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Eichinger S, Minar E, Bialonczyk C, et al. D-Dimer Levels and Risk of Recurrent Venous Thromboembolism. JAMA. 2003;290(8):1071–1074. doi:10.1001/jama.290.8.1071
Author Affiliations: Department of Internal Medicine I (Drs Eichinger, Weltermann, and Kyrle), Ludwig-Boltzmann Institute (Dr Kyrle), Department of Internal Medicine II (Dr Minar), Clinical Institute of Medical and Chemical Laboratory Diagnostics (Drs Quehenberger and Wagner), and Institute of Medical Statistics (Dr Schneider), University of Vienna, Austria; and Wilhelminenspital (Dr Bialonczyk) and Hanuschkrankenhaus (Dr Hirschl), Vienna, Austria.
Context Widespread screening of patients with venous thromboembolism (VTE) for
thrombophilic risk factors has become common clinical practice. Because of
the increasing number of risk factors, assessing the risk of recurrence in
an individual patient is intricate; therefore, a laboratory method that measures
multifactorial thrombophilia is required.
Objective To prospectively study the relationship between the risk of recurrent
VTE and D-dimer, a global marker of coagulation activation and fibrinolysis.
Design, Setting, and Participants Prospective cohort study of 610 patients older than 18 years who were
treated with oral anticoagulants for at least 3 months with a first spontaneous
VTE, in whom D-dimer levels were measured shortly after discontinuation of
oral anticoagulation. The study was conducted at the Department of Internal
Medicine I, University Hospital, Vienna, Austria. Patients entered the study
at time of discontinuation of oral anticoagulants and were observed at 3-month
intervals during the first year and every 6 months thereafter from July 1992
to October 2002.
Main Outcome Measure Objectively documented symptomatic recurrent VTE.
Results A total of 79 (13%) of 610 patients had recurrent VTE with a mean observation
time of 38 months. Patients with recurrence had significantly higher D-dimer
levels compared with those without recurrence (553 ng/mL vs 427 ng/mL, P = .01). Compared with patients with D-dimer levels of
750 ng/mL or higher, the relative risk (RR) of recurrence was 0.6 (95% confidence
interval [CI], 0.3-1.4), 0.6 (95% CI, 0.3-1.2), and 0.3 (95% CI, 0.1-0.6)
in patients with D-dimer levels of 500 to 749 ng/mL, 250 to 499 ng/mL, and
less than 250 ng/mL, respectively. The cumulative probability of recurrent
VTE at 2 years was 3.7% (95% CI, 0.9%-6.5%) among patients with D-dimer levels
of less than 250 ng/mL compared with 11.5% (95% CI, 8.0%-15.0%) among patients
with higher levels (P = .001). Patients with D-dimer
levels of less than 250 ng/mL had a 60% lower RR of recurrence compared with
patients with higher levels (RR, 0.4; 95% CI, 0.2-0.8).
Conclusion Patients with a first spontaneous VTE and a D-dimer level of less than
250 ng/mL after withdrawal of oral anticoagulation have a low risk of VTE
The optimal duration of secondary thromboprophylaxis among patients
with venous thromboembolism (VTE) is unknown. The risk of recurrence is minimal
during oral anticoagulation but increases as soon as anticoagulation is stopped.1-4 The price
for decreasing the risk of recurrence by prolonging anticoagulation is an
increased frequency of bleeding. Screening for risk factors might be helpful
to identify patients in whom the risk of bleeding is outweighed by the risk
of recurrence. This approach is hampered because many patients have more than
1 thrombophilic condition. To tackle the problem of evaluating the overall
risk of recurrence, a single laboratory test that measures multifactorial
thrombophilia is required.
D-Dimer is a global indicator of coagulation activation and fibrinolysis.
D-dimer level is measured in plasma by use of well-standardized assays that
are widely used for the diagnosis of acute VTE.5,6 A
high D-dimer level (>70th percentile of controls) is independently associated
with a 2.2-fold increased risk for a first venous thrombosis.7 In
a population-based cohort study, D-dimer was positively related to the occurrence
of a future first thrombosis.8 With regard
to recurrent VTE, Palareti et al9 reported
a 2.5-fold higher risk of recurrence among patients with VTE and D-dimer levels
higher than 500 ng/mL after discontinuation of oral anticoagulation compared
with patients with lower levels. We measured D-dimer levels in 610 patients
with a first spontaneous VTE and assessed the relationship between the risk
of recurrent VTE and the levels of D-dimer.
Between July 1992 and October 2002, 2044 consecutive patients with VTE
(established by venography, color duplex sonography [in case of proximal vein
thrombosis], ventilation-perfusion scanning, or spiral computed tomography)
older than 18 years, who had been treated with oral anticoagulants for at
least 3 months, were eligible. A total of 1434 patients were excluded because
of more than 1 previous VTE (n = 332); surgery, trauma, or pregnancy within
the previous 3 months (n = 393); deficiency of a natural coagulation inhibitor
(n = 59); the lupus anticoagulant (n = 32); cancer (n = 282); or long-term
antithrombotic treatment (n = 336). The study was conducted at the Department
of Internal Medicine I, University Hospital, Vienna, Austria. The study was
approved by the local ethics committee and all patients gave written informed
consent to participate. Patients entered the study at the time of discontinuation
of oral anticoagulants and were observed at 3-month intervals during the first
year and every 6 months thereafter.
The study end point was recurrent symptomatic deep vein thrombosis or
recurrent symptomatic pulmonary embolism, confirmed by venography, color duplex
sonography (in case of proximal vein thrombosis of the contralateral leg),
ventilation-perfusion scanning, and/or spiral computed tomography.10
Laboratory testing was performed 3 weeks after discontinuation of oral
anticoagulants. D-dimer levels were measured by an enzyme-linked immunoassay
(Asserachrom D-dimer, Boehringer Mannheim, Germany). Antithrombin, protein
C, protein S, factor VIII, and the lupus anticoagulant were determined as
reported.10 Screening for factor V Leiden and
factor II G20210A was carried out as described.11,12
Times to recurrence (uncensored observations) or follow-up times in
patients without recurrence (censored observations) were analyzed by using
survival-time methods.13 The probability of
recurrence was estimated according to Kaplan-Meier method.14 To
test for homogeneity between strata, we applied the log-rank and the generalized
Wilcoxon rank sum test. Categorical data were checked for homogeneity by using
contingency table analyses (χ2 test). SAS version 8.02 (SAS
Institute, Cary, NC) was used for all analyses and P<.05
was considered statistically significant.
The study population consisted of 610 patients with a first spontaneous
VTE. After discontinuation of oral anticoagulants, the patients were followed
up for a mean of 38 months. A total of 175 patients were excluded during the
course of the study because they were diagnosed with cancer (n = 11), required
antithrombotics for reasons other than VTE (n = 105), became pregnant (n =
17), or were lost to follow-up (n = 37). One patient died of gastric cancer,
1 of septicemia, and 3 patients of heart failure. These patients were followed
up until the time of exclusion or death, when the data were censored (mean
follow-up, 14 months).
A total of 79 (13%) of 610 patients had recurrent VTE (deep-vein thrombosis
[n = 54] and pulmonary embolism [n = 25]). Patients with recurrent VTE had
significantly higher D-dimer levels than those without recurrence (553 ng/mL
vs 427 ng/mL, respectively, P = .01). To assess the
risk of recurrence for different ranges of D-dimer levels, we arbitrarily
stratified patients into 4 groups. The distribution of thrombotic risk factors,
such as factor V Leiden, factor II G20210A, and high factor VIII (dichotomized
at a plasma level of 234 IU/dL), and the relative risk (RR) of recurrence
according to the 4 ranges of D-dimer levels are shown in Table 1. Compared with the reference group (patients with D-dimer
levels ≥750 ng/mL), the RR of recurrence was lower among patients with
D-dimer levels of 500 to 749 ng/mL (RR, 0.6; 95% CI, 0.3-1.4), among patients
with D-dimer levels of 250 to 499 ng/mL (RR, 0.6; 95% CI, 0.3-1.2), and was
significantly lower among patients with D-dimer levels of less than 250 ng/mL
(RR, 0.3; 95% CI, 0.1-0.6), respectively. Adjustment for potential confounding
variables, including age, sex, factor V Leiden, factor II G20210A, and high
factor VIII, did not substantially influence the result.
A total of 209 (34%) of 610 patients had D-dimer levels of less than
250 ng/mL. Recurrent VTE was observed in 16 (7.7%) of 209 patients with D-dimer
levels of less than 250 ng/mL. Patients with D-dimer levels of less than 250
ng/mL were significantly younger and had significantly less thrombotic risk
factors, such as factor V Leiden or high factor VIII, compared with patients
with higher levels (Table 2).
No difference between the 2 groups was observed with regard to the mean duration
of anticoagulation (7.8 and 8.3 months, respectively; P = .30).
The cumulative probability of recurrent VTE at 2 years was 3.7% (95%
CI, 0.9%-6.5%) among patients with D-dimer levels of less than 250 ng/mL compared
with 11.5% (95% CI, 8.0%-15.0%) among patients with higher levels (P = .001, Figure 1). Among
patients with D-dimer levels of less than 250 ng/mL, the RR of recurrence
was 0.4 (95% CI, 0.2-0.8), which translates into a 60% lower RR compared with
patients with higher levels.
Our study showed that patients with a first spontaneous VTE and a D-dimer
level of less than 250 ng/mL 3 weeks after discontinuation of oral anticoagulation
are at low risk of recurrence. These patients, who represent approximately
one third of the total cohort, had a probability of recurrent VTE at 2 years
as low as 3.7% with an upper limit of the 95% CI of 6.5%. Compared with patients
with D-dimer levels of 250 ng/mL or higher, those patients with lower levels
had a 60% lower RR of recurrence, which was independent of other potentially
During the last years, several new thrombotic risk factors have been
the risk of recurrence associated with these thrombophilic conditions was
investigated with the intention to optimize secondary thromboprophylaxis.
Many researchers have shown that heterozygous carriers of factor V Leiden2,17-20 or
the prothrombin mutation21,22 do
not have a higher risk of recurrence than patients without the mutation. Conversely,
patients with combined defects,19,20 hyperhomocysteinemia,23 and those with high factor VIII10 have
a high risk of recurrence. As a consequence, extensive thrombophilia screening
has become common practice. However, assessing the overall risk of recurrence
in an individual patient is intricate as many patients carry more than 1 thrombotic
risk factor and the effect of compound defects tends to be multiplicative
rather than additive.24 To overcome this limitation,
a simple laboratory test that measures multifactorial thrombophilia is required.
Our data clearly showed that in patients with a first VTE the use of
a single laboratory test (ie, D-dimer) allows a global assessment of their
thrombotic tendency and a stratification into high-risk and low-risk patients
with regard to the risk of recurrence. In a study from Italy, a high negative
predictive value for VTE recurrence was reported.9 This
study differs from our study in many important aspects, including the diagnosis
of the first VTE (which is uncertain in the Italian study), patient characteristics
(almost 50% of the Italian patients had VTE secondary to removable risk factors),
patient number (396 vs 610), and total duration of follow-up (628 vs 1945
In conclusion, measuring D-dimer levels allows identification of a subset
of patients with thrombosis with a very low risk of recurrence. In these patients,
extensive screening for thrombophilic risk factors may be unnecessary.