Published: 28 May 2018

APPROPRIATE CARE GUIDE www.ace-hta.gov.sg

Venous
thromboembolism
Treating with the
right anticoagulant
and duration

Key messages

1 Unless contraindicated, treat patients with warfarin or a non-vitamin K antagonist oral

anticoagulant if they have proximal deep vein thrombosis or pulmonary embolism.
2 Use warfarin if creatinine clearance (measured with the Cockcroft-Gault formula) is
less than 30 mL/min.
3 If patient has active cancer, use low molecular weight heparin.
4 Continue anticoagulation for at least three months. Consider extended treatment if
recurrence risk is high.
5 Review patients on extended treatment at least once a year.

Anticoagulation — why and when you should commence

Venous thromboembolism (VTE) is a serious
medical condition that covers deep vein thrombosis
(DVT) and pulmonary embolism (PE). It has long-
term complications that adversely affect quality of
life and often leads to substantial healthcare costs.
Unless contraindicated, patients with confirmed
proximal DVT or PE should start anticoagulation
as soon as possible. Absolute contraindications
include severe coagulation defects, severe
thrombocytopaenia, uncontrollable active
bleeding, and acute haemorrhagic stroke.
Isolated distal DVT is monitored using serial
imaging. Anticoagulation may be commenced if
extension is detected or there are severe symptoms
or risk of extension. Risk factors for extension
include positive D-dimer, multiple vein involvement,
thrombosis close to proximal veins, persistent
provoking factor, active cancer, VTE history, and
inpatient status. 2
About 3 in 10 patients with PE and 3% of those
with DVT will die within 30 days. 1

Academy of Medicine, Chapter of Haematologists College of Family Physicians,

Singapore College of Physicians, Singapore Singapore
Choosing an appropriate anticoagulant
Anticoagulants include heparin, warfarin, and NOACs. When selecting Facts on warfarin
an appropriate anticoagulant, consider patient factors, drug properties,
preference, and cost — refer to Figure 1 and Table 1 for selection Start warfarin with
criteria and treatment duration. parenteral anticoagulation
for five days, or until
international normalised
Heparin ratio (INR) is 2 or above—
whichever takes longer—
Heparin is administered parenterally and comprises two types — before stopping parenteral
unfractionated heparin (UFH) and low molecular weight heparin (LMWH). anticoagulation.
UFH is usually reserved for patients undergoing invasive procedures,
thrombolysis or those with high bleeding risks as it requires close
laboratory monitoring to achieve therapeutic anticoagulation. 3 LMWH
such as enoxaparin or tinzaparin has better efficacy for cancer patients
compared to warfarin. 4 Facts on NOACs

• NOACs are also known as

Warfarin direct oral anticoagulants
(DOACs). 5
VTE is traditionally treated with warfarin. Its advantage is that
an overdose is easily reversed with vitamin K. However, it has • D o not use parenteral
numerous dietary and drug interactions, requiring INR monitoring anticoagulation and
and dose titrations. dabigatran concurrently.

• S tart rivaroxaban and

NOACs apixaban without initial
parenteral anticoagulation.
NOACs (dabigatran, rivaroxaban, and apixaban) are as effective as
warfarin in preventing VTE recurrence and may cause less major
bleeding, particularly intracranial haemorrhage. They also have fewer
drug and dietary interactions and can be given in fixed doses.

However, NOACs should be avoided in patients with severe renal

or hepatic impairment, during pregnancy or while breastfeeding. As
there are no head-to-head trials comparing NOACs, there is insufficient
evidence to recommend one NOAC over another in terms of efficacy
and safety.

Dabigatran needs at least five days of parenteral anticoagulation before

starting; do not use both concurrently. Rivaroxaban and apixaban do
not need initial parenteral anticoagulation.
Figure 1. Determining an appropriate anticoagulant and duration

Patients with proximal DVT, isolated distal DVT requiring anticoagulation, or PE

Assess patient factors Select an appropriate anticoagulant Determine the duration of anticoagulation

Use warfarin or a NOAC if not contraindicated.

Provoked VTE by a
Factors favouring warfarin Factors favouring NOACs transient risk factor
Stop treatment after 3 months.2
or
• M
 ay be used in renal • F
 ixed dosing, does not
impairment need titration First unprovoked
General population
isolated distal DVT
• Reliable measurement assay • F
 ewer food and drug
• E
 ffects of drug interactions interactions than warfarin
can be monitored • N
 o initial parenteral agent,
• C
 onsider extended treatment
except for dabigatran
if bleeding risk is acceptable
and patient is agreeable.2
• F
 ollow up patients who are
warfarin overlapping with UFH First unprovoked on extended treatment at
Consider proximal DVT or PE least once a year.
warfarin overlapping with dose-reduced enoxaparin
• In patients who are stopping
(consider anti-Xa monitoring if use of enoxaparin is >5 days)
anticoagulation, consider
Severe renal low dose aspirin if not
impairment* Monotherapy with LMWH or UFH is not recommended. contraindicated.2
(CrCl <30 mL/min) – LMWH is renally excreted and accumulates in renal failure.6
Patients with CrCl <30 mL/min treated with therapeutic enoxaparin
had elevated levels of anti-Xa and an increased risk of a major
bleeding.7 Data for other LMWHs is currently lacking.
– UFH has minimal renal excretion and a short half-life but is
impractical for prolonged use.

Liver disease and Consider LMWH monotherapy.2

coagulopathy* Warfarin is not suitable as INR may not reflect antithrombotic effect.2
• Treat for at least 6 months in total.4
• After 6 months, continue anticoagulation if there is:
– ongoing active cancer, and;
Active cancer* Use LMWH monotherapy.2,8 LMWH is superior to warfarin for preventing
recurrent VTE during the acute treatment phase.9,10 – acceptable bleeding risk.
• W
 ith progressive disease, consider the patient’s wishes and
quality of life. Offer warfarin or a NOAC as an acceptable
alternative to LMWH if a patient requires anticoagulation but
Recurrent/ wishes to stop daily injections after 6 months.4
complicated VTE or Refer to a specialist.
pregnancy

*E xcluded in pivotal clinical trials investigating the effects of NOACs for treating VTE
Table 1. Characteristics of anticoagulants (adapted from local product information leaflets)

Dosing Dosing according to renal function, CrCl

Routine
Mechanism Reversal Extended
Pharmacokinetics coagulation Cost* Active treatment phase >50 30-50 <30
of action agent(s) treatment phase
monitoring (3 months) mL/min mL/min mL/min
(>3 months)
Enoxaparin Accelerates Bioavailability: ~100% Protamine No $$$$ 1 mg/kg subcutaneously Use as Dose Dose 1 mg/kg once
antithrombin Tmax: 3–5 hours twice daily. Use as monotherapy in adjustment is adjustment is a day. Consider
action Half-life: 4–7 hours monotherapy in cancer cancer patients. not necessary. not necessary. monitoring of
Elimination: 40% renal patients. anti-factor Xa
(10% as active compound) activity.
Tinzaparin Accelerates Bioavailability: ~90% Protamine No $$$$ 175 IU/kg subcutaneously Use as Dose Dose Use with
antithrombin Tmax: 4–6 hours once daily. Use as monotherapy in adjustment is adjustment is caution. Consider
action Half-life: 1.3 hours monotherapy in cancer cancer patients. not necessary. not necessary. monitoring of
Elimination: primarily renal patients. anti-factor Xa
activity.
Warfarin Vitamin K Bioavailability: >95% Vitamin K, Yes $$† Day 1– 2: Use maintenance INR-adjusted INR-adjusted INR-adjusted
antagonist Tmax: 72–96 hours fresh frozen 5 mg orally once daily; dose.
Half-life: 40 hours plasma and Day 3 onwards:
Elimination: ~100% prothrombin Titrate according to INR. Give
metabolised, negligible in complex with LMWH for five days,
urine concentrates or until INR is 2 or above—
whichever takes longer—
before stopping LMWH.
Dabigatran Direct Bioavailability: 6.5% Idarucizumab No $$$ Day 1– 5: Use maintenance Dose Day 6 onwards: Not
thrombin Tmax: 0.5–2 hours Use LMWH, dose. adjustment is Consider dose recommended
inhibitor Half-life: 12–14 hours no dabigatran; not necessary. reduction to
Elimination: 85% renal Day 6 onwards: 110 mg twice a
150 mg orally twice a day. day for patients
with high
bleeding risks.
Rivaroxaban Direct factor Bioavailability: 80–100% Not available No $$ Day 1– 21: Use maintenance Dose Day 22 Not
Xa inhibitor Tmax: 2–4 hours 15 mg orally twice a day; dose. adjustment is onwards: recommended
Half-life: 5–13 hours Day 22 onwards: not necessary. Consider dose
Elimination: 67% renal 20 mg orally once a day. reduction to
(36% as active compound) 15 mg once a
day for patients
with high
bleeding risks.
Apixaban Direct factor Bioavailability: ~50% Not available No $$ Day 1–7: Month 3–6: Dose Dose Not
Xa inhibitor Tmax: 3–4 hours 10 mg orally twice a day; 5 mg orally twice adjustment is adjustment is recommended
Half-life: 12 hours Day 8 onwards: a day; not necessary. not necessary.
Elimination: 27% renal 5 mg orally twice a day. Month 7
onwards:
2.5 mg orally
twice a day.

*Based on treatment costs to patients at public healthcare institutions. At the time of publication, rivaroxaban is the only NOAC listed on the Medication Assistance Fund (MAF).
MAF assistance does not apply when rivaroxaban is used for isolated distal DVT.
†
Includes INR monitoring and initial 5 days of LMWH
 Extending duration of anticoagulation
To prevent clot and recurrent VTE, anticoagulation
should be given for at least three months. A
shorter duration of four to six weeks has been
shown to double the risk of recurrent VTE and
may be insufficient for active treatment. 11
Extending treatment beyond three months
involves balancing the risk of VTE recurrence
with the risk of bleeding.
The risk of VTE recurrence depends on the presence
and nature of provoking factors (see Figure 2). 12,13
Unprovoked VTE has a higher risk of recurrence
compared with provoked VTE and may require
extended treatment if bleeding risks are low or
moderate. 2 Extended treatment usually implies that
anticoagulation will continue indefinitely.

Figure 2. Risk of VTE recurrence

Higher

Cancer-associated VTE
• W
 ithout appropriate anticoagulation, about 1 in 5 patients with active cancer will experience
recurrence within a year. 13
• D uration: Treat for at least six months and reassess to see if treatment should continue, especially
Recurrence rate

if there is active malignancy. 4

Unprovoked VTE
• The estimated recurrence rate is 7.4% per patient-year after two years of stopping anticoagulation. 12
• Duration: Treat for at least three months. Consider extended treatment. 2

Provoked VTE by a transient risk factor*

• The estimated recurrence rate is 3.3% per patient-year after two years of stopping anticoagulation. 12
• Duration: Stop treatment after three months. 2
* Transient or reversible provoking factors are those that resolve after they have triggered the VTE,
Lower such as surgery, trauma, immobilisation, bed confinement, lengthy travel and oestrogen therapy.

Include patients in decision-making

Assess and discuss risks and benefits of extended
treatment with your patients. If extending treatment,
use the same anticoagulant unless there are
reasons for switching, for example, from NOACs
to warfarin when renal function deteriorates.
For those with first unprovoked proximal DVT
or PE wishing to stop anticoagulation after
three months, consider low-dose aspirin unless
contraindicated. 2
Aspirin is less effective than anticoagulants, but
more effective than no treatment in preventing
VTE recurrence. 2,8
In patients with cancer and progressive disease,
consider their wishes and quality of life before
extending treatment. While LMWH is preferred in
these patients, consider switching to an oral agent
in patients requiring treatment beyond six months
who wish to stop daily injections. 4

Review patients at least once a year

Patients on extended treatment should be reviewed at least once a year to assess any clinical changes
that could trigger changes in management or choice of agent.

Check for:
Signs and symptoms of bleeding and recurrent VTE
Treatment adherence
Changes in renal or hepatic function
New drug interactions
References
1. Sogaard KK, et al. 30-Year mortality after venous thromboembolism: a population- Expert group
based cohort study. Circulation. 2014.
2. Kearon C, et al. Antithrombotic therapy for VTE disease: CHEST Guideline and Lead discussant
Expert Panel Report. Chest. 2016. Dr Chee Yen Lin (NUHS-NCIS)
3. Streiff MB, et al. Guidance for the treatment of deep vein thrombosis and
pulmonary embolism. J Thromb Thrombolysis. 2016.
Chairperson
4. Watson HG, et al. Guideline on aspects of cancer-related venous thrombosis.
BR J Haematol. 2015. A/Prof Ng Heng Joo (SGH)
5. Barnes G, et al. Recommendation on the nomenclature for oral anticoagulants:
communication from the SSC of the ISTH. J Thromb Haemost. 2015. Group members
6. Kearon C, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy A/Prof Lee Lai Heng (SGH)
and Prevention of Thrombosis: American College of Chest Physicians Evidence-
A/Prof Tay Jam Chin (TTSH)
Based Clinical Practice Guidelines. Chest. 2012.
Dr Doreen Tan Su Yin (KTPH)
7. Lim W, et al. Meta-analysis: low-molecular-weight heparin and bleeding in
patients with severe renal insufficiency. Ann Intern Med. 2006. Dr Lim Ziliang (NHGP)
8. Konstantinides SV. 2014 ESC Guidelines on the diagnosis and management of Dr Sim Kok Ping
acute pulmonary embolism. Eur Heart J. 2014. (Frontier Healthcare)
9. Lee AY, et al. Low-molecular-weight Heparin versus a Coumarin for the Prevention
of Recurrent Venous Thromboembolism in Patients with Cancer. N Engl J Med.
2003.
10. Lee AY, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism
in Patients With Active Cancer: A Randomized Clinical Trial. JAMA. 2015.
11. Kearon C, et al. Duration of anticoagulant therapy for deep vein thrombosis and
pulmonary embolism. Blood. 2014.
12. Iorio A, et al. Risk of recurrence after a first episode of symptomatic venous
thromboembolism provoked by a transient risk factor: a systematic review. Arch
Intern Med. 2010.
13. Barnes GD, et al. Venous thromboembolism: Predicting recurrence and the need
for extended anticoagulation. Vasc Med. 2015.

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