Keywords deep-vein thrombosis - rivaroxaban - routine clinical practice - venous thromboembolism
Introduction
Isolated distal deep-vein thrombosis (IDDVT) accounts for around 30 to 55% of all
deep-vein thrombosis (DVT) diagnosed in the lower limbs.[1 ] Compared with proximal DVT (PDVT), IDDVT is often considered a relatively benign
disease[2 ]
[3 ]; however, as many as one-quarter of thrombi in IDDVT extend into the proximal veins
and up to one-third are associated with asymptomatic pulmonary embolism (PE) at onset.[4 ] Moreover, the risk of recurrent venous thromboembolism (VTE) in patients with IDDVT
is reported to be between 2 and 4% after approximately 1 year,[2 ]
[5 ]
[6 ] and as high as 9 to 25% after approximately 2 to 3 years.[4 ]
[7 ]
[8 ]
[9 ] Between one-sixth and one-half of recurrent venous thromboembolic events in patients
with IDDVT present as PE[2 ]
[4 ]
[5 ]
[6 ]
[7 ]
[9 ]
[10 ]
[11 ]; however, a meta-analysis suggested that the risk of recurrent VTE presenting as
PE is lower in patients with IDDVT than those with PDVT.[12 ] To date there have been few randomized trials on anticoagulation therapy for IDDVT,
and those that have been conducted have yielded conflicting results.[13 ]
[14 ]
[15 ]
For patients who present with IDDVT, current guidelines do not routinely recommend
anticoagulation.[16 ] In patients with severe symptoms or risk factors for extension (e.g., positive D-dimer,
extensive thrombus or close to proximal veins, unprovoked IDDVT, active cancer, or
inpatient status), initial treatment with an anticoagulant is suggested. However,
in patients without severe symptoms or risk factors for extension, initial serial
imaging of the deep veins is suggested to monitor thrombus resolution or extension.
If the thrombus extends, anticoagulation is then suggested or recommended (depending
on whether the thrombus remains confined to the distal veins or extends to the proximal
veins).[16 ] For patients with IDDVT who receive an anticoagulant, treatment recommendations
in guidelines are the same as for patients with PDVT, i.e., at least 3 months of treatment,
with the non-vitamin K antagonist (non-VKA) oral anticoagulants recommended over VKAs.[16 ] Despite these recommendations, in practice many patients with IDDVT are treated
for only 4 to 6 weeks.[4 ]
[8 ]
[9 ]
The EINSTEIN DVT study demonstrated that rivaroxaban was a safe and effective treatment
for DVT; however, only patients with PDVT were enrolled.[17 ] Therefore, data are lacking on outcomes in patients with IDDVT treated with rivaroxaban.
Patients with IDDVT and PDVT were included in the noninterventional XALIA phase IV
study, which demonstrated the safety and effectiveness of the single-drug approach
with rivaroxaban for the treatment of DVT in routine clinical practice.[18 ] The aims of this analysis were to compare baseline characteristics, management strategies,
and clinical outcomes in patients with IDDVT versus those with PDVT with or without
concomitant distal DVT enrolled in the XALIA study.
Materials and Methods
Study Design, Participants, and Procedures
XALIA was a multicenter, international, prospective, noninterventional study of patients
with objectively confirmed DVT. Patients could be included if they were aged ≥18 years
with objectively confirmed DVT (which included both PDVT and IDDVT, as well as DVT
in other venous beds) and an indication to receive anticoagulation treatment for ≥3
months. After the approval of rivaroxaban for the treatment of PE, the protocol was
amended to allow the enrolment of patients with DVT and concomitant PE (but not isolated
PE). Patients in the safety analysis received rivaroxaban or standard anticoagulation
treatment (initial treatment with unfractionated heparin, low-molecular-weight heparin,
or fondaparinux, usually overlapping with and followed by a VKA)—because of the noninterventional
nature of the study, treatment, dose, and duration were at the attending physician's
discretion. The rivaroxaban cohort included patients who received rivaroxaban alone
and those who had received heparin/fondaparinux for a maximum of 48 hours before initiating
rivaroxaban treatment, consistent with the approach in the EINSTEIN DVT study.[17 ] Patients who initially received heparin/fondaparinux for >2 to 14 days or a VKA
for 1 to 14 days before switching to rivaroxaban were designated as “early switchers.”
These patients were not included in the safety analysis. The study observation period
ended 12 months after the date of final patient enrolment; therefore, each patient
was followed up for at least 12 months.
Patients with IDDVT or patients with PDVT with or without distal vein (or other locations)
involvement and who received treatment with rivaroxaban or standard anticoagulation
therapy were included in this analysis. Patients were excluded from this subgroup
study if they had concomitant PE (because this was considered a more severe disease
and likely to influence the physician's behavior and the rate of VTE recurrence),
or if they were “early switchers” (because, similarly, these patients were likely
to have comorbidities or risk factors which could also influence the physician's behavior
and treatment outcomes).
Further details on the XALIA trial design have been described in the XALIA primary
paper.[18 ]
Outcomes
The primary outcomes in XALIA were major bleeding, recurrent VTE, and all-cause mortality.
An adverse event was classified as treatment emergent if it started on or after the
day of the first dose of rivaroxaban or standard anticoagulation and within 2 days
after the last dose. Major bleeding was defined as any of the following: overt bleeding
associated with a fall in hemoglobin of ≥2 g/dL; a transfusion of two or more units
of packed red blood cells or whole blood; a critical-site bleeding (intracranial,
intraspinal, intraocular, pericardial, intraarticular, intramuscular with compartment
syndrome, and retroperitoneal); or fatal bleeding. Recurrent VTE was defined as the
new onset of symptoms confirmed by diagnostic testing. Secondary outcomes included
health care resource use (admissions to hospital and length of stay).
Statistical Analysis
A descriptive analysis was conducted comparing the crude incidences for the primary
outcomes in patients with IDDVT and PDVT. A multivariable Cox regression analysis
was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI)
associated with potential predictors of recurrent VTE during treatment and after treatment
cessation, after maintaining variables that resulted in at least marginal significance
(p < 0.10) in the univariate analysis. Potential confounders in the initial univariate
analysis included active cancer at baseline (yes/no); age (<60 years/≥60 years); first
available creatinine clearance (CrCl; <50 mL/min, ≥50 to <80 mL/min, ≥80 mL/min, unknown);
sex (male/female); fragile (yes/no [patients were defined as fragile if they were
>75 years old or had a CrCl <50 mL/min or body weight ≤50 kg]); and provoked VTE (yes/no).
VTE was classified as provoked if it was caused by the following transient risk factors:
surgery, recent trauma/fracture, postpartum or hospitalization (all <3 months before
the index VTE), pregnancy, oral contraceptives, hormone replacement therapy, central
venous catheter, postthrombotic syndrome, or immobilization. Cancer was not considered
in the definitions of provoked or unprovoked VTE. Treatment assignment (rivaroxaban
versus standard anticoagulation) and lower extremity DVT location (IDDVT vs. PDVT)
were forced covariates in the multivariate analysis irrespective of marginal significance.
A stepwise model was used for each multivariate analysis, with p = 0.10 used for keeping variables in the model or adding variables to the model,
respectively. Finally, the Cox model for treatment-emergent VTE was adjusted for treatment
group and cancer, whereas the Cox model for VTE after treatment cessation was adjusted
for CrCl, cancer, and treatment group. Lengths of treatment duration and lengths of
hospital stay were described by the median (interquartile range).
Results
Baseline Demographics and Clinical Characteristics
Between June 26, 2012 and March 31, 2014, 5,142 patients were enrolled in the XALIA
study; 6 patients did not take rivaroxaban or standard anticoagulation and were excluded
from all subsequent analyses. In the overall XALIA population, 1,065 (20.7%) patients
had IDDVT, 3,317 (64.6%) patients had PDVT, 552 (10.7%) patients had DVT with concomitant
PE, and 202 (3.9%) patients had VTE in other locations (without PDVT). Sixty-one patients
with IDDVT and 219 patients with PDVT were defined as “early switchers,” and were
excluded, leaving a total of 4,102 patients in this analysis—1,004 patients with IDDVT
and 3,098 with PDVT. Patient flow through the study is shown in [Fig. 1 ]. Baseline characteristics of patients with IDDVT and PDVT are shown in [Table 1 ]. Compared with patients with PDVT, patients with IDDVT were younger, more were female,
more had VTE provoked by transient risk factors, and fewer were fragile. Data for
patients included in the safety analysis who had IDDVT, subdivided by duration of
treatment categorized into ≤90, >90 to 180, and >180 days, are shown in [Table 2 ].
Table 1
Baseline demographics and clinical characteristics of patients with IDDVT and PDVT
in the safety analysis set
Characteristic
IDDVT (N = 1,004)
PDVT (N = 3,098)
Age, years, mean ± SD
56.5 ± 17.1
61.0 ± 16.8
Age category, n (%)
<60 y
566 (56.4)
1,315 (42.4)
≥60 y
438 (43.6)
1,783 (57.6)
Male sex, n (%)
453 (45.1)
1,704 (55.0)
Weight, kg, mean ± SD
79.6 ± 16.9
82.2 ± 18.3
<50 kg, n (%)
13 (1.3)
34 (1.1)
≥50 to 70 kg, n (%)
245 (24.4)
643 (20.8)
>70 to <90 kg, n (%)
339 (33.8)
1,029 (33.2)
≥90 kg, n (%)
200 (19.9)
779 (25.1)
Missing, n (%)
207 (20.6)
613 (19.8)
BMI, kg/m2 , mean ± SD
27.6 ± 5.0
28.4 ± 6.3
First available creatinine clearance, n (%)
<30 mL/min
8 (0.8)
57 (1.8)
30 to <50 mL/min
27 (2.7)
173 (5.6)
50 to <80 mL/min
138 (13.7)
557 (18.0)
≥80 mL/min
366 (36.5)
1,253 (40.4)
Missing
465 (46.3)
1,058 (34.2)
Previous VTE, n (%)
241 (24.0)
749 (24.2)
Active cancer at baseline, n (%)
78 (7.8)
352 (11.4)
Known thrombophilia, n (%)
54 (5.4)
177 (5.7)
Previous major bleeding event, n (%)
17 (1.7)
70 (2.3)
Hospitalized in previous 3 months, n (%)
159 (15.8)
441 (14.2)
Fragile,[a ] n (%)
167 (16.6)
753 (24.3)
Provoked VTE, n (%)
416 (41.4)
1,053 (34.0)
Abbreviations: BMI, body mass index; IDDVT, isolated distal deep-vein thrombosis;
PDVT, proximal deep-vein thrombosis; SD, standard deviation; VTE, venous thromboembolism.
a Fragile: age >75 years or body weight ≤50 kg or creatinine clearance <50 mL/min.
Table 2
Baseline demographics and clinical characteristics of patients with IDDVT in the safety
analysis set by treatment duration
Characteristic, n (%)
≤90 days
(n = 272)
>90 to 180 days (n = 452)
>180 days
(n = 280)
Age, years
<60
154 (56.6)
250 (55.3)
162 (57.9)
≥60
118 (43.4)
202 (44.7)
118 (42.1)
Male sex
122 (44.9)
195 (43.1)
136 (48.6)
Region
Eastern Europe
18 (6.6)
52 (11.5)
50 (17.9)
Western Europe, Canada, and Israel
254 (93.4)
400 (88.5)
230 (81.1)
First available CrCl, mL/min
<50
11 (4.0)
16 (3.5)
8 (2.9)
≥50 to <80
36 (13.2)
60 (13.3)
42 (15.0)
≥80
99 (36.4)
165 (36.5)
102 (36.4)
Missing
126 (46.3)
211 (46.7)
128 (45.7)
Active cancer at baseline
30 (11.0)
26 (5.8)
22 (7.9)
BMI, kg/m2
≤25
54 (19.9)
102 (22.6)
52 (18.6)
>25 to ≤35
108 (39.7)
159 (35.2)
102 (36.4)
>35
11 (4.0)
19 (4.2)
23 (8.2)
Missing
99 (36.4)
172 (38.1)
103 (36.8)
Provoked DVT
119 (43.8)
216 (47.8)
81 (28.9)
Fragile[a ]
55 (20.2)
70 (15.5)
42 (15.0)
Abbreviations: BMI, body mass index; CrCl, creatinine clearance; DVT, deep-vein thrombosis;
IDDVT, isolated distal deep-vein thrombosis.
a Fragile: age >75 years, body weight ≤50 kg, or CrCl <50 mL/min.
Fig. 1 Patient flow through the study. Abbreviations: IDDVT, isolated distal deep-vein thrombosis;
PDVT, proximal deep-vein thrombosis; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Treatment Patterns
Details of the treatment patterns are shown in [Table 3 ]. Compared with patients with PDVT, patients with IDDVT were more likely to receive
rivaroxaban (641 [63.8%] vs. 1,683 [54.3%] patients, respectively) and were treated
for a shorter duration (102 vs. 192 days, respectively). In patients receiving rivaroxaban,
a smaller proportion of patients with IDDVT received initial parenteral treatment
compared with patients with PDVT (119/641 [18.6%] vs. 493/1,683 [29.3%] patients,
respectively). Rivaroxaban was dosed in accordance with the label in most patients
with IDDVT and those with PDVT. In patients with IDDVT, 603/641 (94.1%) received an
initial rivaroxaban dose of 15 mg twice daily, and 474/641 (73.9%) underwent a planned
switch at 21 days to rivaroxaban 20 mg once daily. In patients with PDVT, 1,583/1,683
(94.1%) received an initial rivaroxaban dose of 15 mg twice daily and 1,239/1,683
(73.6%) underwent a planned switch to rivaroxaban 20 mg once daily.
Table 3
Treatment details in patients with IDDVT and PDVT in the safety analysis set
IDDVT
(N = 1,004)
PDVT
(N = 3,098)
Anticoagulant, n (%)
Standard anticoagulation
363 (36.2)
1,415 (45.7)
Heparin/fondaparinux only
107 (10.7)
302 (9.7)
Heparin/fondaparinux and VKA
256 (25.5)
1,113 (35.9)
Rivaroxaban
641 (63.8)
1,683 (54.3)
Initial parenteral treatment for ≤48 h
119 (11.9)
493 (15.9)
Rivaroxaban only
522 (52.0)
1,190 (38.4)
Overall
Standard anticoagulation
Rivaroxaban
Overall
Standard anticoagulation
Rivaroxaban
Treatment duration, median (IQR)
102 (89–188)
107 (88–202)
99 (89–182)
192 (106–366)
207 (109–376)
187 (105–359)
Treatment duration, n (%)
≤90 d
272 (27.1)
100 (27.5)
172 (26.8)
453 (14.6)
223 (15.8)
230 (13.7)
>90 to ≤180 d
452 (45.0)
148 (40.8)
304 (47.4)
779 (25.1)
303 (21.4)
476 (28.3)
>180 d
280 (27.9)
115 (31.7)
165 (25.7)
1,866 (60.2)
889 (62.8)
997 (58.1)
Patients hospitalized for index VTE, n (%)
150 (14.9)
92 (25.3)
58 (9.0)
1,107 (35.7)
631 (44.6)
476 (28.3)
Duration of hospital stay, median (IQR)
7 (3–11)
8 (6–13)
4 (2–6)
6 (4–9)
7 (5–10)
5 (3–7)
Abbreviations: IDDVT, isolated distal deep-vein thrombosis; IQR, interquartile range;
PDVT, proximal deep-vein thrombosis; VKA, vitamin K antagonist; VTE, venous thromboembolism.
Treatment-Emergent and Posttreatment Cessation Outcomes
Treatment-Emergent Outcomes in Patients with IDDVT versus PDVT
In total, 10 (1.0%) patients with IDDVT and 73 (2.4%) patients with PDVT had a treatment-emergent
recurrent venous thromboembolic event. In a multivariate analysis, the risk of recurrent
VTE was nonsignificantly lower in patients with IDDVT versus PDVT (adjusted HR: 0.56;
95% CI: 0.29–1.08; p = 0.08) ([Table 4 ]). Nine (0.9%) patients with IDDVT and 43 (1.4%) patients with PDVT had a treatment-emergent
major bleeding event. All-cause mortality occurred in 8 (0.8%) patients with IDDVT
and 67 (2.2%) patients with PDVT.
Table 4
Adjusted hazard ratios for on-treatment and off-treatment recurrent VTE in patients
with IDDVT or PDVT treated with rivaroxaban or standard anticoagulation in safety
analysis set
HR (95% CI)
p -Value
Treatment-emergent recurrent VTE[a ]
Rivaroxaban vs. standard anticoagulation
0.64 (0.41–1.01)
0.054
IDDVT vs. PDVT
0.56 (0.29–1.08)
0.084
Posttreatment cessation recurrent VTE[b ]
Rivaroxaban vs. standard anticoagulation
1.17 (0.68–2.04)
0.57
IDDVT vs. PDVT
0.65 (0.32–1.35)
0.25
Abbreviations: CI, confidence interval; DVT, deep-vein thrombosis; HR, hazard ratio;
IDDVT, isolated distal vein deep-vein thrombosis; PDVT, proximal deep-vein thrombosis;
VTE, venous thromboembolism.
a Model was adjusted for active cancer at baseline (yes/no).
b Model was adjusted for active cancer at baseline (yes/no) and first available CrCl
(<50 mL/min, ≥50 to <80 mL/min, ≥80 mL/min, unknown).
Outcomes after Treatment Cessation in Patients with IDDVT versus PDVT
Overall, 824 patients with IDDVT (82%) and 2,107 patients with PDVT (68%) continued
follow-up after cessation of treatment; the mean follow-up time after treatment cessation
was 81 and 104 days, respectively. After treatment cessation, symptomatic recurrent
VTE was experienced by 9 (1.1%) patients with IDDVT and 45 (2.1%) patients with PDVT.
In a multivariate analysis, the risk of recurrent VTE after treatment cessation was
nonsignificantly lower in patients with IDDVT than in those with PDVT (adjusted HR:
0.65; 95% CI: 0.32–1.35; p = 0.25) ([Table 4 ]). Major bleeding occurred in 3 (0.4%) patients with IDDVT and 7 (0.3%) patients
with PDVT. In total, 6 (0.7%) patients with IDDVT and 39 (1.9%) patients with PDVT
died in the period between treatment cessation and the end of follow-up.
Additional HRs (stratified by cancer and noncancer only) were calculated, as well
as the p -values, for interaction between “IDDVT versus PDVT” and “active cancer at baseline
(yes/no)” Cox regression analyses for treatment-emergent outcomes and outcomes after
treatment cessation. The only significant association was found for the comparison
between rivaroxaban and standard anticoagulation in noncancer patients (HR: 0.61;
95% CI: 0.37–0.99; p = 0.046). Therefore, there was no statistical sign of an effect of cancer on outcome
events in patients with IDDVT (most likely because of the low number of events). Nevertheless,
cancer was added as a covariate in the adjusted analysis.
Treatment-Emergent Outcomes in Patients with IDDVT or PDVT Treated with Rivaroxaban
and Standard Anticoagulation
Outcomes from the anticoagulation treatment groups in patients with IDDVT and those
with PDVT are reported in [Table 5 ] and illustrated in [Fig. 2 ]. The incidences of recurrent VTE with rivaroxaban and standard anticoagulation were
0.8 and 1.4% in patients with IDDVT and 1.7 and 3.1% in those with PDVT, respectively.
Major bleeding incidences with rivaroxaban and standard anticoagulation were 0.6 and
1.4% in patients with IDDVT and 0.7 and 2.2% in those with PDVT, respectively, whereas
incidences for all-cause mortality were 0.2 and 1.9%, and 0.6 and 4.0%, respectively.
Fig. 2 Unadjusted treatment-emergent outcomes in patients with (A ) IDDVT or (B ) PDVT in the safety analysis set treated with rivaroxaban or standard anticoagulation.
Abbreviations: IDDVT, isolated distal deep-vein thrombosis; PDVT, proximal deep-vein
thrombosis; VTE, venous thromboembolism.
Table 5
Treatment-emergent primary outcomes in patients with IDDVT or PDVT in the safety analysis
set treated with standard anticoagulation or rivaroxaban
IDDVT
PDVT
Rivaroxaban
(n = 641)
Standard anticoagulation
(n = 363)
Risk difference
(95% CI)
Rivaroxaban
(n = 1,683)
Standard anticoagulation
(n = 1,415)
Risk difference
(95% CI)
n
%/% per 100 patient-years
n
%/% per 100 patient-years
n
%/% per 100 patient-years
n
%/% per 100 patient-years
Recurrent VTE
5
0.8/1.9
5
1.4/3.1
−0.68
(−2.67, 0.76)
29
1.7/2.7
44
3.1/4.5
−1.03
(−2.20, 0.04)
Major bleeding
4
0.6/1.5
5
1.4/3.1
−0.27
(−1.98, 0.84)
12
0.7/1.1
31
2.2/3.1
−1.32
(−2.28, −0.49)
All-cause mortality
1
0.2/0.4
7
1.9/4.3
−1.01
(−2.88, 0.12)
10
0.6/0.9
57
4.0/5.6
−1.93
(−3.01, −0.98)
Abbreviations: CI, confidence interval; IDDVT, isolated distal deep-vein thrombosis;
PDVT, proximal deep-vein thrombosis; VTE, venous thromboembolism.
Note: Risk differences and 95% CIs were calculated stratified by active cancer at
baseline using the Newcombe method.
Outcomes after Treatment Cessation in Patients with IDDVT or PDVT Treated with Rivaroxaban
and Standard Anticoagulation
Outcomes from the anticoagulation treatment groups in patients with IDDVT and those
with PDVT after stopping treatment are reported in [Table 6 ]. The incidences of recurrent VTE with rivaroxaban and standard anticoagulation were
1.3 and 0.7% in patients with IDDVT and 2.0 and 2.3% in patients with PDVT, respectively.
Major bleeding incidences with rivaroxaban and standard anticoagulation were 0.2 and
0.7% in patients with IDDVT, respectively, and 0.3% in both groups in patients with
PDVT. All-cause mortality with rivaroxaban and standard anticoagulation was 0.6 and
1.0% in the IDDVT group, and 1.5 and 2.3% in the PDVT group, respectively.
Table 6
Primary outcomes after treatment cessation in patients with IDDVT or PDVT in patients
treated with standard anticoagulation or rivaroxaban who were followed up after treatment
cessation
IDDVT
PDVT
Rivaroxaban
(n = 526)
Standard anticoagulation
(n = 298)
Risk difference
(95% CI)
Rivaroxaban
(n = 1,241)
Standard anticoagulation
(n = 866)
Risk difference
(95% CI)
n
%/% per 100 patient-years
n
%/% per 100 patient-years
n
%/% per 100 patient-years
n
%/% per 100 patient-years
Recurrent VTE
7
1.3/6.5
2
0.7/2.7
0.63
(−1.44, 2.22)
25
2.0/7.6
20
2.3/7.5
−0.15
(−1.53, 1.09)
Major bleeding
1
0.2/0.9
2
0.7/2.7
−0.52
(−2.49, 0.65)
4
0.3/1.2
3
0.3/1.1
−0.06
(−0.85, 0.55)
All-cause mortality
3
0.6/2.8
3
1.0/4.0
−0.08
(−2.04, 1.25)
19
1.5/5.6
20
2.3/7.2
0.03
(−1.12, 0.99)
Abbreviations: CI, confidence interval; IDDVT, isolated distal deep-vein thrombosis;
PDVT, proximal deep-vein thrombosis; VTE, venous thromboembolism.
Note: Risk differences and 95% CIs were calculated stratified by active cancer at
baseline using the Newcombe method.
Discussion
The results of this analysis of patients enrolled in the XALIA study confirm differences
in baseline characteristics between patients with IDDVT and those with PDVT. This
finding is consistent with data from the RIETE registry and the OPTIMEV and DOTAVK
studies, in which patients with IDDVT were younger and less likely to have unprovoked
VTE than patients with PDVT.[5 ]
[6 ]
[10 ] Reported also in previous studies, patients with IDDVT were treated with anticoagulants
for a shorter period of time than patients with PDVT.[2 ]
[5 ]
[6 ] These differences in treatment duration may reflect the perception of IDDVT as a
more benign disease than PDVT, but may also be driven by the differences in clinical
characteristics and underlying risk factors between patients with IDDVT and those
with PDVT.
The incidences of recurrent VTE during treatment and after treatment cessation were
numerically lower in patients with IDDVT than in those with PDVT, although this difference
was nonstatistically significant after adjustment for differences in baseline characteristics.
This finding is also consistent with results from an analysis of patients with IDDVT
or PDVT in the RIETE registry[10 ] and apparently supports the recommendations in the guidelines from the American
College of Chest Physicians (ACCP) that PDVT and IDDVT should be treated for the same
length of time.[16 ] Other studies have reported lower crude incidences of VTE recurrence in patients
with IDDVT compared with those with PDVT. In the prospective DOTAVK and OPTIMEV studies
and a retrospective single-center cohort study, the incidences of recurrent VTE in
patients with IDDVT were approximately half of those seen in patients with PDVT; however,
with the exception of the study by Barco et al, no adjustments were made for differences
in baseline characteristics.[2 ]
[5 ]
[6 ] There have been few randomized trials to date on anticoagulation therapy for IDDVT
and results have been conflicting. In a 1985 study comparing 3 months' warfarin treatment
versus no treatment for calf vein thrombosis, none of the patients who received warfarin
experienced a recurrent venous thromboembolic event, whereas the event rate in the
no-treatment group was 29%[13 ]; however, the study was small (51 patients in total) and included patients at high
risk of a recurrent event (based on symptomatic painful thrombosis at enrolment and
high pain scores, which were associated with recurrent events). A subsequent study
in 2010 compared the safety and efficacy of short-term (10 days) low-molecular-weight
heparin plus compression therapy versus compression therapy alone for isolated calf
muscle DVT; efficacy was not superior with anticoagulation, although there were no
major bleeding events in either group.[14 ] In a 2016 study of nadroparin versus placebo for 42 days for the treatment of calf
vein DVT in low-risk outpatients,[15 ] nadroparin was not superior to placebo for reducing the risk of proximal extension
or recurrent VTE and was associated with a higher rate of bleeding.
Based on the results of this and previous studies, the identification of patients
with IDDVT requiring the same treatment intensity and duration as for patients with
PDVT remains unclear. Although the differences in the incidence of recurrent events
in our study were not statistically significant, patients enrolled in XALIA were required
to have an indication to receive 3 months' anticoagulation to be eligible. This means
that IDDVT patients with more risk factors for VTE recurrence were more likely to
have been enrolled than those with fewer risk factors; therefore, it is uncertain
whether the outcomes observed in this analysis are representative of the wider IDDVT
patient population. In addition, outcomes with rivaroxaban and standard anticoagulation
in the on-treatment phase may have been influenced by a greater imbalance in baseline
risk factors and comorbidities in the rivaroxaban versus standard anticoagulation
group in patients with PDVT compared with those with IDDVT, or because a perception
of IDDVT as being more benign than PDVT impacted prescribing decisions (which is possibly
reflected in the lower rates of standard anticoagulation prescribing in the IDDVT
group). Finally, treatment duration in patients with PDVT was longer than in patients
with IDDVT, which may have impacted between-treatment differences in each group. Because
of these reasons, no conclusions can be drawn regarding the differences in incidence
rates between rivaroxaban and standard anticoagulation users.
Limitations
XALIA was a noninterventional study, and treatment decisions were at the physician's
discretion with potential for selection bias. In particular, as mentioned above, because
patients were only eligible for inclusion if the intended duration of treatment was
3 months or more,[19 ] lower-risk patients with IDDVT that some physicians would normally treat for a shorter
period would have been ineligible for inclusion. For example, this is the case with
a thrombus confined to the muscular veins (i.e., soleus/gastrocnemius veins), which
is considered to have a lower risk of extension than a thrombus confined to the axial
veins (i.e., true deep, peroneal, or tibial veins).[16 ] Unfortunately, information on the site of distal DVT was not collected. In addition,
XALIA was an open-label study, which raised the possibility of bias in the investigator
reporting of events. However, this was addressed by the use of objective diagnostic
methods and by the adjudication of all events by the Adjudication Committee, which
was blinded to treatment choice. Because of the low event numbers, full control of
confounding factors was not possible in the multivariate analysis and hence the results
may still have been influenced by differences in demographics. Unlike in the XALIA
primary analysis, a propensity score-adjusted analysis was not possible in this sub-study
because of the small group sizes. Furthermore, independent risk factors may have been
masked by the effect of treatment group comparison and thus would not have appeared
in the stepwise regression analysis. Finally, the comparison of events occurring after
cessation of treatment may have been influenced by the different proportions of patients
being followed up.
Conclusions
Patients with IDDVT had fewer comorbidities and were more frequently treated with
rivaroxaban than those with PDVT. This may reflect IDDVT being considered more benign
than PDVT. Consequently, the risks of VTE recurrence in patients with IDDVT treated
with either rivaroxaban or standard anticoagulation were lower than in patients with
PDVT, although this difference was not statistically significant after adjustments
for some major underlying factors. Uncertainty still exists as to whether patients
with IDDVT require anticoagulation and, if so, if they require the same treatment
intensity and duration as for patients with PDVT. Indeed, the study population of
XALIA did not include patients with IDDVT who received less than 3 months' anticoagulation
therapy and would likely have fewer risk factors and a lower risk for recurrence than
those eligible to enroll. Therefore, additional studies specifically designed to address
this issue are warranted.
