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240 Medical treatment of acute deep venous thrombosis and pulmonary embolism
https://t.me/med1917
Uncomplicated DVT case:
Start anticoagulation
LMWH daily dosing
DVT without comorbid risk
factors
Start oral anticoagulant
with LMWH, discontinue
LMWH when stable INR
(2.0–3.0) is reached*
Confirmed diagnosis of
DVT
Contraindication to, or
failure of anticoagulation
Insert IVC filter
Start anticoagulation
when safe to do so
DVT during pregnancy
Continue LMWH until 24 h
prior to delivery. Continue
anticoagulation for a
minimum of 6 weeks
Limb threatening DVT or
proximal DVT < 14 days,
good functional status,
long life expectancy
Catheter directed
thrombolysis (CDT)
CDT unavailable or fails,
consider operative
thrombectomy
Cancer related DVT
Anticoagulation with
LMWH for 6 months,
extend anticoagulation
until malignancy cured
For idiopathic DVT use oral
anticoagulant for 3
months and consider
extended duration
For DVT caused by
reversible risk factor use
oral anticoagulant for 3
months
For DVT cases at high risk
of recurrence, consider
extended duration oral
anticoagulation
Figure 19.1 Treatment algorithm for acute deep venous thrombosis. *Some of the new oral anticoagulants do not require
a LMWH bridge, and the new oral anticoagulants are not monitored with INRs. CDT: catheter-directed thrombolysis;
DVT: deep venous thrombosis; INR: international normalized ratio; IVC: inferior vena cava; LMWH: low-molecular-weight
heparin.
beginning anticoagulation.2 High-risk patients are likely
best served by immediate anticoagulation. Risk factors
for major bleeding, such as a recent operation, may support a longer delay to initiation of anticoagulation, whereas
patients with poor cardiopulmonary reserve may benet
from earlier initiation of anticoagulation. Even with appropriate anticoagulant therapy, however, recurrent DVT can
still occur in up to a third of patients over an 8-year period
of time.2 Treatment agents that are available for immediate
anticoagulation include UFH, LMWH, warfarin, and the
new anticoagulants such as fondaparinux, rivaroxaban and
apixaban. Additionally, dabigatran and edoxaban maybe
used as monotherapy aer initial treatment with a UFH or
LMWH bridge (Table 19.1).
3
advantages of reliable weight-based dosing that does not
require monitoring (except in morbid obesity, renal failure, or perhaps pregnancy) and ease of administration
(subcutaneous route), allowing for home administration
(Table 19.2) and lower bleeding risk. LMWH is at least as
eective and safe as UFH, and in practical terms it allows
achievement because therapeutic dosing is more rapid
and dependable. A number of high-quality randomized
controlled trials have compared LMWH to UFH in the
treatment of DVT. LMWH confers a lower risk of major
bleeding (absolute risk reduction of approximately 2 per
100 patients treated; relative risk [RR]: 0.6–0.7), a lower
risk of recurrent thromboembolic disease (RR: 0.7–0.8),
and a lower risk of death (RR: 0.7–0.8).
4
Several LMWHs
are currently marketed. Each is dosed dierently; some are
19.3.1 LMWH/heparin
administered intravenously or subcutaneously, and some
subcutaneously only—however, in all cases, their dosage is
e current recommended therapy for the acute treatment
of DVT is LMWH, derived from the lower molecular range
of UFH (4–5 kDa compared to 10–16 kDa), which has the
xed in total amount or by body weight. e two most com-
monly used LMWHs are enoxaparin (1 mg/kg subcutane-
ously every 12 hours or 1.5 mg/kg every 24 hours for VTE)
19.3 Standard initial therapy 241
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Table 19.1 Dosing of new oral anticoagulants for the initial treatment of venous thromboembolism
Medication Mechanism of action Initial dosing Long-term dosing
Dabigatran
Ingelheim)
Rivaroxaban
Apixaban
Edoxaban
Note: LMWH: low-molecular-weight heparin; UFH: unfractionated heparin.
16
(Pradaxa, Boehringer
18,19
(Xarelto, Bayer) Direct Xa inhibitor 15 mg twice daily for 3 weeks 20 mg every day
20
(Eliquis, Bristol Myers-Squibb) Direct Xa inhibitor 10 mg twice daily for 1 week 5 mg every day
22
(Savaysa, Daiichi Sankyo) Direct Xa inhibitor 5–10 days standard anticoagulant
Direct thrombin inhibitor 5–10 days standard anticoagulant
(LMWH or UFH)
(LMWH or UFH)
150 mg twice daily
60 mg every day
and dalteparin (120 anti-Xa units/kg subcutaneously every
12 hours for VTE). Once-daily dosing is superior to twicedaily dosing due to improved patient compliance for nonpregnant patients (Table 19.2). Twice-daily dosing should
be used in pregnancy, considering the increased glomerular ltration rate (GFR). Due to their pleotropic eects or
more consistent anticoagulation, LMWH tinzaparin have
been found to decrease indices of chronic venous insufciency compared to standard therapy when used over an
extended period. In 480 patients, tinzaparin for 12 weeks
was superior to warfarin in this regard.
2,5
Historically, most patients were treated with a hepa-
rin infusion, consisting of a weight-based bolus dose (80
units/kg) following by weight-based infusion with adjustments every 6 hours based on a nomogram. In recent
years, a shi away from measuring partial thromboplastin time (PTT) towards using Xa levels for UFH monitoring has occurred due to an improvement in the time
within the therapeutic range and the time to rst therapeutic result (Table 19.2).6 is treatment is still common,
especially among post-operative patients in whom the
short half-life and relatively straightforward reversal of
anticoagulation is desirable should a bleeding complication or need for re-intervention be encountered. UFH also
may still be elected for in the case of renal insuciency
(GFR < 30 mL/minute). A 5-day course has been shown
to be as eective as longer courses at preventing recurrent
thrombosis, provided that warfarin is started early (usually within 24 hours of diagnosis) and oral anticoagulation
is therapeutic prior to discontinuing heparin.7 LMWH has
not been specically tested, but is believed to behave similarly. Anticoagulation with heparin followed by warfarin
reduces the incidence of recurrent thrombosis and PE in
patients with lower extremity DVT, and also reduces mortality due to PE. In a study of 4221 patients with DVT and
1302 patients with PE, the rates of fatal PE during and aer
therapy for DVT were only 0.4% and 0.3%, respectively,
while the rates of fatal PE during and aer therapy for PE
were only 1.5% and 0%, respectively.
7
UFH or LMWH are given for 5 days. During the time
of heparin bridging, oral anticoagulation is begun, traditionally with a VKA, although current guidelines support the use of NOACs over VKAs (grade 2B, Table 19.2).
Edoxaban and dabigatran require a bridge, whereas rivaroxaban, apixaban and fondaparinux do not.
8
Warfarin
alone without a heparin or LMWH “bridge” is inadequate.
Certain patients may use LMWH as the sole antithrombotic
agent throughout their course. For patients with malignancies and acute DVT, this strategy appears to roughly halve
the risk of recurrence without an increase in adverse events,
and avoids dicult warfarin management resulting from
variable food intake. e recommended treatment duration
is indenite in both patients at low risk of bleeding and high
risk of bleeding (Figure 19.1, Table 19.2).
19.3.2 Warfarin
Warfarin and other VKAs reduce the incidence of the
recurrence of thrombosis in patients with DVT and PE by
30 or more per 100 patients treated. Warfarin (Coumadin)
should be started aer anticoagulation is therapeutic (heparin bridging) to prevent paradoxical thrombosis—so-called
warfarin-induced skin necrosis. e reason for this is that
warfarin causes inhibition of protein C and protein S before
factors II, IX, and X, leading to potential hypercoagulability
when the drug is started. For standard UFH, this requires
measuring a therapeutic activated PTT or anti-factor Xa
level (Figure 19.2), while for LMWH, an appropriate weightbased dose of LMWH being administered and allowed to
circulate is adequate.
Transition from heparin to VKAs (warfarin) involves
an overlap between heparin and warfarin therapy. Clinical
trials suggest that heparin can be discontinued safely once
the INR enters the therapeutic range (2.0–3.0) if the patient
has received ≥5 days of heparin therapy. Some recommend that heparin be continued until the INR has been
in the therapeutic range for at least 24 hours (essentially
two measurements over 2 days), since the antithrombotic
eect of warfarin may be delayed relative to its eect on the
prothrombin time. However, clinical trials have not tested
whether this approach oers greater protection against
thrombosis than discontinuation of heparin as soon as the
INR is therapeutic.
e goal of warfarin dosing is an INR between 2.0 and 3.0.
e use of loading doses of warfarin is not recommended,
as the coagulation factors are not reduced symmetrically,
and the INR may not accurately reect the antithrombotic
eect of warfarin during the initiation phase of therapy.
e initial warfarin dosing is 5 mg daily, with doses usually
given in the evenings. Lower doses are oen considered for
242 Medical treatment of acute deep venous thrombosis and pulmonary embolism
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Table 19.2 Summary of key recommendations to the American Venous Forum on the medical therapy of acute deep vein
thrombosis and pulmonary embolism
Grade of evidence
(A:highquality;
B:moderate quality;
C:lowor very low
quality)
No. Guideline
a
3.3.1
If home circumstances are adequate, we recommend that
Grade of
recommendation
(1:strong; 2: weak)
1 B
initial treatment of acute deep venous thrombosis (DVT)
take place at home rather than in the hospital.
a
3.3.2
We suggest low-molecular-weight heparin (LMWH) over
2 B
unfractionated heparin for the treatment of acute DVT.
a
3.3.3
We suggest once- over twice-daily administration of
2 C
LMWH for the treatment of acute DVT.
b
3.3.4
We suggest LMWH over NOACs or VKAs for patients with
2 C
cancer and acute DVT.
3.3.5
b
In patients with acute DVT and no cancer, as a long-term
2 B
anticoagulant therapy we susggest dabigatran,
rivaroxaban, apixaban, or edoxaban over vitamin K
agonist (VKA) therapy.
b
3.3.6
We suggest that patients with an unprovoked proximal
2 B
DVT who are stopping anticoagulant therapy should
take an aspirin to prevent recurrent VTE.
3.3.7
b
We recommend 3 months of treatment for acute proximal
1 B
DVT provoked by transient risk factors (surgical or
non-surgical).
3.3.8
b
We suggest monitoring over 2 weeks with serial imaging
2 C
over anticoagulation for the treatment of acute isolated
distal DVT without severe symptoms or risk factors.
b
3.3.9
We suggest anticoagulation for acute isolated distal DVT
2 C
with severe symptoms and risk factors.
3.3.10
b
We suggest extended anticoagulation therapy in patients
2 B
with an acute unprovoked proximal DVT who have low
or moderate bleeding risk.
3.3.11
b
We recommend 3 months of anticoagulant therapy rather
1 B
than extended therapy in patients with an acute
unprovoked proximal DVT who have high bleeding risk.
3.3.12
b
We recommend extended anticoagulation beyond 3
1 B
months for acute DVT of the leg in the setting of active
cancer if the risk of bleeding is not high.
b
3.3.13
We suggest that anticoagulation be preferred over
2 C
catheter directed thrombolysis for acute proximal DVT.
3.3.14
b
We suggest systemic thrombolysis for pulmonary
2 C
embolism associated with hypotension or when
hypotension is likely without a high bleeding risk.
a
Based on the recommendations of Kearon C etal. Chest 2012;142:1698–704.
b
Kearon C etal. Chest 2016;149(2):315–52; Meissner MH etal. J Vasc Surg 2012;55:1449–62.
elderly, debilitated, liver disease, or heart failure patients.
Subsequent dosing depends on the results of laboratory
monitoring of the PTT/INR, which should be performed at
least twice during the rst week of therapy. A target INR
of 2.0–3.0 is eective at preventing thrombus extension or
recurrence, and is associated with a relatively low risk of
bleeding.
7
Despite careful monitoring, patients with VTE
treated with warfarin have a major bleeding risk of 5%–6%
9
per year, even within the target INR range.
Long-term anticoagulation with lower-dose warfarin (INR: 1.5–2.0) does
not reduce the risk of thrombus recurrence/extension and
carries the same bleeding risk as a higher INR (2.0–3.0).
10,11
Another diculty with warfarin is the eect of both diet
and drug interactions on the eectiveness of the agent.
19.3 Standard initial therapy 243
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Repeat heparin
Anti-Xa (units/mL)
Less than 0.2
0.2–0.29 40 units/kg 0 Increase 1units/kg/hour 6 hours
0.3–0.7 None 0 No change 6 hours
0.71–0.8 None 0 Decrease 1 units/kg/hour 6 hours
0.81–0.99 None 30 Decrease 1.5 units/kg/
*
≥1
Figure 19.2 Weight-adjusted heparin nomogram. Table created by Anticoagulation Committee (subcommittee of Pharmacy &
Therapeutics Committee) © University of Michigan Health Systems, used with permission. *Notify physician if two consecutive
anti-Xa values are in this range. **When two consecutive anti-Xa values are in therapeutic range (0.3–0.7 units/mL), obtain antiXa assay the next morning and every 24 hours thereafter.
*
bolus dose
80 units/kg 0 Increase 1.5 units/kg/hour 6 hours
None 60 Decrease 3 units/kg/hour 6 hours
Patients should receive information on dietary vitamin K,
which can reduce the eectiveness of warfarin, as well as
Hold infusion
(minutes) Rate change
hour
19.3.4 New anticoagulants (factor Xa
andfactor IIa inhibitors)
Repeat
anti-Xa level
6 hours
warnings about over-the-counter vitamins and information
on dietary interactions.
There are many agents in development for anticoagulation, aiming to replace either LMWH or warfarin.
19.3.3 Location of treatment
Fondaparinux (Arixtra®, GlaxoSmithKline), a synthetic
pentasaccharide that has an antithrombin sequence
Outpatient treatment has become preferred due to its advantages of lower cost and greater patient comfort. Patients
must be able to clearly understand and eectively adhere to
the detailed instructions. Proper patient (or caregiver) education is critical to safe outpatient management. Patients
who may have diculty understanding or adhering to therapy, who have high-risk comorbid conditions, or who have
severe symptoms, should be hospitalized, at least initially.
Inpatient treatment provides closer monitoring and quicker
responses to clinical changes. LMWH is less costly in terms
of overall treatment expense, although its acquisition cost
is higher. Shorter, (or even no), hospital stay(s) account for
some of that advantage. However, even in the inpatient setting, the costs of intravenous administration and monitoring make UFH more expensive than LMWH.
Many patients with DVT may be safely treated as outpatients, and a smaller number of patients with PE also
have suciently low risk to justify an outpatient treatment recommendation. ese patients should be hemodynamically stable and normoxemic before outpatient
treatment is considered, without signs of right ventricular
dysfunction by echocardiography. Absolute contraindications to outpatient management of DVT would also apply
to PE patients, and include massive thrombosis, presence of active bleeding, high risk for hemorrhage, history
of heparin sensitivity, underlying liver disease, clinical instability, and extensive thrombus burden leading
to severe swelling, cyanosis, and/or severe shortness of
breath. Biomarkers can help predict outcome but are not
denitive, with a normal brain natriuretic peptide being
highly predictive of good outcome, and elevated troponin being predictive of patients who are at higher risk of
adverse outcome.
identical to heparin, targets factor Xa. Fondaparinux has
been approved for the treatment of DVT and PE when
administered in conjunction with warfarin, for thrombosis prophylaxis in patients with total hip replacement,
total knee replacement, and hip fracture, and in patients
undergoing abdominal surgery. Fondaparinux, administered subcutaneously, has a 17-hour half-life and dosage
is based on body weight. It exhibits no endothelial or protein binding, and importantly does not produce thrombocytopenia. No antidote is readily available for this
agent. In VTE prophylaxis, a meta-analysis involving
more than 7000 patients demonstrated a greater than 50%
risk reduction in VTE using fondaparinux begun 6 hours
after surgery compared to LMWH begun 12–24 hours
after surgery.12 Although major bleeding was increased,
critical bleeding was not increased. Fondaparinux has
also been found to be effective in the prophylaxis of other
groups of patients, including general medical patients.13
For the treatment of VTE, fondaparinux was found to be
equal to standard heparin and LMWH for DVT and for
13,14
PE.
Fondaparinux has also been found to be effective
for the treatment of superficial thrombophlebitis over a
45-day course of treatment at a prophylactic dose (level
of evidence:2B).
2,15
More recently, several novel oral anticoagulants
(NOACs) have gained Food and Drug Administration
(FDA) approval to replace warfarin (Tables 19.1 and 19.2).
Dabigatran targets active factor II (factor IIa), whereas rivaroxaban, apixaban, and edoxaban target activated factor X
(factor Xa). Similar to warfarin, dabigatran and edoxaban
require the use of a LMWH or UFH “bridge” during initiation of therapy, whereas rivaroxaban and apixaban can
be instituted as immediate monotherapies. All agents are
244 Medical treatment of acute deep venous thrombosis and pulmonary embolism
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currently FDA approved in the United States for the treatment of acute DVT, although dierences amongst the particular pharmacokinetics may lead a practitioner to choose
one over another (Table 19.2).
19.3.4.1 DABIGATRAN
Dabigatran etexilate (Pradaxa®, Boehringer Ingelheim
Pharmaceuticals) is FDA approved for stroke and systemic
embolization prevention in patients with atrial brillation,
and for the treatment and prevention of DVT and PE in
patients who have been treated with a parenteral anticoagulant for 5–10 days.16 Dabigatran has the longest half-life of all
of the NOACs at 12–17 hours, which is prolonged with age
and decreased renal function. It is the only one which can
be at least partially reversed with dialysis.17 It is also the only
NOACs which has a commercially available reversal agent.
19.3.4.2 RIVAROXABAN
Rivaroxaban (Xarelto®, Bayer) is FDA approved for VTE prophylaxis in patients undergoing hip or knee replacements,
for stroke and systemic embolization prevention in patients
with atrial brillation, and for VTE treatment. is is the
rst monotherapy agent to be approved of the NOACs. e
EINSTEIN trial evaluated rivaroxaban compared to standard
anticoagulation in the treatment of acute DVT.18 Rivaroxaban
was found to be statistically noninferior to standard therapy,
without increased bleeding. Additionally, the EINSTEIN
group added a continued treatment group compared to placebo for an additional 6–12 months aer the completion of
6–12 months of therapy. Extended rivaroxaban showed a
signicant decrease in recurrent VTE without an increase
in major bleeding compared to placebo, although it was not
directly compared to VKAs or LMWHs. A similar nding
with PE has been noted (EINSTEIN-PE).19 Rivaroxaban has
the benet of once-daily dosing and immediate monotherapy, making it a convenient choice for patients.
19.3.4.3 APIXABAN
Apixaban (Eliquis®, Bristol Myers-Squibb) is currently FDA
approved for the prevention of complications of atrial brillation, for the prophylaxis of DVT following hip or knee
replacement surgery, for the treatment of DVT/PE, and for
reduction in the risk of recurrence of DVT/PE. is is the
only new oral agent that has shown superiority to standard
therapy without an increase in bleeding. Recently, apixaban
as an extended treatment of VTE was investigated compared
to placebo. e study revealed a signicant decrease in the
rate of VTE without an increase in bleeding risk.
20
Apixaban
is the only agent among the NOACs to demonstrate a slight
decrease in gastrointestinal bleeding compared to warfarin.
19.3.4.4 EDOXABAN
21
Edoxaban (Savaysa®, Daiichi Sankyo) is the most recently
22
approved agent for treatment of DVT.
It is currently FDA
approved for the prevention of stroke and non-central nervous system systemic embolism in patients with non-valvular atrial brillation, as well as for the treatment of DVT and
PE in patients who have been treated with a parenteral anticoagulant for 5–10 days. Edoxaban carries a boxed warning
stating that the novel anticoagulant is less eective in atrial
brillation patients with a creatinine clearance of >95 mL/
minute, and that kidney function should be assessed prior
to starting treatment. According to the FDA, patients with a
creatinine clearance of >95 mL/minute have a greater risk of
stroke compared with similar patients treated with warfarin. Edoxaban is the only agent specically tested at a lower
dose in patients at high risk of bleeding complications (low
body weight and/or decreased creatinine clearance).
19.3.4.5 COMPLICATIONS WITH NOACS
22
Problems with these new agents include the inability at
the present time to reliably follow their levels, reverse their
anticoagulant eects, and the lack of data available on the
bridging of these agents when interventions need to be performed. Situations in which it might be useful to monitor
drug levels have been published by the International Society
of rombosis and Hemostasis (ISTH) and include: (1)
bleeding; (2) before surgery or an invasive procedure when
the patient has taken the drug in the previous 24hour, or
longer if creatinine clearance is <50 mL/minute; (3) the
identication of subtherapeutic or supratherapeutic levels in patients taking other drugs that are known to signicantly aect pharmacokinetics; (4) the identication
of subtherapeutic or supratherapeutic levels in patients at
the extremes of body weight; (5) patients with deteriorating
renal function; (6) peri-operative management; (7) reversal
of anticoagulation; (8) suspicion of overdose; and (9) assessment of compliance in patients suering from thrombotic
events while on treatment (this application may be limited
by the short half-life of the oral agents).
23
Currently, the only FDA reversal agent is approved for
dabigatran. Idarucizumab is a humanized monoclonal antibody fragment that binds to dabigatran and sequesters both
thrombin-bound and free dabigatran. e REVERSE AD
phase III trial demonstrated that 5 g of antibody administered to patients requiring emergent reversal normalized
thrombin time at a median of 11.4 hours. It was well tolerated
without any major side eects. Until the time that specic
reversal agents exist for the remaining NOACs, supportive
care is the mainstay of therapy. In cases of trauma or severe/
life-threatening bleeding, administration of concentrated
clotting factors (prothrombin complex concentrate) or dialysis (dabigatran only) can be utilized, although data from large
clinical trials are lacking (Figure 19.3).
19.3.5 Aspirin
Although aspirin (ASA) is not a new agent, the use of ASA
for the extended treatment of VTE aer a standard course of
therapy has gained renewed interest. Two trials have evaluated ASA versus placebo in idiopathic DVT in patients who
had completed initial treatment with heparin followed by
warfarin for a minimum of 6 weeks (most 3 months); ASA
was used at a dose of 100 mg every day for 2–4 years. In the
19.4 Duration of therapy 245
Algorithm for severe bleeding on novel anticoagulant
Anticoagulation
treatment
https://t.me/med1917
Patient assessment:
Name and dose of medication
Timing of last dose
Indication for therapy
Concurrent antiplatelet therapy
Hemodynamic status
Location and source of bleeding
Evaluate renal and hepatic function
CBC and coagulation parameters
Apixaban Rivaroxaban Dabigatran
Monitoring
parameters:
PT, aPTT, INR
Anti-factor Xa
Supportive measures: Treat anemia with packed red blood cells, treat DIC with fresh frozen plasma, consider platelet transfusion if
on concurrent antiplatelet therapy; consider use of desmopressin and antifibrinolytic agents for on-going hemorrhage.
Reversal agents:
Four factor PCC (50 U/kg)
Activated PCC (80 U/kg)
a
b
Monitoring
parameters:
PT, INR
Anti-factor Xa
Reversal agents:
Four factor PCC (50 U/kg)
Activated PCC (80 U/kg)
a
b
Monitoring
parameters:
aPTT, ECT, TCT,
Hemoclot assay
Reversal agents:
Idarcuzimab (5 g)
Hemodialysis
a
Figure 19.3 Reversal of novel anticoagulants. aPreferred monitoring parameter. bPreferred reversal agent. (Reproduced
and modified with permission from Knepper J etal. J Vasc Surg Venous Lymphat Disord 2013;1(4):418–26.)
WARFASA study of 402 patients, recurrence rates of 6.6%/
year versus 11.2%/year (hazard ratio [HR]: 0.58, P = 0.02)
VTE
were found, while in the ASPIRE study of 822 patients,
recurrence rates of 4.8%/year versus 6.5%/year (HR: 0.74,
P = 0.09) were found.
24,25
Combining studies, there was a
Provoked Unprovoked
32% reduction in the rate of recurrence of VTE (7.5%/year
vs. 5.1%/year; HR: 0.68, P = 0.008) and a 34% reduction in
the rate of major vascular events (recurrent VTE, myocardial infarction, stroke, cardiovascular disease death; 8.7%/
3 mo
anticoagulation
3–6 mo
anticoagulation
year vs. 5.7%/year; HR: 0.66, P = 0.002), without an increase
in major bleeding.
new anticoagulants for extended treatments, the decrease in
26,27
Interestingly, when compared to the
Low risk High riskModerate risk
recurrence of 32% is much less than the 83%–88% decrease
in recurrence with the new agents.28 ese data suggest that
No further
ASA
patients at increased risk of bleeding from anticoagulation
or a moderate increase in thrombosis might benet from
long-term therapy with ASA (Table 19.2, Figure 19.4).
19.4 DURATION OF THERAPY
Figure 19.4 Incorporation of aspirin (ASA) into venous
thromboembolism (VTE) extended treatment paradigm.
(Reproduced with permission from Wakefield TW, Obi A,
Henke PK, Circulation 2014:13 0(13):1031–3.)
e duration of anticoagulation depends on a number of
factors, including the thrombotic risks at presentation,
continuing risk factors for thrombosis, the type of thrombosis (idiopathic or provoked), how oen thrombosis has
occurred, the level of D-dimer measured approximately
1month aer stopping warfarin, and the status of the veins
when stopping anticoagulation.
tion of anticoagulation aer a rst episode of provoked
VTE is 3 months for both proximal and distal thrombi,
although under certain circumstances, distal thrombi
may not require treatment (Table 19.2).2 For asymptomatic
2,29
e recommended dura-
246 Medical treatment of acute deep venous thrombosis and pulmonary embolism
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patients with calf-level DVT and no risk factors, serial ultrasound imaging is preferred over anticoagulation. On the
other hand, in symptomatic calf-level DVT, anticoagulation is recommended (Table 19.2).2 Aer a second episode
of VTE, prolonged oral anticoagulation is recommended,
unless the patient is very young at the time of presentation or there are other mitigating factors (Tabel 19.2). VTE
recurrence is more common with heterozygous factor V
Leiden combined with a prothrombin 20210A mutation, or
homozygous states of each, protein C or protein S deciency
(especially with a family history), antithrombin deciency,
antiphospholipid antibodies, and unresolved cancer.30 In
these circumstances, long-term oral anticoagulation is recommended. When they occur in isolation, the most common hypercoagulable states—heterozygous factor V Leiden
and prothrombin 20210A—do not carry the same risk for
recurrence as their homozygous counterparts. For these
conditions, the length of oral anticoagulation is shortened.31
In certain circumstances, such as active cancer, the use of
LMWH is superior to warfarin for long-term treatment, at
least when given over a 6-month period of time.
2
Regarding unprovoked (idiopathic) DVT, the recommended length of treatment is extended therapy for more
than 3 months, especially in those patients at low bleeding
risk (grade 2B, Table 19.2). If indenite therapy is consid-
ered in patients with idiopathic VTE, decision making may
be aided by D-dimer testing 1 month aer completion of
warfarin therapy. An elevated D-dimer suggests ongoing
increased risk, indicating resumption of full-dose anticoagulation. In one study of patients with idiopathic VTE, a
low rate (6.2%) of recurrence of VTE was found when the
D-dimer was normal at 1 month aer discontinuation of
warfarin, but a 15% rate of recurrence was found among
those with abnormal D-dimer. Resumption of warfarin
among those with abnormal D-dimer reduced the recurrence rate to 2.9%.32 Similar ndings have been reported
in other studies. e use of repeat (serial) lower extremity
ultrasound has also been proposed as a test for whether
to continue anticoagulation beyond the usual timeframe,
although its usefulness is less certain and the ability to
quantify this eect clinically is dicult. For a second
unprovoked VTE, recommendations are for anticoagulant
therapy beyond 3 months in patients with a low bleeding
risk (grade 1B). Criteria that have been described for discontinuing anticoagulation are given a level of evidence of
1B–2B, depending on the clinical situation. Acute DVT of
the leg in the setting of active cancer should be treated with
extended anticoagulation rather than 3 months of treatment if the risk of bleeding is not high (Table 19.2).
19.5 COMPLICATIONS
e most common complication of anticoagulation is bleeding. With standard heparin, bleeding occurs in approximately 10% of patients over the rst 5 days. Major bleeding
with UFH has been reported at a rate of 2.0%–4.5%, while
for LMWH, this rate is between 1.5% and 4.7%.
33
With oral
anticoagulation, major bleeding with warfarin has been
reported at a rate of between 1.6% and 2.0%, and for all bleeding, this rate is between 8.5% and 10.3%. For the NOACs,
major bleeding rates of 0.6%–1.4% and major and non-major
bleeding rates of 4.3%–9.4% have been reported.
34
Another potentially devastating complication is heparin-
induced thrombocytopenia (HIT). is syndrome occurs in
0.6%–30% of patients. Morbidity and mortality rates have
decreased with early diagnosis and appropriate treatment.
Although HIT usually begins 3–14 days aer the start of
heparin treatment, it can occur earlier if the patient has been
exposed to heparin previously. In terms of pathophysiology,
a heparin-dependent antibody binds to platelets, activating
them with the release of pro-coagulant microparticles, leading to thrombosis and thrombocytopenia.35 Although the
incidence and severity of the thrombosis appears to be less
with LMWH than standard UFH, both bovine and porcine
UFH and LMWH have been associated with HIT.36 Even
slight exposure to heparin, such as a heparin coating on
indwelling catheters, can also lead to the clinical manifestations of the syndrome. e diagnosis should be suspected
when thrombosis occurs during heparin or LMWH therapy, with a 50% or greater drop in platelet count, or when
the platelet count falls below 100,000.37 Heparin induced
thrombocytopenia and thrombosis syndrome (HITTS) is
dened as HIT associated with episodes of thrombosis.
A highly sensitive but poorly specic diagnostic test is
the enzyme-linked immunosorbent assay (ELISA), which
detects the anti-heparin antibody in plasma. A more specic but less sensitive test is the serotonin release assay.
Oen a combination of both tests gives the best diagnostic accuracy. When the diagnosis is made, heparin must be
stopped and oral anticoagulation with warfarin should not
be given until an adequate alternative anticoagulant is given
and established. Additionally, warfarin should not be given
until the platelet count has normalized, or at least returned
to 150,000. LMWHs cannot be substituted for standard heparin in patients with HIT, as they demonstrate high crossreactivity with standard heparin antibodies. e direct
thrombin inhibitor argatroban has been FDA approved as
an alternative agent. Although fondaparinux (Arixtra) has
also been found to be eective for the treatment of HIT in
some cases, it is not FDA approved for this indication. e
use of these alternative agents is given either a 2C or 1C level
of evidence according to the 2012 ACCP guidelines.
19.6 NON-PHARMACOLOGIC
TREATMENTS
e use of strong compression and early ambulation aer
DVT treatment can signicantly reduce the pain and swelling resulting from the DVT. It has been shown that the rate
and severity of PTS aer proximal DVT can be decreased
by approximately 50% with the use of compression stock-
38
In addition, walking with good compression does
ings.
not increase the risk of PE, while signicantly decreasing the incidence and severity of PTS.
39
However, a recent
19.8 Special situations 247
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multicenter randomized trial has challenged this concept.
is study concluded that stockings do not prevent PTS
aer a rst proximal DVT.40 is large randomized study,
although of great interest, brings up many questions, and its
data should be conrmed in other studies before no longer
recommending stockings aer DVT (in our opinion).
19.7 AGGRESSIVE THERAPIES
For DVT treatment, the goals are to prevent the extension/recurrence of DVT, prevent PE, and minimize the late
sequel of thrombosis, namely PTS. Standard anticoagulation accomplishes the rst two goals, but not the third goal.
PTS occurs in up to 30% of patients aer DVT, and in an
even higher percentage of patients with iliofemoral DVT.41
More aggressive therapies for extensive thrombosis are thus
indicated. Patients who present with DVT that could potentially result in signicant long-term pain and swelling or
limb loss due to ischemia, or who are clinically unstable due
to PE (hypotensive, tachycardia, hypoxia, and tachypnea),
may benet from initial treatment beyond simple anticoagulation. Patients in this situation are best managed in the
inpatient setting. Options for management include catheterdirected thrombolysis (CDT, with or without a mechanical
device), thrombectomy, and systemic thrombolysis.
Experimentally, the thrombosis initiates an inammatory response in the vein wall that leads to vein wall brosis
and valvular dysfunction. Prolonged contact of the thrombus with the vein wall increases damage.42 us, removing
the thrombus should be an excellent solution to decreasing
this interaction, although, depending on the timing of treatment initiation, it may not completely eliminate alterations
in the vein wall. For example, the longer a thrombus is in
contact with a vein valve, the more chance there is that this
valve will no longer function.
Venous thrombectomy—removal of thrombus with a
catheter under direct operative vision—has proved superior
to anticoagulation over 6 months to 10 years as measured
by venous patency and the prevention of venous reux.44
Catheter-directed thrombolysis has been employed in many
non-randomized studies, and in small, randomized trials
was more eective than standard therapy for improving
quality of life. Results are optimized further by combining
catheter-directed thrombolysis with mechanical devices.
e devices include the Angiojet rheolytic catheter, Trellis
balloon occlusion catheter, and the EKOS ultrasound accelerated catheter. ese various devices hasten thrombolysis
and decrease the amount of thrombolytic agent needed,
thus decreasing bleeding potential. Additionally, the use of
venous stents for iliac venous obstruction has been shown
to decrease the incidence of PTS and chronic venous insufciency.47 e Attract Trial, which compares catheterdirected pharmacomechanical thrombolysis to standard
anticoagulation for signicant iliofemoral venous thrombosis, has nished recruitment. is study will evaluate
anatomic, physiologic, and quality-of-life endpoints, along
with complications. Its results should help direct therapy
43
45,46
and determine the characteristics of patients to whom physicians should apply more aggressive treatment. At present,
aggressive therapy is not recommended by the ACCP 2016
guidelines, although it is noted that such therapies may be
pursued by patients who place a high value on prevention
of PTS and low value on cost and risk associated with CDT
(Table 19.2).48 Current evidence to support the use of catheter-directed thrombolysis or more aggressive treatments
with mechanical and surgical thrombectomies for acute
iliofemoral DVT is discussed in more detail in Chapter 20.
For acute PE, evidence exists that thrombolysis is indicated when there is hemodynamic compromise from the
embolism.49 In controlled trials, systemic thrombolysis has
been shown to improve hemodynamics, imaging, and echocardiography faster than heparin alone; however, mortality
is not improved. e signicant risk of systemic bleeding
must be balanced against the relatively uncertain benet of
systemic thrombolytics. e risk of dying from PE is estimated at 70% if associated with cardiopulmonary arrest
and 30% if associated with hypotension requiring inotropic support. In cases of hemodynamic instability, and in the
absence of a high risk of bleeding, systemic thrombolysis
has been recommended (tissue plasminogen activator [t-PA]
100 mg over 2 hours or 50 mg over ≤15 minutes) (Table 19.2).
Consensus does not exist on whether thrombolysis should
be used in situations in which there is no hemodynamic
compromise but evidence of right heart dysfunction, or if
there are positive biomarkers.50 Future studies will address
these situations.50 Until then, in selected patients with submassive PE (evidence of right ventricle strain on echocardiogram, worsening clinical status aer anticoagulation
instituted, and/or relative hypotension with a systolic blood
pressure drop of >40 mmHg), systemic thrombolysis can be
considered if the patient is at very low risk of bleeding. As
thrombolysis for PE becomes more localized, with catheters
placed into the pulmonary circulation being associated with
less systemic bleeding potential, it is likely that indications
for pulmonary thrombolysis will broaden, as discussed in
much more detail in Chapter 21.
19.8 SPECIAL SITUATIONS
19.8.1 Anticoagulation and pregnancy
e incidence of VTE associated with pregnancy is not precisely known, but it is believed to be substantially greater
than in non-pregnant women. Approximately two-thirds
of DVTs occur before delivery, and are distributed fairly
uniformly throughout the pregnancy, but 40%–60% of
PEs occurs in the 4–6 weeks aer delivery. Symptomatic
VTE is estimated at 5–12 per 10,000 pregnancies, and in
the rst 6 weeks postpartum, VTE is estimated at 3–7 per
10,000 deliveries. is translates to a 7- to 10-fold increase
in antepartum and a 15- to 25-fold increase in postpartum VTE compared to non-pregnant patients of the same
51
DVT has a marked predilection for the le leg in
age.
pregnancy because of compression eects on the le iliac
248 Medical treatment of acute deep venous thrombosis and pulmonary embolism
https://t.me/med1917
vein by the overlying right iliac artery being pushed by the
graviduterus.
VTE in pregnancy appears to be strongly associated with
thrombophilia. e most important thrombophilias are factor V Leiden, prothrombin gene mutation, anticardiolipin
antibody elevation, antithrombin deciency, and protein C
and protein S deciencies. However, routine thrombophilia
screening does not seem to be cost eective in this group of
patients.
52
LMWH is safe and eective for the treatment of VTE
during pregnancy and in the postpartum period. It is superior to warfarin due to the potential risk for embryopathy
with warfarin (between 6 and 12 weeks’ gestation) and risk
of intracranial hemorrhage at the time of delivery, and it
is preferred to UFH. Warfarin for VTE should be discontinued in favor of LMWH when pregnancy is planned or
discovered. As UFH and LMWH do not cross the placenta,
they can be continued throughout pregnancy. Although
heparin anticoagulation could increase the risk of abruption, it causes neither teratogenicity nor fetal bleeding.
Patients with a need for ongoing anticoagulation may reinitiate warfarin 12 weeks aer delivery. Warfarin does not
cross into breast milk in an active form, and thus it is not
contraindicated and may be used during nursing.
19.8.2 Testing for thrombophilias
Identifying thrombophilias can guide the assessment of risk
of future VTE events and provide guidance for therapeutic
decisions regarding duration of anticoagulation. Guidelines
and expert opinions suggest testing in some of the following populations: rst episode of idiopathic thrombosis
at 50 years of age or younger; history of two or more episodes of recurrent thrombosis, especially if the events were
unprovoked; thrombosis in an unusual site (e.g., cerebral
or mesenteric); positive family history with two or more
rst-degree relatives with documented venous thrombosis; women who develop thrombosis during pregnancy or
in the setting of a hormonal agent; and women who have
unexplained recurrent pregnancy loss.53 e advantages of
testing include improving the understanding of the pathogenesis of thrombosis, identifying and counseling aected
family members, and obviating the need for expensive diagnostic testing, such as computed tomography scans, looking
for malignancy. e disadvantages include the infrequent
identication of patients with defects whose management
would change, the potential for overaggressive management, insurance implications, and the cost of testing. Data
from the large RIETE Registry have suggested that thrombophilia testing for a rst episode of VTE is not advisable.
Several genetic thrombophilias are now known, and
their testing requires knowledge of specic interactions if
testing is going to be carried out. Acute thrombosis and
pregnancy can transiently reduce the levels of antithrombin,
proteins C, and protein S. erefore, these assays should be
delayed by at least 6 weeks from the acute event or until a
similar time into the postpartum phase. Heparin treatment
31
can reduce antithrombin activity and antigen levels, and
interfere with the interpretation of clot-based assays for a
lupus anticoagulant. Warfarin can increase antithrombin levels, and will reduce protein C and protein S levels,
as they are vitamin K-dependent factors. e eect from
warfarin may persist for up to 6 weeks aer its discontinuation. Importantly, ELISAs for antiphospholipid antibodies
and molecular diagnostic testing for factor V Leiden and
prothrombin gene mutations are not aected by anticoagulation, and may be performed at any time.
19.9 IVC FILTERS
Traditional indications for the use of IVC lters include a
contraindication to, a complication of, or a failure of, anticoagulation. Overall, protection from PE is greater than
95% using cone-shaped, wire-based permanent lters in
the IVC.54 With the success of these lters, indications have
expanded for some to include the presence of free-oating
thrombus tails, prophylactic use when the risk of anticoagulation is excessive and when the risk of PE is thought to
be high, and even for facilitating the use of peri-operative
epidural anesthesia. IVC lters can be either permanent or
optional (retrievable). Today, over a dozen IVC lters are FDA
approved. Most lters are placed in the infrarenal location
in the IVC. However, they may be placed suprarenally or in
the superior vena cava. Indications for suprarenal placement
include active pregnancy, in women of childbearing age, or in
previous device failure lled with thrombus. Currently, only
one randomized prospective study is available on the use of
IVC lters as a treatment of DVT (which is not how lters are
traditionally used).55 Chapter 26 presents current indications,
techniques, and results of IVC lters in detail, and includes
recommendations of the American Venous Forum.
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