© 1996 American Heart Association, Inc.
Articles |
Antithrombin III and Fibrinogen as Predictors of Cardiac Events in Patients With Angina Pectoris
From the Medical Statistics Unit (S.G.T., E.S.), London School of Hygiene and Tropical Medicine, London, UK, and the Departments of Internal Medicine (Cardiology and Angiology) and Institute for Arteriosclerosis Research (C.F., U.H., G.B.) and Internal Medicine (Haematology) (J.C.W. van de L., J.K.), University of Münster, Münster, Germany.
Correspondence to S.G. Thompson, Medical Statistics Unit, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK. E-mail sthompso@lshtm.ac.uk.
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Abstract |
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Abstract Because measurements of hemostatic factors might aid the prediction of cardiovascular clinical events, we investigated the long-term prognostic importance of selected hemostatic factors in patients with angina pectoris. At recruitment, 209 patients underwent clinical assessment and coronary angiography, and a range of hemostatic factors were measured. During the follow-up period of 9 years, 58 patients (28%) suffered a cardiac event (acute myocardial infarction or death from cardiac causes). The risk of cardiac events was positively related to baseline measurements of fibrinogen (risk ratio per SD [RR] increase 1.29, 95% confidence interval [CI] 0.99 to 1.68, P=.06) and negatively related to antithrombin III activity measurements (RR 0.75, 95% CI 0.59 to 0.95, P=.02). No other hemostatic factor measured was significantly related to the risk of having a cardiac event. Worsening of angina in the few weeks before and ejection fraction evaluation at the initial angiography were both strongly related to the risk of cardiac events. However, the relationships of fibrinogen and antithrombin III measurements to risk remained almost unchanged after adjusting for worsening of angina and ejection fraction. Fibrinogen and antithrombin III may have an important etiologic role in the prognosis of patients with angina pectoris.
Key Words: hemostatic factors • antithrombin III • fibrinogen • angina pectoris • prognosis
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Local thrombus formation plays a fundamental role in the progression of atherosclerosis and in the pathogenesis of acute coronary syndromes.1 This has raised interest in the possibility that measurements of hemostatic and fibrinolytic factors that allow the detection of a thrombogenic state might aid the prediction of cardiovascular clinical events. The most compelling evidence in support of this hypothesis is for plasma fibrinogen, with clearly increased levels being found both in healthy subjects and patients with angina pectoris who subsequently suffer a cardiovascular event.2 3 In healthy subjects, high factor VII, increased tissue-type plasminogen activator antigen, and low fibrinolytic activity are also indicated as determinants of coronary risk.4 5 6 Furthermore, studies in patients after MI have demonstrated that platelet hyperreactivity,7 defective fibrinolysis,8 9 10 high plasma fibrinogen levels,11 12 and increased vWF levels13 are associated with an increased risk of reinfarction or death.
However, there is only limited information to date on the role of hemostatic factors in the prognosis of stable or unstable angina pectoris. In comparatively small patient samples, increased plasma viscosity14 and high levels of vWF15 and tissue-type plasminogen activator antigen16 were associated with increased coronary risk. The latter two findings were recently confirmed in a large European multicenter study of 3000 patients with angina pectoris who were followed up for 2 years; the study also found that increased fibrinogen was independently predictive of the risk of coronary events.3
More recently, tests have become available that allow the detection of coagulation activation. These include measurements of TAT complexes17 and F 1+2.18 Initial studies have indicated increased levels in patients with CAD,19 20 but their prognostic relevance has not been studied in a prospective setting.
The purpose of the present study was to investigate the long-term prognostic importance of selected hemostatic variables, including markers of coagulation activation, in patients with angina pectoris following initial clinical assessment and coronary angiography.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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The design of the study, including patient recruitment and coagulation assays, has been described.21
Recruitment of Patients
Briefly, 263 consecutive patients,
men and women of any age with
angina pectoris who were referred to the cardiology
department for coronary angiography, were investigated.
Patients who had suffered an acute MI within the preceding 2 months
were excluded, as were patients with noncardiac diseases likely to
cause death within 1 year and patients with severe right heart failure
or valve defects. Patients were recruited between May 1983 and March
1984. Of the 263 patients, 12 were excluded because relevant
information was lacking and another 12 because incompatibilities with
the eligibility criteria were detected after entry. An additional 14
patients were excluded because blood sampling was considered inadequate
for hemostatic test measurements due to prolonged stasis applied to the
upper arm prior to venipuncture, difficult entry to the
vein, or insufficient blood flow. Of the remaining 225 patients, 120
(53%) reported worsening of angina (attacks of chest pain increasing
in frequency or severity) within recent weeks.
Baseline Clinical and Angiographic Data
Data recorded for
each patient at recruitment comprised
medical history, current medication (in particular the use of oral
anticoagulants), a physical examination, and standard laboratory tests
including hematocrit, total serum cholesterol, and
triglyceride levels. Coronary angiography was
performed by using Judkins' technique.22 A significant
stenosis of a coronary vessel was assumed when a major
coronary vessel (left anterior descending, right circumflex, or
right coronary arteries) or a major side branch had a 
70%
diameter reduction by visual assessment.23 The EF was
calculated from the right anterior oblique projection of the left
ventricular angiocardiogram,24 as modified by
Kennedy et al,25 by using a computer system (Volumat
Compact, Siemens).
Blood Sampling and Hemostatic Tests
Before the qualifying
angiogram a blood sample was obtained in
the morning from patients at rest who had fasted and not smoked for at
least 8 hours. Blood was drawn by antecubital venipuncture
with a 19G butterfly system by trained staff members. The first 5 mL of
blood was not used for hemostatic analyses.
For coagulation assays, blood was mixed with 0.13-mol/L trisodium citrate (9:1, vol/vol) and centrifuged at 2500g for 30 minutes at 20°C within 1 hour of venipuncture. For platelet factor 4 and ß-thromboglobulin assays, blood was collected into Thrombotect reagent (9:1, vol/vol; Abbott) in precooled tubes and centrifuged at 1900g for 60 minutes at 0°C. Samples of platelet-poor plasma were snap-frozen and stored at -70°C until assayed. Plasma samples for determination of the activated partial thromboplastin time were kept at room temperature and analyzed immediately.
Coagulation assays were performed.21 In particular, fibrinogen was measured according to the method of Clauss,26 vWF-related antigen by using a Laurell electroimmunoassay,27 and the biological activity of antithrombin III by using the synthetic substrate S2238.28 The markers of thrombin generation, F 1+2 and TAT complexes, were determined in 1990 on stored plasma samples20 by using commercially available enzyme immunoassays.17 18 Platelet factor 4 and ß-thromboglobulin were measured by using specific radioimmunoassays.21
Follow-up
Patients were followed up between January and May
1993, giving a
mean follow-up time of 9.5 years. A questionnaire was sent to the
general practitioners of all patients with detailed
questions about the fate of the patients, especially with regard to
circumstances of death and details of cardiac events including MI,
repeat coronary angiography, percutaneous
transluminal coronary angioplasty, and coronary artery
bypass grafting. In cases of cardiac death or events, hospital
records were searched. In cases of inadequate or
inconsistent answers by the general
practitioners, and in all event cases, the patients
themselves or their next-of-kin were contacted as appropriate.
Deaths were classified as cardiac or noncardiac based on hospital
records and postmortem results when available. Nonfatal MIs were
documented by using hospital or general practitioner
records and on the basis of chest pain symptoms, cardiac enzyme
levels, and electrocardiographic findings.3
For 16 (7%) of the 225 patients, only incomplete follow-up information could be obtained. No information at all was available for 8 patients, 3 were known to have died (but at an unknown date or from uncertain cause), and 5 had limited information based only on hospital records; of these 5, 3 were known to have been alive in 1991. For the further analyses in this article, we included only the 209 patients (93%) with complete follow-up information.
Statistical Methods
Patients who suffered cardiac events, ie,
acute MI or cardiac
death, during the follow-up period were compared with those who did
not in terms of baseline measurements of hemostatic variables and
other clinical characteristics. Kaplan-Meier incidence
curves29 according to quartiles of the distributions of
selected baseline variables were constructed. Cox proportional
hazards regression models30 were used to investigate
relationships of baseline factors with the risk of cardiac events,
using the date of the qualifying angiogram as the start point for each
patient and censoring noncardiac deaths at the date of death. The RRs
(technically, hazard ratios) derived from these Cox regressions are
used as a summary of the overall strength of the predictive
relationships. The assumptions underlying the Cox regression
models31 were investigated, but no evidence that they were
violated was found.
Logarithmic transformation of many of the
hemostatic test results was
performed (see Table 1
) to improve the normality of
their distributions. Apart from factor VIII, which was missing for 24
patients, no hemostatic test had more than seven missing values.
However, the 38 patients using oral anticoagulants at the time of the
blood sample were omitted from analyses involving
activated partial thromboplastin time, factor VII, TAT
complexes, and F 1+2.
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Since neither age nor gender had a marked or
convincing effect on the
risk of cardiac events, the results presented in Table 1
are
not adjusted for age and gender. When such adjustment was performed, it
did not materially alter the numerical results or the conclusions
reached.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical Characteristics of Patients at Entry
Of the 209 patients, 41 (20%) were women. The patients' mean age at the time of the qualifying angiogram was 53 years, with a range of 28 to 69 years. Of the patients, 99 (47%) had suffered an MI at least 2 months before the qualifying angiogram; patients with more recent MIs were excluded (see "Methods"). At the qualifying angiogram, 42% of patients had no coronary vessel with
70% diameter
stenosis; 28% had one-, 19% had two-, and 11% had
three-vessel disease. The mean EF for all patients was 66%, with
95% of the patients having an EF in the range 18% to 89%.
Clinical Events and Surgical Interventions During
Follow-up
Among the 209 patients, 35 cardiac deaths and 10 noncardiac
deaths
occurred during the 9.5-year follow-up. Of the 35 cardiac deaths,
18 were classified as due to acute MI, 9 as sudden cardiac deaths, 4 as
deaths due to cardiac failure, and 4 as related to cardiac surgery. Of
the 10 noncardiac deaths, 8 were from cancer, 1 from pancreatitis, and
1 from cerebral hemorrhage. A total of 32 patients suffered a
nonfatal MI, 9 of whom subsequently died from cardiac causes. Hence, 58
patients (28% of the total) suffered a cardiac event (ie, nonfatal MI
or cardiac death) during the follow-up.
The cardiac event rate was substantially higher in the first year after the qualifying angiogram (10 events per 100 patients per year) than in the subsequent years, when the rates were fairly constant (about three events per 100 patients per year). Surgical interventions were also much more common in the first year of follow-up than in subsequent years: 55 patients underwent coronary artery bypass grafting, 37 (67%) of whom had this procedure during the first year; of the 23 patients who underwent percutaneous transluminal coronary angioplasty, 12 (52%) had this procedure performed during the first year. Only 2 patients underwent repeat coronary artery bypass grafting, and 6 patients repeat percutaneous transluminal coronary angioplasty, during the follow-up.
Prognostic Significance of Baseline Hemostatic Test
Results
The mean hemostatic test levels of the patients who suffered a
cardiac event during follow-up were compared with those of the
patients who did not (Table 1). There were no significant
differences
between the groups for either of the platelet tests
(ß-thromboglobulin and platelet factor 4) or
the fibrinolysis tests (plasminogen and
2-antiplasmin). Among the coagulation tests, fibrinogen
levels were higher (P=.06) and antithrombin III levels lower
(P=.02) among patients with cardiac events than in those
without. Apart from vWF-related antigen, which was nonsignificantly
higher among the cardiac-event patients, no other coagulation tests
showed any evidence of a difference. Both markers of thrombin
generation (TAT complexes and F 1+2) were nonsignificantly higher in
the cardiac-event patients.
The effect of antithrombin III on prognosis
is shown in Fig 1. Those patients in the upper two quartiles of
the
antithrombin III distribution had an estimated probability of 
15%
of having a cardiac event by 9 years after the qualifying angiogram,
whereas the corresponding probability for those in the lower two
quartiles was 35%. For fibrinogen (Fig 2), the main
difference was apparent only in those in the highest quartile of the
distribution toward the end of the follow-up. The estimated
probability of suffering a cardiac event by 9 years in the lower three
quartiles of the fibrinogen distribution was 25%, compared with
35% in the highest quartile.
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The standardized RRs (ie, RRs per SD
increase) were 0.75 for
antithrombin III and 1.29 for fibrinogen (Table 2).
There was no statistical evidence that fibrinogen or antithrombin III
was more or less predictive early during the follow-up. In
analyses omitting the four deaths associated with cardiac
surgery and the two deaths from cardiac failure that occurred without
previous MI, the cardiac risk relationships of fibrinogen (standardized
RR 1.33, P=.04) and antithrombin III (0.76,
P=.03) were almost unchanged.
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Other Baseline Variables Predictive of Cardiac
Events
The EF measured at the qualifying angiogram was a very strong
predictor of subsequent cardiac events. The mean EF among the patients
suffering a cardiac event was 55.3% and among the other patients,
70.0% (P<.001). The strength of the association is shown
in Fig 3; whereas those with EFs 70% had only 15%
probability of a cardiac event in 9 years, those with lower EFs had a
progressively worse prognosis, with 50% chance of a cardiac event
in 9 years for patients with EFs 
55%. The overall RR per SD increase
in EF was 0.50 (Table 2), substantially more extreme (ie, far
from
unity) than those for antithrombin III and fibrinogen.
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Patients with a
history of MI prior to the qualifying angiogram had a
higher subsequent risk of cardiac events than patients without such a
history (RR 1.93, 95% CI 1.14 to 3.27, P=.01). However, on
adjusting for EF, a history of MI was no longer significantly
associated with the risk of subsequent cardiac events (RR 0.92,
P>.2). Hence, the poorer prognosis of patients with a
history of MI could be explained by their lower EF. A similar situation
arose with the extent of coronary vessel disease. Compared with
patients without vessel disease, those with one-, two-, and
three-vessel disease had RRs for subsequent cardiac events of 2.11,
2.87, and 4.08, respectively (overall, P=.002 for
differences between the four groups). However, after adjusting for EF,
these RRs were much reduced (1.50, 1.62, and 2.45, respectively) and
were no longer significant (P>.2). In contrast, patients
who reported worsening of angina in the few weeks before the initial
angiogram had a much higher risk of subsequent cardiac events than
those who did not (RR 5.38, P<.001; Table 2); this
finding
did not change substantially after adjusting for EF (RR 4.43,
P<.001).
Compared with patients without cardiac events, those who suffered cardiac events had higher average hematocrit (47.9% versus 45.7%, P=.001) and triglyceride (geometric mean, 201 versus 163 mg/dL, P=.005) levels. However, the relationships of these variables again became less significant after adjusting for EF (P=.02 and P=.07, respectively); hematocrit and triglycerides were negatively correlated with EF in these patients (r=-.13 and r=-.10). Hematocrit was almost uncorrelated with fibrinogen and antithrombin III (r=.00 and r=-.01, respectively). The 20 patients with a history of diabetes at recruitment had a higher risk of cardiac events than those without even after adjustment for EF (RR 1.30, P=.02). A history of hypertension, reported smoking habit, and total serum cholesterol concentration at recruitment were not significantly related to the risk of cardiac events.
Initial EF and
recent worsening of angina prior to recruitment were
clearly the most important predictors of subsequent cardiac events. It
was therefore of interest to investigate to what extent antithrombin
III and fibrinogen were related to the risk of cardiac events after
adjusting for EF and other potential confounding factors such as age,
sex, and smoking habit. The RRs of the hemostatic variables
remained largely unchanged in moving from the univariate
analyses to this multivariate analysis
(Table 2). This is because the correlations between the
variables
were quite low (eg, r=-.23 and r=.16 for
EF
with antithrombin III and fibrinogen, respectively, and
r=.06 for antithrombin III with fibrinogen). Additional
adjustment for total serum cholesterol and
triglyceride concentrations again made little
difference.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study is the first to evaluate the long-term prognostic significance of hemostatic factor measurements in patients with angina pectoris and known coronary angiographic status. The clinical follow-up spanned 9.5 years, and complete follow-up information was available for 93% of the 225 patients initially recruited to the study. Although the number of patients investigated was comparatively small, the 58 patients with cardiac events, who represented more than a quarter of the original patient sample, allowed meaningful conclusions on risk relationships with hemostatic and angiographic baseline variables.
Some earlier cross-sectional studies have indicated lower antithrombin III antigen or activity in patients with CAD compared with individuals without,32 33 34 35 while others have reported higher rather than lower values.36 37 In contrast, more recent investigations in large populations or patient cohorts failed to demonstrate an association of antithrombin III with the prevalence or extent of CAD.38 39 Similarly, in the present patient sample antithrombin III levels were unrelated to the coronary angiographic status at baseline.21
Prospective studies have suggested that the relationship of
antithrombin III levels to the risk of subsequent atherothrombotic
events may be different in apparently healthy individuals than in
patients with manifest arterial disease. Meade and
coworkers40 have recently reported data on the prospective
relation between antithrombin III and death from arterial
disease in 893 middle-aged initially healthy men from the Northwick
Park Heart Study. They observed 47 cardiovascular
deaths during a 6- to 10-year follow-up and found a U-shaped risk
association with antithrombin III baseline levels. In contrast, 2-year
follow-up data from the Italian "Progetto Lombardo
Atero-Thrombosi" (PLAT) study indicate a nonsignificant trend toward
an increase of atherothrombotic events with decreasing antithrombin III
activity in 953 patients with preexisting arterial
disease.41 Similarly, in the ECAT Angina Pectoris Study of
3000 patients with manifest CAD, antithrombin III antigen was on
average lower by 3% (P=.07) in the 106 patients with
cardiac events during a 2-year follow-up (Reference 3 and S.G.
Thompson, 1995, unpublished data). In line with these observations, we
found a 5% lower antithrombin III activity in the cardiac-event
patients (P=.02). Substantially more impressive than the
between-group difference in mean values was the graded inverse
relationship with the long-term prognosis, which became evident
from the third year of observation onward (Fig 1). Hence, our
data
suggest a previously unknown protective effect of antithrombin III
availability on the incidence of atherothrombotic cardiac events in
patients with manifest CAD. Recent experimental animal data lend
support to this concept in that antithrombin III administration
prevented thrombin appearance on the vessel wall after in vivo balloon
injury and thereby reduced the risk of local thrombosis.42
However, the increased incidence of deaths from arterial
disease in association with high antithrombin III values reported in
the Northwick Park population study40 remains unexplained
and awaits elucidation.
Fibrinogen was on average 7% higher in the patients with cardiac
events (P=.06). The 95% CI (0% to 14%) was entirely
compatible with the results of larger prospective studies in healthy
subjects2 4 and patients with angina
pectoris,3 in which an 10% average fibrinogen
difference was observed between the event and event-free groups. In
a similar manner, this applies to the risk relationship of vWF levels.
We found a nonsignificant 9% average increase in the event cases,
which closely matches the 10% mean difference (P=.02)
observed in the ECAT Angina Pectoris Study.3 Our data are
thus not at variance with this and other reports of a positive risk
association of vWF concentrations in patients with manifest
CAD.13 15 More generally, the limited number of
cardiac
events and hence the relatively large CIs for between-group
differences in hemostatic factor measurements are a limitation of the
present study in that we cannot entirely dismiss the possible
prognostic importance of any hemostatic factor based on these data.
It is interesting to note that hematocrit was positively associated with cardiac events, as this has also been reported from the Framingham study.43 However, this had no effect on the antithrombin III and fibrinogen relationships with risk, because their correlations with hematocrit were almost exactly zero. Adjusting antithrombin III and fibrinogen values for the strongly prognostic variables of EF and worsening of angina in the few weeks before the qualifying angiogram also made little difference. Similarly, adjusting for other baseline variables,44 including age, sex, smoking habit, and total serum cholesterol and triglyceride concentrations did not detract from their prognostic significance.
Finally, little is yet known about the prognostic significance of measurements indicating activation of the hemostatic system. Plasma levels of platelet-release proteins such as platelet factor 4 and ß-thromboglobulin are increased in patients with angina pectoris.45 46 However, they do not apparently aid the prediction of coronary events in those patients,3 a finding that is corroborated and extended to long-term prognosis by the present data. By quantitative determination of TAT complexes and F 1+2 levels, both markers of thrombin generation, we also had the opportunity to examine the relationship between basal coagulation activity and the incidence of subsequent cardiac events. Data on baseline associations with the presence and severity of coronary atherosclerosis in this patient population have provided evidence for a procoagulant state in patients with angiographically verified CAD.20 Notwithstanding this, the prospective results do not provide evidence of a role of these markers in the long-term prediction of cardiac events.
In conclusion, our results demonstrate that hemostatic factors, in particular low antithrombin III activity and high fibrinogen concentration, may have an important etiologic role in the long-term prognosis of patients with angina pectoris. However, their association with coronary risk cannot be explained by increased basal activation of the hemostatic system, which would be detectable in the systemic circulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from the Dr Karl-Wilder-Stiftung, Verband der Deutschen Lebensversicherer.
Received July 31, 1995; accepted November 29, 1995.
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