts
and 1 died of CHD. They have been included in the analysis of the main effects
of warfarin but omitted from analyses of the main effects of aspirin and of
the 4 separate treatment groups. Forty-two men who had angina at entry to
the trial and who were included in our earlier report,1
11 of whom later had a myocardial infarct, were omitted from all the present
analyses. These omissions make virtually no difference to our previously reported
results on coronary death and myocardial infarction, but mean that all those
described herein as developing angina did so after entry to the trial (and
no reports of angina developing after myocardial infarction were included).
STATISTICAL ANALYSES
Statistical methods have been fully described previously.1
The main effect of warfarin is given by comparing results in the active warfarin and active aspirin and the active
warfarin and placebo aspirin groups with those in the placebo warfarin and active aspirin and the placebo
warfarin and placebo aspirin groups, with
the addition of the few cases of incident angina in the prefactorial (warfarin
only) stage, ie, comparing the active warfarin group
with the placebo warfarin group. For aspirin, the active warfarin and active aspirin and the placebo warfarin and active aspirin groups are compared with the active warfarin and placebo aspirin and the placebo warfarin and placebo aspirin groups. For this report, main is used only in this technical sense. All results
are based on intention to treat. Comparisons are reported as percentage reductions
in the tables, and, where a reduction is negative, this is referred to as
a positive increase in the text.
RESULTS
Results for angina are shown in Table
2. For summary purposes, and to avoid describing results for all
3 categories of certainty, most references are to the results for the combined
category of definite and probable cases. For all cases of angina, ie, stable
and unstable, and by analysis of main effects, warfarin appears to have reduced
cases by 11% (95% confidence interval [CI], –17 to 32) (P = .42). There was a large, but only marginally significant increase
in the incidence of angina in those taking aspirin than in those not, the
percentage excess being 33% (95% CI, 0 to 77) (P
= .05) in the definite and probable category, and being greatest, at 46%,
among the definite cases. These results are based on larger numbers than direct
comparisons of either active agent (warfarin or aspirin) with placebo in the
separate groups (although these comparisons give similar results [data not
shown] that are not statistically significant). There were fewer incident
cases in those taking warfarin alone compared with aspirin alone, the difference
being 31% (95% CI, –5 to 54) (P = .08). To
confine the results only to cases in which a predominantly long-term, atherogenic
process was involved, Table 2
also shows results omitting the 9 unstable cases (7 definite and 2 probable)
and the 38 unclassified cases, among whom there were almost certainly some
others with unstable onsets. By analysis of main effects and by comparison
with all angina (stable and unstable), the apparent reduction due to warfarin
on stable angina only is somewhat greater at 16% (95% CI, –14 to 38),
although still not significant(P = .26), while the
increase due to aspirin is greater at 39% (95% CI, 0 to 91) and, once again,
significant (P = .05). The difference between those
taking warfarin alone and aspirin alone is now marginally significant, with
37% (95% CI, –1 to 60) fewer cases among those taking warfarin than
taking aspirin (P = .05).
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Table 2. Onset of Angina by Certainty of Diagnosis*
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Table 3 shows results for
total CHD, ie, the combination of coronary death, nonfatal infarction, and
angina. Of those who developed angina, 36 later experienced major events but
are included only once. Warfarin reduced total events by 18% (95% CI, 4 to
30) (P = .01), resulting from the large decrease
due to warfarin in major fatal events, along with its possible effect on angina
(Table 2) and its small (nonsignificant)
reduction in major nonfatal events.1 For aspirin,
there was a reduction of about 8% (95% CI, –10 to 22) (P = .36), the net result of the reduction due to aspirin in major nonfatal
events, the small (nonsignificant) increase in fatal events,1
and the apparent increase in angina. (Results omitting unstable cases are
not shown because the analysis in Table
3 concerns total CHD.)
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Table 3. Onset of Total Coronary Heart Disease (Coronary Deaths, Nonfatal
Myocardial Infarction, and Angina) by Certainty of Angina Diagnosis*
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COMMENT
Compared with myocardial infarction and sudden coronary death, the onset
of angina is usually gradual and difficult to date precisely, and it represents
the transition from an asymptomatic to a symptomatic stage of a long-term
process chiefly due to long-term changes in the vessel walls. Because angina
is a strong risk factor for major events later, it is useful to consider whether
and, if so, to what extent its onset may be affected by antithrombotic and
other treatments. In the case of warfarin, assessing its effect on stable
angina provides another approach to identifying a possible durable effect.
The diagnosis of angina is often notoriously difficult to establish
with certainty.8 We have therefore avoided
any rigid, single definition and have shown results according to different
levels of certainty. Diagnostic accuracy is improved by inquiring about angina
on several occasions,8 which we were able to
achieve because the physicians asked about it at each annual medical examination
over a median of 5.0 years. Because of the close and frequent contacts of
trial participants with their health care teams and the different ways in
which possible cases of new angina were ascertained, it is probable that most
cases were identified during follow-up, when information on angina was systematically
available on all men. There is no obvious way in which any incomplete ascertainment
could have occurred differentially by trial treatment group. The double-blind
placebo-controlled nature of the trial makes it unlikely that diagnoses (either
by general practitioners or in hospitals) were biased by knowledge of treatment
group or, particularly, whether treatment was with a warfarin- or aspirin-containing
regimen, even when a report of bleeding might have suggested that a man was
taking 1 of the 3 active regimens. In most men (85%), angina occurred more
than a year after entry to the trial, so that treatment would have had time
to exert an effect. Exclusion of the 9 unstable angina cases and the 38 unclassified
cases (among whom there were almost certainly some other unstable cases) omitted
those in whom there was probably a significant acute, thrombotic component.9
Results for stable cases only, ie, those predominantly due to long-term
processes affecting the vessel walls, are somewhat clearer than for all cases
(Table 2). The possible reduction
in stable angina in the warfarin group is 16% (although not significant),
and the increase apparently due to aspirin is 39% (95% CI, 0 to 91) (P = .05). The difference between those taking warfarin
alone and those taking aspirin alone is 37% (95% CI, –1 to 60) (P = .05), so it is possible that the incidence of angina
is truly lower in those taking warfarin than in those taking aspirin.
There appears to have been little research on the effect of warfarin
on angina or on the long-term vessel wall changes in CHD (as distinct from
major end points such as myocardial infarction and coronary death). However,
warfarin reduces thrombin production, which may affect atherogenesis in several
ways. These include its ability to form fibrin and platelet aggregates, to
stimulate the production of tissue plasminogen activator and plasminogen activator
inhibitor-1. This sequence of events may lead to atherogenic fibrin degradation
products and to the production of interleukin 1 by macrophages, thereby
inducing the expression of the intracellular adhesion molecule 1 and the proliferation
of vascular smooth muscle.10 A study in patients
undergoing transesophageal echocardiography has reported that those with more
severe grades of aortic atheroma receiving oral anticoagulants subsequently
experienced a significantly lower mortality rate than those treated with aspirin,11 which, although not from a randomized trial, accords
with our finding1 on mortality. The recent
findings from the Post Coronary Artery Bypass Graft trial3
might be, at least in part, due to some of these effects.
Studies on aspirin do not, until perhaps recently, suggest that it beneficially
affects either the long-term pathologic processes of CHD or the onset of angina
pectoris. Ranke et al12 carried out high-resolution
duplex carotid ultrasound testing for carotid artery atherosclerosis in 27
participants in the Low Dose Aspirin Trial on Restenosis After Angioplasty
in patients with stenoses in lower limb arteries. The carotid plaque area
was unchanged with 900 mg/d of aspirin but increased "markedly" in those taking
50 mg/d. These results are compatible with a benefit due to a high, but not
a low, dosage of aspirin, as in our trial in the latter instance, although
they come from an observational study in a small selected subgroup of patients.
An autopsy study claimed a lower prevalence of atherosclerosis in patients
with a history of arthritis of more than 8 years (but not of 8 years or less)
who had taken aspirin, compared with a control group, but included symptomatic
outcomes, such as myocardial infarction and stroke, and pathological findings.13 We have found a significant increase in incident
angina of about 33% due to aspirin, or somewhat more if only stable angina
is considered (Table 2). The US
Physicians' Health Study, comparing those taking 325 mg of aspirin on alternate
days vs placebo in a double-blind randomized trial, has reported that, in
contrast to its immediate and sustained effect on myocardial infarction, aspirin
conferred no long-term benefit on the development of angina pectoris,14 perhaps marginally, but not significantly, increasing
its incidence. On the other hand, the Collaborative Group of the Primary Prevention
Project in Italy15 has recently reported a
nonsignificant 22% reduction in angina due to a 75-mg/d regimen of aspirin
(including patients undergoing interventions). Table 4 summarizes the findings on aspirin and angina from the 3
studies with data on this association. The only significant effect is the
increase due to aspirin in the TPT. However, there is significant heterogeneity
between the 3 trials, possibly because of the characteristics of those recruited
into each of them. Any effect of aspirin on total CHD depends chiefly on the
substantial reduction in nonfatal major events, which has been reported by
all but one16 of the primary prevention trials.
Other trials besides the TPT have described little or no effect of aspirin
on fatal events in primary prevention,17-18
on which the balance of aspirin on total CHD also depends, although the Italian
trial15 indicates a reduction in these events
and in those that are nonfatal.
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Table 4. Overview of Trials of Aspirin and Incident Angina*
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This study has dealt with the possible effects of antithrombotic therapy
on angina, with the finding (suggested elsewhere14
as well) that aspirin may not only be ineffective but also may increase its
incidence. However, we emphasize the clear value of aspirin on the risk of
myocardial infarction in primary and secondary prevention. In addition, the
combination of low-dose aspirin and low-intensity anticoagulation with warfarin
seems to reduce the risk of fatal events, which is not entirely clear for
aspirin alone, and of nonfatal events. Consequently, the incidence of all
major CHD events may be reduced by about a third, so that the combination
should perhaps be used more frequently when primary prevention by antithrombotic
measures in those at particular risk is under consideration.
In summary, the point estimates for our results on taking warfarin for
stable angina (Table 2) are compatible
with the concept of a durable effect of warfarin in reducing the incidence
of angina on the assumption that this is due to chronic, long-term processes.
However, the findings were not significant, and the CIs indicate that the
incidence may increase, as with aspirin. A difference between the Post Coronary
Artery Bypass Graft trial and the TPT is that benefit in the former was not
apparent until after trial treatment had ceased, whereas any effect of warfarin
on angina in the TPT (if this actually occurred) was seen during the trial
treatment. However, compared with primary prevention, more intensive anticoagulation
may be necessary to achieve the short-term antithrombotic effect of warfarin
in settings other than primary prevention. Warfarin reduced all major events
in the TPT by 20%,1 which is compatible with
the magnitude of its effect on all major events in secondary prevention trials,
so the distinction between its effects on fatal and nonfatal events in the
TPT may not be relevant in assessing its overall effect on the sum of major
events and angina. Our results suggest that the incidence of stable angina
is about a third lower in those taking warfarin than aspirin and clearly need
to be confirmed or refuted, but if warfarin has advantages over aspirin and
if it has a durable and an antithrombotic effect, the case for considering
its use in primary (and secondary) prevention is strengthened. In the TPT,
taking low-dose warfarin was no more hazardous than taking 75 mg of aspirin
per day,1 and the feasibility of dosage monitoring
is improving with near-patient testing and self-testing methods similar to
those used in diabetes mellitus, so regimens of this kind may be more practicable
than is often assumed.
AUTHOR INFORMATION
Accepted for publication August 14, 2001.
This trial was funded by the Medical Research Council and the British
Heart Foundation, London, England; DuPont Pharma, Wilmington, Del; and Bayer
Corporation, Leverkusen, Germany. DuPont Pharma provided warfarin and Bayer
Corporation provided aspirin free of charge. We thank the men in the trial
and the physicians and nurses in the participating practices. We gratefully
acknowledge the help of the many other physicians, nurses, and laboratory
and administrative staff in the Medical Research Council Epidemiology and
Medical Care Unit, London.
Corresponding author and reprints: Tom W. Meade, DM, FRS, Epidemiology
Unit, Department of Epidemiology and Population Health, London School of Hygiene
and Tropical Medicine, University of London, Gower Street, London WCIE 7HT,
England (e-mail: tom.meade{at}lshtm.ac.uk).
From the Medical Research Council's General Practice Research Framework,
London, England. Dr Meade is now affiliated with the Epidemiology Unit, Department
of Epidemiology and Population Health, London School of Hygiene and Tropical
Medicine, University of London. A complete list of the participating general
practices is published in Lancet (1998;351:240).
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