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BARTHOLOMEW, MD
Section Head, Department of Vascular Medicine,
Heart and Vascular Institute, Cleveland Clinic
V
ABSTRACT enous thromboembolism (VTE) includes
Venous thromboembolism (VTE), which includes deep both deep vein thrombosis (DVT) and pul-
vein thrombosis (DVT) and pulmonary embolism, is a com- monary embolism (PE). Although the exact
mon cardiovascular disease associated with significant incidence of VTE is unknown, an estimated 1
morbidity ranging from painful leg swelling, chest pain, million people in the United States are affected each
shortness of breath, and even death. Long-term complica- year, with about a third experiencing a recurrence
tions include recurrent VTE, postpulmonary embolism within 10 years.1 VTE affects hospitalized and nonhos-
syndrome, chronic thromboembolic pulmonary hyperten- pitalized patients, is often overlooked, and results in
sion, and postthrombotic syndrome (PTS). Management of long-term complications including postthrombotic
VTE requires immediate anticoagulation therapy based on syndrome (PTS) for DVT, postpulmonary embolism
a risk assessment for bleeding. Direct oral anticoagulants syndrome and chronic thromboembolic pulmonary
(DOACs) have become an important option for patients hypertension for PE, and death.2
as reflected in the most recent American College of Chest
Physician treatment guidelines. TREATMENT
Treatment for VTE should be initiated in the follow-
KEY POINTS ing cases:
VTE treatment should begin immediately with heparin, Proximal DVT of the lower extremity
low-molecular-weight heparin (LMWH), fondaparinux, or Symptomatic distal (calf vein) DVT
the DOACs (rivaroxaban or apixaban) in patients deemed Symptomatic upper extremity DVT (axillary-
appropriate based on a risk assessment for bleeding. subclavian veins)
PE
For patients with VTE and no cancer, long-term treatment Subsegmental PE in a patient at risk for
with dabigatran, rivaroxaban, apixaban, or edoxaban is recurrence
recommended over the vitamin K antagonists (VKA). Surveillance for subsegmental PE in a patient with
no proximal DVT and a low risk of recurrence.
LMWH is recommended for the long-term treatment of Once VTE is suspected, anticoagulation should be
VTE in patients with cancer. started immediately unless there is a contraindication
such as a risk of bleeding. A risk assessment should be
For extended-duration anticoagulation, the DOACs performed in all patients before and during antico-
(dabigatran, rivaroxaban and apixaban) and the VKA agulation therapy (Table 1).
antagonists are options. In addition to anticoagulants, other more aggres-
sive therapies for VTE may be appropriate, such as
Compression stockings are no longer recommended for systemic thrombolysis in the case of PE or catheter-
prevention of PTS in patients with acute DVT but may be directed thrombolytic or pharmacomechnical thera-
beneficial symptomatically. pies for DVT or PE, surgical intervention (acute pul-
monary embolectomy), or placement of an inferior
vena cava (IVC) filter.
This article reviews the management of VTE,
highlighting the recent changes in treatment and
Dr. Bartholomew reported consulting/advisory fees from Janssen Pharmaceuticals. prevention guidelines from the American College of
doi:10.3949/ccjm.84.s3.04 Chest Physicians (ACCP).3
CL E VE L AND CL I NI C J OURNAL OF MED IC INE VOLUME 84 SUPPLEMENT 3 D EC EMBER 2 0 1 7 39
UPDATE ON VTE
TABLE 2
Anticoagulation agents for patients with venous thromboembolism by treatment phase
Acute Long-term Extended
Patient (0 to ~7 days) (~7 days to ~3 months) (~3 months to indefinite)
Most patients UFH, LMWH, fondaparinux DOACs (rivaroxaban, apixaban, Use same anticoagulant used
or DOACs (rivaroxaban dabigatran, or edoxaban) in long-term phase
or apixaban) or VKA (warfarin) If first or second VTE is
unprovoked proximal DVT of the
leg or PE with low or moderate
bleeding risk
Renal failure UFH VKA (warfarin) Warfarin
(CrCL < 30 mL/min)
or liver failure with
coagulopathy
Hemodynamically unstable UFH or LMWH N/A N/A
PE patient
Pregnancy or cancer patient UFH or LMWH LMWH LMWH
Once-daily dosing Fondaparinux or LMWH at VKA (warfarin), rivaroxaban VKA (warfarin), edoxaban,
1.5 mg/kg/day (after 21 days) or edoxaban rivaroxaban
Recurrent VTE N/A If on a non-LMWH anticoagulant, If on a non-LMWH anticoagulant,
convert to LMWH convert to LMWH
If on LMWH, increase the dose If on LMWH, increase the dose
Need for reversal agent UFH VKA (warfarin) Warfarin
LMWH (partially reversible) Dabigatran Dabigatran
CrCL = creatinine clearance; DOAC = direct oral anticoagulant; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; N/A = not applicable; PE = pulmonary
embolism; UFH = unfractionated heparin; VKA = vitamin K antagonist; VTE = venous thromboembolism
Data from references 3 and 4.
for treatment of patients with acute VTE when used in ing twice the upper limits of normal or active liver
combination with a VKA (warfarin) or dabigatran or disease) or renal disease (CrCL < 30 mL/min), as well
edoxaban. It also has approval for VTE prophylaxis in as patients unable to afford DOACs. Additionally,
patients undergoing hip fracture, hip or knee replace- select patient populations may still be best served by
ment, and abdominal surgery. Fondaparinux is admin- warfarin as these groups were underrepresented or not
istered as a once-daily subcutaneous injection of 2.5 included in DOAC trials, including pediatric patients,
mg for DVT prophylaxis and a body weight-based dose individuals with body weight less than 50 kg or greater
for the treatment of VTE (5 mg < 50 kg; 7.5 mg 50 to than 150 kg, and patients with select types of throm-
100 kg; 10 mg > 100 kg).6 Fondaparinux is contraindi- bophilia (eg, antiphospholipid syndrome). Warfarin
cated in patients with severe renal impairment (CrCL is also advised for patients with poor compliance, as
les 30 mL/min) and bacterial endocarditis.6 international normalized ratio of prothrombin time
Warfarin. Warfarin, a VKA, was the mainstay of (PT/INR) monitoring is required using a point-of-care
therapy for long-term and extended treatment of VTE testing device or during a visit to an anticoagulation
until the advent of the DOACs. Warfarin must be clinic. DOACs do not require monitoring, and non-
coadministered with heparin, LMWH, or fondaparinux compliance will not be readily apparent.
initially and continued as overlap therapy for a mini- Direct oral anticoagulants. The DOACs, which
mum of 5 days until the international normalized ratio include the factor Xa inhibitors rivaroxaban (Xarelto),
[INR] is at least 2.0 for 24 hours.4 Early initiation of a apixaban (Eliquis), and edoxaban (Savaysa) and the
VKA on the first day of parenteral therapy is advised. direct thrombin inhibitor dabigatran (Pradaxa), been
Warfarin remains the best option for patients on studied extensively and shown to be noninferior to
long-term or extended anticoagulation with liver VKAs for treatment of VTE.7 DOACs are currently
dysfunction (elevated serum transaminases exceed- recommended by the ACCP for long-term treatment
of VTE, and several have extended treatment recom- also approved for extended treatment of VTE. In a
mendations for VTE over the VKAs.3 randomized, double-blind study of 2 doses (2.5 mg and
The advantages of DOACs include no need for 5 mg, twice daily) of apixaban compared with placebo,
PT/INR monitoring, a fixed dosage, shorter half-life, apixaban reduced the risk of recurrent VTE without
rapid onset of action (for monotherapy), and in most increasing the risk of bleeding.13
cases, no need for bridging for interventional or surgi- Both dabigatran and edoxaban require an initial
cal procedures. Additional advantages may include 5-day overlap with a parenteral anticoagulant.14,15
a decreased burden of care for the physician and Dabigatran is given at 150 mg orally twice daily if the
improved quality of life for the patient. DOACs are CrCL is greater than 30 mL/min for the long-term
also the agents of choice for patients who prefer oral treatment of VTE. Edoxaban is given orally at 60
therapy (avoiding parenteral therapy), have limited mg once daily but reduced to 30 mg once daily if the
access to an anticoagulation clinic (home bound or CrCL is 30 mL/min to 50 mL/min, if body weight is
geographic inaccessibility for PT/INR monitoring), 60 kg or greater, or with use of certain P-glycoprotein
or have food or drug-drug interactions. Patients at inhibitors. Dabigatran has been evaluated in 2 dou-
risk of gastrointestinal bleeding or dyspepsia should ble-blind, randomized controlled trials comparing the
avoid dabigatran, while apixaban may be preferred if extended use of dabigatran with warfarin or placebo
there is a history of gastrointestinal bleeding.8 in patients with VTE.16 Dabigatran carried a lower
Rivaroxaban or apixaban can be used as mono- risk of major or clinically relevant bleeding than war-
therapy for the initial treatment of VTE, while a farin but a higher risk than placebo. Dabigatran was
5-day course of heparin, LMWH, or fondaparinux is noninferior to warfarin but significantly reduced the
necessary with dabigatran or edoxaban. Rivaroxaban rate of recurrence in the placebo group.16
has been approved by the FDA for use in the preven- The major side effect observed with all DOACs is
tion and treatment of VTE.9,10 For VTE prophylaxis, bleeding, but they have been proven safer particularly
rivaroxaban is given orally at 10 mg once daily for in the terms of major bleeding compared with the
35 days for patients undergoing total hip replace- standard heparin-LMWH-VKA regimen for treat-
ment surgery and for 12 days for patients undergoing ment of VTE.1719 The risk of major bleeding, and
knee replacement surgery. For the treatment of VTE, in particular intracranial bleeding, has been shown
rivaroxaban is given orally at 15 mg twice a day for to be less with DOACs compared with VKAs in 2
the initial 21 days of treatment, followed by once meta-analysis trials.17,18 Of the 4 new DOACs, only
daily at 20 mg per day for long-term treatment. It is dabigatran currently has an anticoagulant-reversing
also approved for extended-duration therapy in both agent (idarucizumab), although an antidote for the
10-mg and 20-mg doses. In a recently published ran- other 3 agents is awaiting FDA approval.20
domized double-blind trial of rivaroxaban compared
with aspirin, the risk of a recurrent event was lower Subsegmental pulmonary embolism
with either dose of rivaroxaban compared with aspi- There is debate as to the need for treatment of patients
rin without an increase in bleeding.11 Rivaroxaban is with subsegmental PE. The most recent guidelines
contraindicated in patients with renal insufficiency advise clinical surveillance over anticoagulation for
(CrCL < 30 mL/min). Both the 15-mg and 20-mg patients with a low risk for recurrent VTE and no evi-
tablets must be taken with food. dence for a proximal DVT.3 However, individuals who
Apixaban is also approved for monotherapy of VTE are hospitalized, have reduced mobility, have active
and was found to be noninferior to standard therapy of cancer or are being treated with chemotherapy, or have
LMWH and warfarin with less bleeding.12 Apixaban is a low cardiopulmonary reserve should be considered for
used for VTE prophylaxis in patients undergoing hip anticoagulation unless they have a high bleeding risk.
or knee replacement surgery, given at 2.5 mg twice
daily beginning 12 to 24 hours postoperatively for 35 Thrombolytic therapy
days (hip) or 12 days (knee). The acute-phase dosage Thrombolytic therapy may be beneficial in select
is 10 mg twice daily for 7 days followed by 5 mg twice patients with VTE and can be delivered systemi-
daily for long-term treatment of VTE. The recom- cally or locally per catheter-directed therapy (CDT).
mended dose should be reduced to 2.5 mg twice daily Both routes carry an increased risk of hemorrhage
in patients that meet 2 of the following criteria: age compared with standard anticoagulation. The Cath-
80 or older; body weight of 60 kg or greater; or with eter-Directed-Venous Thrombolysis (CaVenT) trial
a serum creatinine 1.5 mg/dL or greater. Apixaban is and Thrombus Obliteration by Rapid Percutaneous
Endovenous Intervention in Deep Venous Occlusion monary hypertension, decreased anatomic burden,
(TORPEDO) trial compared CDT with standard and minimized the risk of intracranial hemorrhage in
therapy.21,22 In CaVEnT, CDT resulted in increased patients with massive and submassive PE.28
clinical benefit during the 5-year follow-up but did not Alteplase (Activase) is a recombinant tissue-type
result in improved quality of life.21 In the TORPEDO plasminogen activator approved by the FDA for
trial, patients with proximal DVT receiving percuta- treatment of acute PE. Alteplase is administered as
neous endovenous intervention and anticoagulation a 100-mg infusion over 2 hours. Because of favor-
compared with anticoagulation alone demonstrated able outcomes with prompt recognition and antico-
superiority in the reduction of PTS at greater than 2 agulation for PE, the ACCP guidelines recommend
years.22 Early results of the Acute Venous Thrombo- systemic thrombolysis for hemodynamically unstable
sis: Thrombus Removal With Adjunctive Catheter- patients (systolic blood pressure < 90 mm Hg) with
directed Thrombolysis (ATTRACT) trial show that acute PE and a low risk of bleeding using a peripheral
most patients with DVT did not have a long-term vein.3 These guidelines also recommend thromboly-
benefit from CDT, buy they did have reduced leg pain sis for the patient whose condition deteriorates after
and swelling and some had reduced risk of moderate- starting anticoagulant therapy but who have yet to
to-severe PTS.23 develop hypotension.
The 2012 and 2016 ACCP guidelines advise anti- If the appropriate expertise is available, CDT
coagulant therapy over CDT for patients with acute is suggested for patients with acute PE if they have
DVT of the leg but suggest patients who may benefit hypotension and a high bleeding risk, have failed
are those with iliofemoral DVT with symptoms for systemic thrombolysis, or are in shock that is likely
less than 14 days, good functional status, a life expec- to cause death before systemic thrombolysis can take
tancy greater than 1 year, and a low risk of bleeding.3,4 effect.3 An area of ongoing debate is whether there
This is in contrast to the 2008 CHEST guidelines that is a benefit for thrombolytic therapy in patients with
recommended patients who have extensive proximal submassive PE who are hemodynamically stable but
DVT, who have a high risk of limb gangrene, who are have evidence of right ventricular dysfunction on
at low risk of bleeding, and who otherwise have good echocardiography or computed tomographic angiog-
functional status be given CDT if the expertise and raphy. Bleeding remains the most serious complica-
resources are available.24 It has been suggested that tion of thrombolytic therapy.4
CDT promotes early recanalization and minimizes
the incidence of PTS. Surgical interventions: Pulmonary embolectomy
Thrombolytic therapy for acute PE remains contro- and IVC filters
versial because there is no clearly established short- Pulmonary embolectomy. According to ACCP guide-
term mortality benefit. In the Pulmonary Embolism lines, surgical pulmonary embolectomy for the initial
Thrombolysis (PEITHO) trial, thrombolysis pre- treatment of PE is reserved for patients with massive
vented hemodynamic decompensation but increased PE (documented angiographically, if possible), shock
the risk of major hemorrhage and stroke.25 A lower despite heparin and resuscitation efforts, and failure of
dose (50 mg) of thrombolytic therapy was studied in thrombolytic therapy or a contraindication to its use.4
the Moderate Pulmonary Embolism Treated With To date, there have been no randomized trials evaluat-
Thrombolysis (MOPPET) trial and was found to be ing this procedure. Pooled data published by Stein et
safe and effective in the treatment of moderate PE.26 al29 reported a 20% operative mortality rate in patients
CDT has also been shown to be effective in the undergoing pulmonary embolectomy between 1985
treatment of PE. The Ultrasound Acceleration and 2005 compared with 32% in patients undergoing
Thrombolysis of Pulmonary Embolism (ULTIMA) the procedure before 1985. A more recent retrospec-
trial demonstrated that catheter-directed thrombolysis tive review of 214 patients undergoing surgical embo-
with ultrasonographic guidance in patients with acute lectomy for massive and submassive PE reported an
intermediate-risk PE was superior in reversing right in-hospital mortality rate of 11.7%, with the highest
ventricular dilatation without an increase in bleeding death rate (32.1%) in patients who had a preoperative
complications compared with UFH.27 The Ultrasound- cardiac arrest.30 The use of surgical embolectomy has
Facilitated, Catheter-Directed, Low-Dose Fibrinolysis also been reported in patients with intermediate-risk
for Acute Massive and Submassive Pulmonary Embo- to high-risk conditions (defined as elevated biomark-
lism (SEATTLE II) study found that this approach ers and evidence of right heart strain on computed
decreased right ventricular dilation, decreased pul- tomographic angiography or echocardiography).19
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anticoagulants: a systematic review and meta-analysis. Blood 2014; 32. Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recur-
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Outcomes after surgical pulmonary embolectomy for acute pulmo- Correspondence: John R. Bartholomew, MD, Department of Vascular
nary embolus: a multi-institutional study. Ann Thorac Surg 2016; Medicine, Heart and Vascular Institute, ST20, Cleveland Clinic, 9500 Euclid
102:14981502. Avenue, Cleveland, OH 44195; barthoj@ccf.org