Chapter 6 Discussion
6.5 Initial Treatment Pattern of VTE
Among patients who were hospitalized with VTE diagnosis (definition 1), only
33.6% of patients received anticoagulants or surgical thromboectomy during the
hospitalization. Treatment for VTE was performed in 7.9% and 62.9% of patients with
intra-abdominal thrombosis and other sites of venous thrombosis/PE (excluding
superficial venous thrombosis), respectively.
In a retrospective study in patients with gastric cancer, anticoagulant therapy was
administered to 38% of patients.14 Anticoagulant therapy was performed in most of the
DVT/PE cases (86%), but only in 8% of the intra-abdominal thrombosis cases
(including portal vein, hepatic vein, renal vein, inferior vena cava, and internal iliac
vein).14 Similarly, in the study of Choi et al,15 which included 2,006 patients with
colorectal cancer, anticoagulant therapy was administered in 53% of patients with VTE.
Although anticoagulation was administered to most patients with DVT/PE (91%), only
15% of patients with intra-abdominal thrombosis received anticoagulant therapy.15
Consistent with previous studies,14,15 we observed that most patients with
thrombosis of renal, portal or hepatic veins did not received anticoagulant treatment in
clinical practice. The recently published 9th ACCP guidelines in 2012 suggested
therapeutic anticoagulation to patients with symptomatic splanchnic vein thrombosis but
not patients with incidentally detected splanchnic vein thrombosis.75 However, due to
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limited understanding of the natural histories of both symptomatic and incidentally
detected splanchnic vein thrombosis in patients who are not treated with anticoagulants
(ie., frequency of bowel infarction, development of portal hypertension, recurrence), a
paucity of data from prospective cohort studies, and a lack of randomized trials of
standardized anticoagulant therapy for splanchnic vein thrombosis, the role of
anticoagulation for this condition is uncertain.75 Given the common prevalence of
intra-abdominal thrombosis, further studies are needed to clarify the role and duration of
anticoagulant therapy in these patients.
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6.6 Long-term Treatment of VTE
Our study found that the adherence to treatment guidelines was poor in Taiwan.
Long-term anticoagulant therapy was only initiated in 64.1% of patients (definition 2).
In treatment guidelines, 3-6 months of LMWH was recommended over warfarin for
long-term treatment of VTE in cancer patients.1,69,70,75 However, in our study, among
patients who received long-term treatment of VTE, LMWH was administered to 15.0%
of patients only at any time. Most patients received warfarin monotherapy for the
long-term treatment of VTE (72.2%) (Table 5.11).
In contrast, in the study of Trujillo-Santos et al. (2008)109, long-term LMWH
monotherapy was administered to 53.3% of cancer patients. Among cancer patients with
VTE, 46.8% of them received warfarin for long-term treatment.109 In the study of Lee et
al.14 and Choi et al.15, long-term LMWH monotherapy and warfarin was performed in
71.1% versus 28.9% of patients, and 66.7% versus 33.3% of patients, respectively. The
clinical studies of long-term treatment of VTE among cancer patients were summarized
in Table 6.2. In Taiwan, most patients use warfarin instead of LMWH monotherapy for
long-term treatment of VTE. This is probably because reimbursement for outpatient use
of LMWH by NHI was limited to pregnant patients with prosthetic valve
replacement.101
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Furthermore, in our study, treatment duration of long-term anticoagulant therapy
was shorter than those recommended in clinical guidelines.1,69,70,75 Instead of
recommendation of long-term treatment for 3-6 months, more than half of the patients
(58.7%) in our study received long-term anticoagulant therapy for less than three
months (Table 5.12). The median duration of long-term anticoagulant therapy was 66
days, which is also shorter than the median duration recorded in the study of Lee et al.14
and Choi et al.15 (85 days and 90 days, respectively).
Table 6.2 Clinical studies of long-term treatment of VTE among cancer patients
Study LMWH (%) VKA (%) Median duration (days)
Our study 15.0a 72.2 66
Lee et al. (2010)14 71.1 28.9 85
Choi et al. (2011)15 66.7 33.3 90
Trujillo-Santos et al.
(2008)109
53.3 46.8 NAb
a Use of LMWH at any time
a Not available
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6.7 Recurrence of VTE and Bleeding Complications
Use of administrative database to evaluate the recurrence of VTE has been scarce.
Due to the limitations of NHI database, we could not assess radiographs of patients to
verify the recurrence of VTE. Therefore, we defined recurrent VTE as a second
hospitalization with a diagnosis of VTE and treatment with IV/SC anticoagulant therapy
or thromboectomy during the hospital stay after the first hospital admission for VTE, as
proposed by Lee et al.10 In that study, Lee et al.10 used Taiwan’s NHI database to
explore the incidence and cumulative recurrence rates of VTE among general
population.
In our study, 19.5% of patients had recurrent VTE after the first hospitalization for
VTE event. In a prospective study which included 842 patients, Prandoni et al.66
reported that cancer patients were 4 times more likely to develop recurrent VTE
compared to general population. However, the proportion of patients with recurrent
VTE in our patients was only slightly higher than the recurrence rates reported by Lee et
al10 among general population (19.5% versus 14.4%).
Four clinical trials enrolling cancer patients with VTE found that, compared to
treatment with VKA, three to six months of LMWH was associated with fewer VTE
recurrence or fewer bleeding events.76-79 Cochrane meta-analysis also showed that,
long-term treatment with LMWH, compared with VKA, provided significantly
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reduction in recurrence of VTE.110 In our study, there is no significant difference in the
rate of recurrent VTE and bleeding event between the warfarin and LMWH/UFH group.
However, long-term treatment with warfarin may cause more fatal bleeding events than
LMWH/UFH. In our study, 2/5 of intracranial bleeding events occurred in patients
receiving warfarin alone for long-term treatment of VTE. In contrast, no intracranial
bleeding event occurred in LMWH/UFH group.
In our study, we only evaluate GI and intracranial bleeding complications. The
definition of GI bleeding in our study was same as Chang et al.,111,112 which used
Taiwan NHI databases to evaluate GI adverse events associated with nonsteroidal
anti-inflammatory drugs (NSAIDs). Common sites for anticoagulant-associated
bleeding including soft tissues, the GI and urinary tract, the nose and the oral
pharynx.113 Rate of fatal bleeding ranged from 0.1-1.0% patient-years.114 In the
Computerized Registry of Patients with Venous Thromboembolism (RIETE) registry,
among 3,805 cancer patients with VTE events, 4.1% of patients developed major
bleeding. The most common bleeding sites were GI tract (47%), genitourinary (19%),
and brain (8.3%).109 As GI bleeding is the most common bleeding complications of
anticoagulant therapy,109 the risk of GI bleeding has an important influence on clinical
practice in Asian countries,115 and intracranial bleeding resulting in hemorrhagic stroke
represents the most common cause of fatal bleeding associated with anticoagulants,113
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we only focused on GI and intracranial bleeding complications in our study. Besides,
validation studies using administrative healthcare databases in Canada and Italy
reported that use of ICD-9-CM codes to identify upper GI bleeding had a positive
predictive value of 90%.116,117
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