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Regular Article
CLINICAL TRIALS AND OBSERVATIONS
D-dimer to guide the duration of anticoagulation in patients with venous
thromboembolism: a management study
Gualtiero Palareti,1 Benilde Cosmi,1 Cristina Legnani,1 Emilia Antonucci,2 Valeria De Micheli,3 Angelo Ghirarduzzi,4
Daniela Poli,2 Sophie Testa,5 Alberto Tosetto,6 Vittorio Pengo,7 and Paolo Prandoni,8 on behalf of the DULCIS (D-dimer and
ULtrasonography in Combination Italian Study) Investigators
1
Angiology and Blood Coagulation, University Hospital of Bologna, Bologna, Italy; 2Thrombosis Centre, Department Heart and Vessels, University Hospital
of Florence, Florence, Italy; 3Haemostasis and Thrombosis Centre, Hospital of Lecco, Lecco, Italy; 4Internal Medicine, ASMN-IRCCS-Reggio Emilia, Reggio
nell’Emilia, Italy; 5Haemostasis and Thrombosis Centre, Hospital of Cremona, Cremona, Italy; 6Haematology and Thrombosis Centre, Hospital of Vicenza,
Vicenza, Italy; and 7Department of Cardiothoracic and Vascular Sciences and 8Internal Medicine, Department of Medical and Surgical Sciences, University
Hospital of Padua, Padua, Italy
The optimal duration of anticoagulation in patients with venous thromboembolism
(VTE) is uncertain. We investigated whether persistently negative D-dimers in patients with
• The duration of anticoagulation vein recanalization or stable thrombotic burden can identify subjects at low recurrence risk.
Outpatients with a first VTE (unprovoked or associated with weak risk factors) were eligible
after VTE is uncertain; this
management study intended to after at least 3 months (12 in those with residual thrombosis) of anticoagulation. They
received serial D-dimer measurements using commercial assays with predefined age/
identify patients with low/high
sex-specific cutoffs and were followed for up to 2 years. Of 1010 patients, anticoagulation
recurrence risk.
was stopped in 528 (52.3%) with persistently negative D-dimer who subsequently ex• Patients with persistently
perienced 25 recurrences (3.0% pt-y; 95% confidence interval [CI], 2.0-4.4%). Of the
negative D-dimers after
remaining 482 patients, 373 resumed anticoagulation and 109 refused it. Recurrent VTE
stopping standard therapy
developed in 15 patients (8.8% pt-y; 95% CI, 5.0-14.1) of the latter group and in 4 of the
have a low recurrence risk
former (0.7% pt-y; 95% CI, 0.2-1.7; hazard ratio 5 2.92; 95% CI, 1.87-9.72; P 5 .0006). Major
and can stop anticoagulation. bleeding occurred in 14 patients (2.3% pt-y; 95% CI, 1.3-3.9) who resumed anticoagulation.
Serial D-dimer measurement is suitable in clinical practice for the identification of VTE
patients in whom anticoagulation can be safely discontinued. This study was registered at clinicaltrials.gov as #NCT00954395.
(Blood. 2014;124(2):196-203)
Key Points
Introduction
Venous thromboembolism (VTE), encompassing deep vein thrombosis
(DVT) and pulmonary embolism (PE), tends to recur, especially when
the event is idiopathic or associated with a permanent prothrombotic
conditions.1 The cumulative rate of recurrence 10 years after withdrawal of anticoagulation was reported to be ;50% in patients with
a first unprovoked VTE and ;20% after a provoked event.2 Anticoagulation for 3 months is recommended in all VTE patients,
whereas indefinite anticoagulation is suggested3 in patients with
idiopathic VTE and without high bleeding risk, because the recurrence
rate after stopping anticoagulation is independent of the duration of
initial treatment.4,5
Altered D-dimer levels after anticoagulation is stopped in patients
with a first VTE6 and the persistence of residual vein thrombosis
(RVT) after DVT7 have been shown to be a risk factor for recurrence.
We performed a prospective cohort study in outpatients with a
single episode of proximal DVT of the lower limbs and/or PE who
had received a standard course of anticoagulation (.3 months), or
at least 12 months in case of RVT. We sought to assess whether
Submitted January 6, 2014; accepted May 7, 2014. Prepublished online as
Blood First Edition paper, May 30, 2014; DOI 10.1182/blood-2014-01-548065.
a management procedure involving serial D-dimer testing and
RVT assessment can identify a subset of subjects at low risk of
recurrence in whom anticoagulation can be safely discontinued.
Methods
Study patients
This was a multicenter, prospective cohort study involving patients of both
sexes aged $18 years who had experienced a first symptomatic VTE episode,
including proximal DVT of the legs, PE, or both, that was either idiopathic or
associated with weak risk factors (WRFs; Table 1). The index event was
objectively confirmed by compression ultrasonography (CUS), ventilationperfusion lung scan, or computed tomographic pulmonary angiography
(CTPA), as appropriate, and treated according to international guidelines,
including acute and long-term anticoagulant therapy and, in the case of DVT,
compression elastic stockings (30-40 mm Hg at the ankle). All screened
patients were examined to assess for the presence of criteria for exclusion,
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked “advertisement” in accordance with 18 USC section 1734.
© 2014 by The American Society of Hematology
196
BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
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BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
Table 1. Criteria for exclusion/inclusion in the study
Inclusion criteria
Age $18 y
MANAGEMENT OF ANTICOAGULATION AFTER VTE
197
VKA and to repeat D-dimer testing after 15 to 18 days (T15), 25 to 35 (T30),
55 to 65 (T60), and 85 to 95 (T90) days from T0. Patients were recommended
to resume anticoagulation at the first positive D-dimer result.
First episode of proximal VTE of lower limbs and/or PE that was:
idiopathic or associated with one or more of following factors:
minor, arthroscopic, or laparoscopic general surgery
pregnancy or puerperium
contraceptive or replacement hormonal therapy
long trip (.6 h)
minor trauma (not requiring hospitalization, plaster casting, or immobilization)
hospitalization in a medical hospital
reduced mobility (not complete immobilization)
Anticoagulation therapy (VKA, INR 2.0-3.0) for at least 3 mo
Ability to provide informed consent
Prespecified criteria for exclusion
Age ,18 y
Duration of anticoagulation ,3 mo
Inability or refusal to give consent
Limited life expectation (,1 y)
Increased systolic pulmonary arterial pressure (values $35 mm Hg [or $40 mm
Hg if BMI $30 or age $75 y] estimated with echocardiography)
Geographical inaccessibility
Venous thrombosis in different sites (upper limbs, splanchnic veins, jugular or
cerebral veins)
Pregnancy or puerperium (first 6 weeks after birth) at the time of screening
examination
Severe renal (creatinine level .2 mg/dL [177 mmol/L]) or liver failure (eg, acute
hepatitis, chronic active hepatitis, or cirrhosis; or an alanine aminotransferase
D-dimer assays and prespecified cutoff values
D-dimer levels were assessed with the quantitative assay routinely used
in each participating center, provided that it was one of the following: (1)
VIDAS D-dimer Exclusion (bioMerieux, Lyon, France), (2) Innovance
D-DIMER (Siemens, Deerfield, IL), (3) HemosIL D-dimer HS (Instrumentation Laboratory, Milan, Italy), (4) HemosIL D-dimer (Instrumentation
Laboratory), and (5) STA Liatest D-dimer (DiagnosticaStago, Asnieres-surSeine, France). As discussed elsewhere,9 age and sex specific cutoff values
were calculated for risk of recurrence and used in the aforementioned tests,
instead of those recommended by the manufacturers for VTE exclusion.
These specific cutoff values were determined by using stored frozen plasma
aliquots collected from the patients included in the Prolong6 and Prolong II10
studies. These aliquots were centralized in the coordinating center laboratory.
Two predefinite criteria were adopted to select cutoff values for the assays:
(1) the percentage of patients with above cutoff D-dimer after one month from
anticoagulation was stopped had to be as close as possible to that obtained in
the Prolong study at the same timing (36.7%) and within 95% confidence
interval (CI, 32.8-40.6), and (2) the percentage of VTE recurrence in patients
with below cutoff D-dimer had to be as low as possible.
The adopted D-dimer cutoffs (Table 2) differed markedly in relation to
age and sex. The adopted cutoffs for young males were similar or even lower
than those recommended for VTE exclusion; they were slightly higher for
young females but noticeably higher for males and females over 70 years.
level that was 3 times the upper limit of the normal range or higher)
Criteria for short anticoagulation
VTE post major surgery (within 3 mo)
VTE post bed resting ($4 d)
VTE post major trauma (within 3 mo)
VTE post plasters or immobilization (within 3 mo)
High bleeding risk
Criteria for extended anticoagulation
.1 documented VTE episode (proximal DVT and/or PE)
Active cancer or hematologic disease
Antithrombin deficiency
Antiphospholipid antibody syndrome (Sydney criteria)
PE with shock or life-threatening prolonged hypotension
Different indications for anticoagulation
Severe cardiorspiratory insufficiency (NYHA 3 or 4)
BMI, body mass index; INR, international normalized ratio; NYHA, New York
Heart Association.
for short or extended anticoagulation, and finally for inclusion in the study
(see detailed criteria in Table 1). Patients were eligible if they had completed
at least 3 months of therapy with a vitamin K antagonist (VKA, either warfarin
[Coumadin, Bristol-Myers Squibb] or acenocoumarol [Sintrom, Novartis
Pharma]), with a target INR of 2.5 (range, 2.0-3.0).
Management procedures
All eligible patients were examined after at least 3 months of anticoagulation
to assess their conditions for study enrollment. Before inclusion, all patients
received a bilateral CUS examination of the proximal deep veins (common
femoral, superficial femoral, and popliteal), and those presenting with RVT
(.4-mm vein diameter at probe compression in the transverse section8) in at
least one of the aforementioned veins were included in the study only after
completing a total of 12 months of VKA therapy.
All included patients underwent a serial D-dimer assessment starting at
baseline during anticoagulation (T0). Patients with positive baseline D-dimer
(adopting the criteria indicated next) were instructed to continue anticoagulation, whereas those with negative D-dimer were recommended to stop
Study outcomes and follow-up
Patients were followed for a maximum of 2 years, and were seen at the clinical
centers at intervals of 3 to 6 months, or they were monitored for VKA dosing.
Patients were instructed to contact the clinical center immediately in case of
symptoms suggestive of VTE or bleeding.
The main study outcome was the composite of confirmed recurrent VTE
and death caused by VTE. In cases of suspected DVT recurrence, CUS results
were compared with those of the last available previous examination. Any
recurrent DVT was adjudicated if a previously fully compressible segment
(contralateral or ipsilateral) was no longer compressible or if an increase of
at least 4 mm in the diameter of the residual thrombus during compression
was detected.8 In patients with suspected PE, recurrence was diagnosed on
the basis of objective algorithms11,12 incorporating clinical probability;
ventilation-perfusion lung scanning; or CTPA, CUS, and/or D-dimer testing
as appropriate. Major bleeding events, defined by the International Society of
Thrombosis and Haemostasis,13 were also recorded.
All suspected outcome events and deaths were evaluated by a central adjudication committee whose members were unaware of patient name, D-dimer
testing results at inclusion, management, or enrolling center. All patients gave
their written informed consent for participation. The institutional review
boards of all participating centers approved the study, which was conducted in
accordance with the Declaration of Helsinki.
Statistical analysis and sample size
On the basis of a cumulative recurrence rate in patients with provoked VTE
of 6.7% after 24 months from VKA suspension,14 we designed the study to
have an 80% power to detect a recurrence rate below a clinically acceptable
incidence of 9% of the composite end point after 24 months. According to
Shen,15 the required sample size in those suspending VKA was 530.
Differences between groups were assessed using the x2 test with Yates’
correction for categorical variables and the Mann-Whitney U test for
continuous variables. Kaplan-Meier survival curves were plotted to estimate the cumulative incidence of symptomatic recurrent VTE; hazard
ratios (HR) and their 95% CIs were calculated. The data were analyzed
with the use of Prism software (Version 3.0, GraphPad Software Incorporated,
San Diego, CA) and SPSS software (version 11.0 SPSS Inc., IBM,
Armonk, NY).
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198
BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
PALARETI et al
Table 2. Age- and sex-specific cutoff levels for the different D-dimer assays adopted in the study
Commercial D-dimer assay
(manufacturer) ng/mL
Females £70 y
Females >70 y
Cutoff values currently recommended by
manufacturers for VTE exclusion
Males £70 y
Males >70 y
VIDAS D-dimer Exclusion (bio-Merrieux)
490
1050
600
1300
500
Innovance D-DIMER (Siemens)
500
950
550
1150
500
230
HemosIL D-dimer HS (Instrumentation Laboratory)
170
345
215
430
HemosIL D-dimer (Instrumentation Laboratory)
205
300
225
330
230
STA Liatest D-dimer (Diagnostica Stago)
340
700
450
1050
500
For comparison, the cutoff values recommended by manufacturers for VTE exclusion are also shown.
Results
Patients and management
Figure 1 shows the study flow chart. In the 18 participating centers,
2458 patients with a first episode of VTE were screened between
July 2008 and December 2011. Of these patients, 1401 (57.0%)
were excluded for predefined criteria (442) or for criteria leading
to short (353) or extended anticoagulation (606). A total of 1057
patients (43.0% of the screened population) were eligible. Fortyseven (4.4%) patients were then excluded from the study because
of consent withdrawal (16) or for conditions requiring continued
anticoagulation (27), or they were lost to follow-up after the first
D-dimer test (4). The remaining 1010 patients (560 males) followed
the management procedure and were analyzed; the index event was
idiopathic in 771 (76.3%) patients and was associated with WRF in
the remaining 239 (23.7%).
Table 3shows the characteristics of the analyzed patients. D-dimer
was persistently negative (below cutoff levels) in 528 patients
(52.3%; 277 males) who stopped anticoagulation and included 15
patients (as intention-to-treat analysis) with incomplete serial D-dimer
testing and/or a short follow-up. D-dimer was positive (above cutoffs)
in 482 (47.7%) patients (significantly older than those with normal
D-dimer) who were advised to resume VKAs at the first positive
D-dimer result. However, 109 of these (10.8%, 70 males; 22.6% of all
Figure 1. Flow chart of the DULCIS study. The
prespecified criteria for exclusion from the study and
for short or extended anticoagulant treatment are
reported in Table 1. #Patients were excluded for the
following reasons: consent withdrawal (16), presented
conditions requiring anticoagulation (27), had only the
first D-dimer testing, were then lost to follow up (4).
71 (13.5)
.12 mo
57*
,1 y
63 (13.1)
56 (10.6)
53 (10.0)
Presence of RVT (.4 mm), n (%)
Associated antiplatelet treatment, n (%)
.784
.553
.263
.179
.697
.508
.786
1.000
10 (9.2)
5 (4.6)
1 (0.9)
14 (12.8)
7
29
59
1.97 (1.23-2.00)
171
19 (17.4)
61 (56.0)
29 (26.6)
FU, follow-up; IQ, interquartile range; NA, not available.
*Fifteen of these patients were included in the analysis (as intention-to-treat), though their serial D-dimer testing was still incomplete (being enrolled late) and/or had a short follow-up.
42 (8.7)
1 (0.2)
29 (6.0)
49
165
239
1.90 (1.29-2.00)
772
69 (14.3)
272 (56.4)
141 (29.3)
6 (1.1)
Lost to FU, n (%)
36 (6.8)
169
Patients censored during FU, n (%)
266
1-2 y
1.93 (1.25-2.00)
2y
Duration of FU, n
FU, y, median (IQ)
829
297 (56.2)
1
8
3
1
11
1
1
83 (76.1)
26 (23.9)
,.0001
29 (26.8) (1 NA)
26 (24.1)
53 (49.1)
32 (29.3)
,.0001
.379
.037
.384
.011
70 (64.2)
64 (49-72)
.055
Positive D-dimer without
anticoagulation (N 5 109)
,.0001
P value
32 (8.6)
58 (15.5)
0
15 (4.0)
42
136
180
1.88 (1.29-2.00)
601
50 (13.4)
211 (56.6)
112 (30.0)
23
13
5
1
19
0
1
62 (16.6)
311 (83.4)
89 (24.3) (6 NA)
87 (23.7)
191 (52.0)
191 (51.2)
71 (61-80)
213 (57.1)
Positive D-dimer with
anticoagulation (N 5 373)
.999
.005
.535
.002
.990
.375
.999
.574
.115
.115
.689
.968
.677
,.0001
,.0001
.230
P value
BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
Total duration of FU for all patients, y
160 (30.3)
27
21
7-12 mo
20
17
8
2
5
8
#6 mo
Duration of previous anticoagulation, n (%)
Hospitalization in a medical ward
Minor trauma, leg injury, reduced mobility
Long travel
1
30
3
Hormonal contraceptive replacement therapy
2
88 (18.3)
394 (81.7)
118 (24.8) (7 NA)
113 (23.8)
244 (51.4)
223 (46.3)
69 (58-79)
283 (58.7)
Positive D-dimer (N 5 482)
90
Pregnancy or puerperium
surgery
7
WRFs
Minor general, laparoscopic, or arthroscopic
377 (71.4)
151 (28.6)
Idiopathic
Type of risk factors, n (%)
141 (27.0) (5 NA)
97 (18.5)
Isolated PE
285 (54.5)
Proximal DVT with no PE
201 (38.1)
63 (45-75)
277 (52.5)
Negative D-dimer (N 5 528)
DVT plus symptomatic PE
Type of VTE, n (%)
Age .70 y, n (%)
Age (y), median (IQ)
Male sex, n (%)
Characteristic
Table 3. Baseline characteristics of the 1010 study patients
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MANAGEMENT OF ANTICOAGULATION AFTER VTE
199
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PALARETI et al
Figure 2. Prevalence of first-time-ever D-dimer result above the predefined
cutoff levels in the investigated study population at the serial measurement
days after VKA withdrawal. The percentages are calculated vs the total number of
patients included.
the subjects with positive D-dimer) refused to do so and continued
follow-up, whereas the remaining 373 (36.9%; 213 males), significantly older than those who refused, resumed anticoagulation therapy.
The prevalence of positive D-dimer was significantly higher in patients
with an idiopathic index event (51.1%) than in those with events
associated with WRF (36.8%, P , .0001); it was lower (P , .01) in
young females (38.3%) than in the other subgroups in which the
prevalence ranged between 50.4% and 53.7%. As is shown in
Figure 2, the highest rate of positive D-dimer in the whole study
population was detected at 15 days (20.8%) after stopping anticoagulation, with an overall positivity of 48.8% at the end of serial
testing (at 90 days). A persistent RVT was detected in 119 patients,
of whom 56 had negative D-dimer (10.6% of the 528 total patients
with persistently negative assay), and 63 had positive D-dimer
(13.1% of the 482 patients with positive assay).
Outcomes
Primary outcomes (Table 4) occurred in 25 of 528 patients with
negative D-dimer (4.7%; 95% CI, 3.2-6.9; 3.0 per 100 pt-y, 95% CI,
2.0-4.4) and in 15 of 109 patients who had positive D-dimer results
but refused to resume anticoagulation (13.8%; 95% CI, 7.9-21.7; 8.8
per 100 pt-y; 95% CI, 5.0-14.1). The HR of outcome incidence of the
latter vs the former was 2.92 (95% CI, 1.87-9.72; P 5 .0006). The
effect of age, sex, and type of index event on the occurrence of
primary outcomes in patients who did not resume anticoagulation is
shown in Table 5. In patients with negative D-dimer, events were
significantly more frequent in those aged .70 years than in younger
patients (8.9% vs 2.1%; P 5 .0008), and in patients with idiopathic
than in those with secondary VTE (6.1% vs 1.3%; P 5 .036), although
no differences were present in relation to age and type of index event
in patients with positive D-dimer. No difference was detected
between males and females, either with negative or positive D-dimer.
Thirty of 120 women who received hormonal contraception at the
moment of the event (included in the study for this WRF) had positive
D-dimer. However, 11 of them refused to resume anticoagulation and
there was subsequently one recurrent event in this subgroup (9.1%;
4.9% per 100 pt-y), whereas only one event occurred in the remaining
90 women who always had negative D-dimer (1.1%; 0.65 per 100
pt-y). Four events (1 young male and 3 elderly women, all with
negative D-dimer at T0) occurred during the interval before the T15
D-dimer control. In patients with positive D-dimer, there were no
differences in age, sex, or type of index event. Among all patients who
did not resume anticoagulation, there was no difference in recurrence
in those either with or without RVT (5.3% vs 6.3%, respectively) or in
those who either received aspirin or did not (6.3% vs 6.2%, respectively).
Among the patients with positive D-dimer who did not resume
anticoagulation, the rate of recurrence was higher in those whose
D-dimer became positive within one month from VKA withdrawal
than in those whose D-dimer became positive later; however, the
difference did not reach statistical difference, probably owing to
the low number of cases (13/77 [16.9%] vs 2/32 [6.2%], P 5 .247;
the 2 subjects with late-positive D-dimer who recurred were both
young).
In patients who resumed anticoagulation after a positive D-dimer
result, 4 thrombotic events (1.1%; 95% CI, 0.3-2.7; 0.7 per 100 pt-y,
95% CI, 0.2-1.7) and 14 major hemorrhages (fatal in 1) (3.7%, 95% CI,
2.1-6.2; 2.3 per 100 pt-y, 95% CI, 1.3-3.9) occurred. The rate of
Table 4. Clinical events occurred in the investigated patients
Primary outcomes, n, % (95% CI)
Incidence per 100 pt-y, % (95% CI)
Negative D-dimer,
no anticoagulation
(n 5 528; 829 y)*
Positive D-dimer,
anticoagulation refused
(n 5 109; 171 y)*
Positive D-dimer,
anticoagulation resumed
(n 5 373; 601 y)*
25 (4.7%; 3.2-6.9)
15 (13.8%; 7.9-21.7)§
4 (1.1%; 0.3-2.7)
3.0% (2.0-4.4)
8.8% (5.0-14.1){
0.7% (0.2-1.7)
Type of event (idiopathic), n
16 (14)
8 (6)
1
PE
DVT
5 (5)
3 (3)
2 (1)
DVT1PE
4 (3)
4 (2)
1
5
Other outcomes, n
Death†
1
0
Isolated distal DVT
9
2
0
SVT
19
2
2
Arterial vascular event
3
0
1
0
0
14‡ (3.7%; 2.1-6.2)
Major bleeding, n, % (95% CI)
Incidence per 100 pt-y, % (95% CI)
SVT, superficial vein thrombosis.
*Total follow-up.
†No death could be attributed to thrombotic event.
‡1 major bleeding was fatal.
§P 5 .0008 patients with negative D-dimer.
{P , .0009 vs patients with negative D-dimer.
2.3% (1.3-3.9)
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BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
MANAGEMENT OF ANTICOAGULATION AFTER VTE
201
Table 5. Cumulative rates (no. per 100 patient-years) of primary study outcomes in relation to age, sex, and type of index event in patients
who did not resume anticoagulation
Age
£70 y
>70 y
Patients with negative D-dimer, n (%)
327 (61.9)
201 (38.1)
Primary outcomes, % (95% CI)
2.1 (0.9-4.4)
8.9 (5.4-13.8)
Patients with positive D-dimer who
77 (70.6)
32 (29.4)
Sex
P value
.0008
Males
Females
277 (52.2)
251 (47.8)
4.7 (2.5-7.9)
4.8 (2.5-8.2)
70 (64.2)
39 (35.8)
Type of index event
P value
.886
Idiopathic
WRF
377 (71.4)
151 (28.6)
6.1 (3.9-9)
1.3 (0.2-4.7)
83 (76.1)
26 (23.9)
P value
.036
did not resume anticoagulation n (%)
Primary outcomes, % (95% CI)
14.3 (7.4-24.1) 12.5 (3.5-29.0)
.956
bleeding was higher in elderly (4.7%) than in younger (2.7%) patients,
but the difference was not significant (P 5 .460).
Discussion
Our study shows that a management procedure based on repeated
D-dimer testing can be used in patients with a single VTE event that
is either idiopathic or associated with WRFs to identify those with
a low risk of recurrence and in whom anticoagulation can be
discontinued. Anticoagulation was withdrawn on the basis of D-dimer
tests persistently below age- and gender-specific cutoffs in .50% of
patients, in whom the subsequent annual recurrence rate was 3%.
The recurrence rate in the present study was below the rates
recommended as acceptable by the Subcommittee on Control of
Anticoagulation of the International Society on Thrombosis and
Haemostasis to justify stopping anticoagulant therapy (5% at 1 year
and 15% at 5 years, with an upper boundary limit of 8% at 1 year).16
In our study, all the screened patients underwent investigation for
the presence of RVT before inclusion, and those with RVT were
included only after completing one year of anticoagulation. RVT has
long been considered a predictor of recurrence17-19 and a criterion to
guide the duration of anticoagulation.7,20 A recent systematic review
of available studies21 found that RVT is associated with a significant,
albeit modest, increase in the risk of recurrent VTE in patients with
(unprovoked or provoked) DVT. The authors concluded that the role
of RVT in assessing the risk of recurrent VTE after stopping anticoagulation in patients with unprovoked DVT remains unclear and
warrants further investigations. Although the present study was not
designed to give an answer to the issue of whether detecting RVT
may help guide the duration of anticoagulation, we decided to give
patients with RVT a period of anticoagulation long enough (1 year)
to achieve a steady-state thrombus condition before starting D-dimer
measurements. Of interest, in our cohort patients who did not resume
anticoagulation, we failed to show any appreciable difference in
recurrence rates between those with and without RVT.
Regarding D-dimer measurement, the current study had important
differences from the previous and similar Prolong and Prolong II
studies,6,10 in which the same assay (qualitative and calibrated for
VTE exclusion) was used in all participating centers. In the present
study, centers used their routine commercial quantitative assay, but
with age- and sex-specific cutoffs. D-dimer levels increase with
age22-24 and are higher in women.25 Compared with the cutoff levels
recommended by manufacturers for VTE exclusion, those set for this
study were much higher in elderly patients, but were similar or even
lower in younger patients, especially in men. As a result, more elderly
patients discontinued anticoagulation, whereas the opposite was true
for younger patients, especially males. This effect, together with the
higher thrombosis risk associated with age, may account for the
10.0 (4.1-19.5) 20.5 (9.3-36.5)
.220
15.7 (8.6-25.3)
7.7 (1.0-25.1)
.483
higher recurrence rate in elderly than in younger patients. Lower
cutoff levels might have further lowered the recurrence rate in elderly
patients; however, this would have been offset in part by an increase
in the proportion of those to be anticoagulated indefinitely, with the
associated bleeding risk. Although the cutoff levels adopted in the
present study for young subjects proved to be very effective, we
believe that a refinement in the cutoff levels for elderly patients is
advisable to optimize the relationship between an acceptable rate of
recurrence and the proportion of anticoagulated patients. We currently
cannot indicate specific cutoff values, different from those used in the
study, to be recommended for managing this patient population, and
we propose this issue as an important target for future clinical studies.
In the Prolong study, D-dimer was tested only once at one month
after VKA interruption,6 whereas in the Prolong II study, patients
whose D-dimer levels became abnormal beyond one month after
VKA withdrawal had a higher risk of recurrence.10 As is shown in
Figure 2, the highest rate of positive D-dimer tests was detected after
15 days (20.8%), with 13.1% positive results at 30 days after VKA
withdrawal and another 10% positive results afterward. Among the
patients who refused to resume anticoagulation, the recurrence rate in
those whose D-dimer became positive after one month (2 cases, both
young patients) was lower but not statistically different than in those
with earlier positive results. Although we may suggest omitting the
D-dimer measurement during anticoagulation (T0) in clinical practice
(4 very early recurrences could not be avoided after a negative D-dimer
at T0), we believe that the present results confirm the validity of
extending D-dimer assessment beyond one month to increase the
protection from recurrence, especially in young patients.
The risk of recurrent VTE has consistently been found to be
higher in men than in women.26-30 In our study, the difference in
the recurrence rate between men and women disappeared when the
comparison was made separately among patients with or without
positive D-dimer (Table 5). This suggests that D-dimer is an important
marker of recurrent thromboembolism and has the potential to
compensate for the difference in the gender-related recurrence risk
once a proper adjustment of cutoff levels is performed.
Patients were invited to prolong or resume anticoagulation as
soon as the D-dimer test result was positive. However, approximately
one-fifth of patients refused to resume VKA, and their recurrence rate
was about threefold higher than in patients with persistently negative
D-dimer (Figure 3). Patients with positive D-dimer who refused to
resume anticoagulation were significantly younger than those who
agreed to resume anticoagulation, thus showing that young patients
with a first VTE are more reluctant to accept an indefinite anticoagulation; no other significant differences could be detected between
these 2 groups (Table 3). These results provide further compelling
evidence that D-dimer testing can be used to distinguish patients with
a high recurrence risk.
The risk of recurrence is higher after idiopathic events1,2; however,
it is not negligible when the events are associated with WRFs. In fact,
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
202
BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
PALARETI et al
Figure 3. Kaplan-Meier cumulative event rates for the primary efficacy outcome
in patients with persistently negative D-dimer results in whom anticoagulation
was definitively stopped (dotted line) and in those with positive D-dimer results
who refused to resume anticoagulation (continuous line).
Iorio et al showed a recurrence rate of 4.2% patient-years in subjects
whose index event was secondary to nonsurgical risk factors.14 The
proportion of patients with VTE events associated with WRFs is
generally relevant (one-fourth of all included patients in our study) and
it is important to give them justified clinical advice. This is why our
study included patients with either idiopathic events or events
associated with WRFs, because we intended to propose and analyze
the efficacy and safety of a practical model to manage the duration of
anticoagulation in patients after a first VTE event. Our study showed
that the majority of the patients with an index event associated with
a WRF (64.4%) had negative D-dimer and stopped anticoagulation.
As expected, among the patients with positive D-dimer who did not
resume anticoagulation, the rate of recurrence was almost twice
as high in patients with an idiopathic event as in those with WRFs;
however, among the latter patients, the rate of recurrence was higher
in those with positive than in those with negative D-dimer (Table 5;
the difference did not reach statistical significance, probably for the
limited number of patients). Furthermore, among young women who
had a VTE during hormonal contraception, a population usually
considered at low risk, one case of recurrence occurred among the
11 of those with positive D-dimer who did not resume anticoagulation,
and only one recurrence occurred among the 90 of them with negative
D-dimer (9.1% vs 1.1%). These results, while confirming the higher
risk of recurrence when the index VTE event is idiopathic, also indicate
that D-dimer can be useful to evaluate the risk of recurrence in individual patients with nonidiopathic VTE.
Among the 373 patients who resumed anticoagulation, 4 experienced VTE events (1.1%) (mainly in association with temporary
interruption of anticoagulation), and 14 (3.7%) had major bleeding
events (1 fatal) during follow-up. Thus, the cumulative rate of
harmful events associated with anticoagulation in these subjects was
not different from that observed in patients with negative D-dimer
who discontinued anticoagulation. This further supports the benefit
of identifying patients at lower risk of recurrence in whom anticoagulation can be discontinued.
The most innovative aspects of the management procedure
adopted in this study also have potential limitations. First, serial
D-dimer testing may be inconvenient for both patients and physicians;
to simplify this approach, we suggest the omission of testing during
anticoagulation (T0), but we still advise to repeat D-dimer measurement beyond one month after anticoagulation is stopped. Second,
some patients, especially younger ones, can disagree with prolonging
or resuming anticoagulation based only on a single blood test result.
Third, the age and sex-specific D-dimer cutoff levels adopted in this
study for patients aged .70 years were substantially high (twice as
high as the upper normal limit indicated for diagnostic purposes).
This may generate some confusion in professionals used to the
cutoffs established for VTE exclusion and may raise perplexity in
labeling as negative such high results. Finally, repeating the D-dimer
assay in the first 3 months after anticoagulation is stopped, using
cutoff values different than those for VTE exclusion, may generate
confusion in professionals, especially in the case of VTE recurrence
suspicion during this period.
In conclusion, our study showed that, based on persistently normal
D-dimer tests, anticoagulation could be stopped in .50% of patients
included after a single idiopathic VTE or associated with WRFs;
the recurrence rate during follow-up was as low as 3.0 per 100 pt-y
(95% CI, 2.0-4.4), which is below the rates recommended as
acceptable to justify anticoagulation discontinuation.16
Acknowledgments
The Italian Federation of Anticoagulation Clinics (FCSA) supported
this study by inviting the affiliated centers to take part in the study and
by organizing and supporting the meetings necessary to start and
finalize the study. The Department of Angiology and Blood Coagulation of University Hospital of Bologna supported the collection
and analysis of the data
Authorship
Contribution: All authors contributed to the design of the study; B.C.,
V.D.M., A.G., D.P., S.T., and A.T. contributed to data collection; B.C.,
E.A., and C.L. contributed to data analysis; all authors contributed to
the interpretation of the data collected; and G.P. wrote the first draft
of the manuscript, and all the authors contributed to its final changes.
Conflict-of-interest disclosure: The authors declare no competing
financial interests.
A full list of study investigators can be found in the Appendix.
Correspondence: Gualtiero Palareti, Department of Angiology &
Blood Coagulation, University Hospital Policlinico S. OrsolaMalpighi, Via Albertoni 15, 40138 Bologna, Italy; e-mail: gualtiero.
[email protected].
Appendix
The following were members of the DULCIS study group (the numbers
of patients who participated in the study appear in parentheses):
Gualtiero Palareti, Benilde Cosmi, Cristina Legnani, Divisione di
Angiologia e Malattie della Coagulazione, Azienda Ospedaliero–
Universitaria di Bologna, Policlinico S. Orsola–Malpighi, Bologna,
Coordinator Center (270); Nicoletta Erba, Valeria De Micheli, U.O.
Patologia Clinica, Azienda Ospedaliera provincia di Lecco (139);
Angelo Ghirarduzzi, Maria Rosaria Veropalumbo, Ugolotti Maria
Chiara, Angiologia, ASMN-IRCCS–Reggio Emilia, Reggio Emilia
(126); Daniela Poli, Domenico Prisco, Emilia Antonucci, Malattie
Aterotrombotiche, AOU–Careggi, Firenze (114); Sophie Testa, Oriana
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
BLOOD, 10 JULY 2014 x VOLUME 124, NUMBER 2
MANAGEMENT OF ANTICOAGULATION AFTER VTE
Paoletti, Centro Emostasi e Trombosi, AO Istituti Ospitalieri, Cremona
(87); Alberto Tosetto, Divisione Ematologia, Ospedale S. Bortolo
ULSS 6–Vicenza (54); Anna Falanga, Teresa Lerede SIMT Centro
Emostasi e Trombosi Ospedali Riuniti di Bergamo (48); Steidl Luigi,
Marco Donadini, Elena Rancan, Medicina Interna 1°–Ambulatorio
Emostasi e Trombosi, Ospedale Di Circolo-Università dell’Insubria,
Varese (42); Roberto Quintavalla, Piera Maria Ferrini, Medicina
Interna a d indirizzo Angiologico e Coagulativo, Ospedale Maggiore
Azienda Ospedaliero–Universitaria di Parma (36); Rita C. Santoro,
Centro Emofilia Emostasi e Trombosi, Az. Osp. “Pugliese-Ciaccio”,
Catanzaro (34); Francesco Orlandini, Raffaella Benedetti, Medicina
Interna, Osp. Civile S.Andrea–ASL 5 presidio Levante Ligure, La
Spezia (32); Marco Cattaneo, Federico Lussana, Elena Bertinato,
Medicina III, A.O. San Paolo–Università di Milano, Milano (28);
Roberto Cappelli, Medicina Interna 2, Azienda Ospedaliero–
Universitaria Senese, Siena (21); Attilia Maria Pizzini, Medicina 1°
Centro Emostasi e Trombosi, Ospedale Santa Maria Nuova, Reggio
Emilia (20); Lucia Angeloni, Geriatria, Ospedale Maggiore Bologna
203
(10); Armando D’Angelo, Luciano Crippa, Ambulatorio Emostasi e
Trombosi, Ospedale S. Raffaele, Milano (10); Roberta Bortolotti,
Medicina, Ospedale di San Giovanni Persiceto, Bologna (8); Maria
Rita Vandelli, Med. Cardiovascolare–Mod. Organizzativo Angiologia,
Centro Trombosi, Nuovo Ospedale Civile S. Agostino Estense,
Baggiovara Modena (4). Executive Committee: Gualtiero Palareti
(Bologna), Vittorio Pengo (Padova), Paolo Prandoni (Padova);
Steering Committee: Walter Ageno (Varese), Angelo Ghirarduzzi
(Reggio Emilia), Domenico Prisco (Firenze), Sophie Testa (Cremona),
Alberto Tosetto (Vicenza), Armando Tripodi (Milano); Adjudication
Committee: Davide Imberti (Piacenza), Marco Moia (Milano),
Raffaele Pesavento (Padova); External Safety Committee: Nicola
Magrini (Bologna), Francesco Marongiu (Cagliari), Pietro Zonzin
(Rovigo); Scientific Secretariat: Benilde Cosmi (Bologna); referent
for laboratory issues: Cristina Legnani (Bologna); data manager
(collection and processing): Noemi Piaggesi (Bologna); data analysis:
Benilde Cosmi (Bologna), Daniela Poli (Firenze), Mauro Silingardi
(Reggio Emilia).
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From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
2014 124: 196-203
doi:10.1182/blood-2014-01-548065 originally published
online May 30, 2014
D-dimer to guide the duration of anticoagulation in patients with venous
thromboembolism: a management study
Gualtiero Palareti, Benilde Cosmi, Cristina Legnani, Emilia Antonucci, Valeria De Micheli, Angelo
Ghirarduzzi, Daniela Poli, Sophie Testa, Alberto Tosetto, Vittorio Pengo and Paolo Prandoni
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