In patients with a moderate-to-high clinical probability
of PE, diagnostic imaging studies should be performed.
CASE 11-5, QUESTION 2: What anticoagulant strategy should be initiated for A.W.?
When the diagnosis of PE is suspected, anticoagulation should be initiated
immediately while awaiting results of more definitive diagnostic procedures. There
are several agents that can be used for the acute treatment of PE. IV UFH therapy
initiated with a loading dose followed by a continuous infusion was the mainstay of
therapy for many years. Alternatively, SC UFH can be used. However, if there is a
concern about adequate SC absorption or in patients in whom fibrinolytic therapy is
being considered, initial treatment with IV UFH is preferred to the SC route.
LMWHs are noninferior to UFH in the management of PE and are recommended over
UFH in stable PE patients because of their ease of use, less major bleeding, and
ability for outpatient management or early discharge.
60,61 Fondaparinux demonstrated
noninferiority when compared with IV UFH for rate of recurrent PE, with similar
62 More recently, the DOACs have been evaluated for both
the initial and long-term management of VTE, with dabigatran, rivaroxaban,
apixaban, and edoxaban all FDA-approved for the initial management of PE. All of
the DOACs were compared to LMWH/VKA and found to be noninferior for the rate
63–67 Rivaroxaban and apixaban were studied as monotherapy,
whereas dabigatran and edoxaban patients were initially treated with at least 5 days
of parenteral therapy prior to receiving a DOAC. If A.W. is being kept in the hospital
for observation because of the severity of her symptoms, UFH therapy could be
started at a loading dose of 5,600 units (80 international units/kg × 70 kg), followed
by continuous infusion of 1,300 units/hour (18 units/kg/hour × 70 kg). Monitoring of
the aPTT would be used to adjust dosing to maintain treatment within the therapeutic
Alternatively, SC LMWH 70 mg every 12 hours (1 mg/kg every 12 hours × 70 kg)
or SC fondaparinux 7.5 mg daily may be given while transitioning the patient to
warfarin (Table 11-13). A.W. could receive fixed-dose enoxaparin 70 mg SC every
12 hours (1 mg/kg every 12 hours × 70 kg) or dalteparin 15,000 international units
SC every 24 hours (200 international units/kg, rounded to nearest syringe size). Use
of initial therapies such as LMWH, fondaparinux, and DOACs allows for outpatient
therapy and early discharge in hospitalized patients with acute PE. For patients with
low-risk PE and home circumstances that are adequate, early discharge is suggested
Original and Simplified Pulmonary Embolism Severity Index (PESI) Scoring
Age Points = age, (years) 1 (if age > 80 years)
Chronic pulmonary disease 10 1
Systolic blood pressure < 100 mm
Arterial oxygen saturation < 90% 20 1
Very low: 0%–1.6% Class I: < 65 points 0 points: 1%
Low: 1.7%–3.5% Class II: 66–85 points
Moderate: 3.2%–7.1% Class III: 86–105 points
High: 4%–11.4% Class IV: 106–125 points ≥1 point: 10.9%
Very High: 10–24.5% Class V: >125 points
these comorbidities can obtain only 1 point.
BPM, beats per minute; mm Hg, millimeters of mercury.
Fibrinolytic therapy reverses right ventricular dysfunction and restores pulmonary
perfusion more rapidly than anticoagulant therapy alone. It is generally reserved for
patients with a high risk for mortality and a low risk for bleeding.
catheter-directed treatment provides localized delivery of fibrinolytics to the
pulmonary thrombi and is an alternative invasive method for removal of pulmonary
emboli. It is a less invasive approach compared to surgical embolectomy in patients
has emerged as a promising option for patients who would also be candidates for
systemic fibrinolytic therapy.
Transition from Injectable Anticoagulant Therapy
CASE 11-5, QUESTION 3: If A.W. is to start on warfarin, rather than a DOAC, when should it be
administered, and how should the transition from injectable anticoagulant therapy be accomplished?
As in the treatment of DVT, if warfarin is to be started, the use of heparin, LMWH,
or fondaparinux therapy for PE treatment should be continued for at least 5 days and
until warfarin therapy is therapeutic for at least 24 hours. Warfarin should be started
on the first day of treatment and continued for 3 months, or longer if indicated.
However, a delay in the initiation of warfarin may be acceptable in the setting of an
anticipated extended hospitalization, recent or anticipated surgery or other invasive
procedures, or a medical condition with the potential for uncontrolled bleeding.
There are several reasons to overlap heparin/LMWH/fondaparinux and warfarin
6 The onset of warfarin activity depends not only on its inherent
pharmacokinetic characteristics (half-life > 36 hours), but also on the rate of
elimination of circulating clotting factors. Although warfarin inhibits production of
the vitamin K dependent clotting factors, previously synthesized clotting factors must
be eliminated at rates that correspond with their elimination half-lives (Table 11-8).
Approximately four half-lives are required for these factors to reach a new steady
state after their production is inhibited, so the effect of warfarin can be delayed for
several days. Initial increases in the INR reflect only reductions in factor VII activity,
but full anticoagulation with warfarin requires adequate suppression of factors II and
X, which have significantly longer elimination half-lives. By overlapping a quick
onset injectable anticoagulant such as heparin/LMWH/fondaparinux with warfarin
therapy, adequate anticoagulation can be continued until warfarin therapy reaches a
In addition to suppressing the synthesis of the vitamin K-dependent clotting factors,
warfarin also inhibits the formation of the naturally occurring anticoagulant protein C
and its cofactor, protein S. In patients with congenital protein C or protein S
deficiency, initial warfarin therapy can suppress these proteins to concentrations that
may result in hypercoagulability with possible thrombus extension, unless concurrent
heparin therapy provides adequate anticoagulation. To prevent these complications,
heparin/LMWH/fondaparinux and warfarin therapy should overlap.
Heparin therapy has been observed to prolong the INR,
69 Thus, interference with laboratory tests should be
considered in the evaluation of the intensity of anticoagulation during the overlap of
Initiation of Warfarin Therapy
What are more effective approaches to initiating therapy?
Initiation of warfarin dosing is complex because dosing requirements vary
significantly among individuals. Daily doses as low as 0.5 mg and as high as 20 mg
or more may be required in individual patients to reach a therapeutic INR.
primary methods for initiation of warfarin therapy are used.
dosing method relies on an understanding that although dosing requirements for
warfarin vary significantly among patients, an average dosing requirement of 4 to 5
mg/day of warfarin is necessary to maintain an INR of 2.0 to 3.0 in most patients.
When average daily dosing is used for initiation of warfarin therapy, patients are
typically started at 4 to 5 mg daily, with dosing adjustments as necessary until the
therapeutic goal is reached. However, patients who may be more sensitive to the
effects of warfarin (Table 11-17) are expected to require lower dosages of warfarin.
In these patients, therapy should be initiated at 1 to 3 mg daily, with subsequent
dosing adjustments as necessary. Several dosing algorithms, using a 4-mg to 5-mg
initiation dose, have been developed to aid with dosing decisions after the first few
doses of warfarin have been administered.
72–74 Another popular dosing algorithm
recommended by the American College of Chest Physicians (ACCP) for outpatients
uses a 10-mg initiation dose for the first 2 days, with the INR on day 3 measured to
guide dosing on days 3 and 4, and the INR on day 5 used to guide the next three
(Fig. 11-4). Although using this dosing algorithm helps achieve a
therapeutic INR more quickly than using a 5-mg initial dose, these findings may not
be generalizable to all patient populations because the patients evaluated were
relatively healthy, young outpatients.
76 The 10-mg initiation dose may lead to
overanticoagulation and heightened bleeding risk in elderly and ill patients with
77 Average daily dosing is often used to initiate therapy in
ambulatory patients; in this case, the first INR should be evaluated within 3 to 5 days
of initiation of warfarin therapy (Table 11-18). In hospitalized patients, it is more
common to evaluate the INR daily during initiation of therapy.
Factors that Increase Sensitivity to Warfarin
Clinical congestive heart failure
Known CYP2C9 or VKORC1 variant
INR, international normalized ratio.
Flexible initiation of warfarin is an alternative approach for starting therapy that is
based on evaluating the rate of increase in the INR and making daily dosing
adjustments based on daily INR evaluation, with a goal of determining the eventual
maintenance dosing requirement. A popular flexible initiation nomogram is presented
78,79 Using this nomogram, warfarin can be initiated with either a 10-
mg or a 5-mg starting dose, with daily dosing adjustments based on the rate of
increase in the INR. Flexible initiation does not necessarily shorten the time to reach
the goal INR, and initiating therapy with a 10-mg dose as described in some
protocols may be associated with an increased risk of early overanticoagulation in
certain patients. Nonetheless, these methods offer a more individualized approach to
outpatient treatment of venous thromboembolism. Pathophysiol Haemost Thromb. 2002;32:131.)
The baseline INR for A.W. was 1.0. Using the flexible initiation protocol
presented in Table 11-19, the first dose of warfarin should be 10 mg administered in
the evening on the first day of hospitalization. Subsequent INR values obtained daily
will guide dosing requirements until a therapeutic INR is reached. The order for
warfarin 10 mg orally every evening for three doses should be discontinued and
replaced with daily orders for warfarin and INR monitoring.
Warfarin Initiation for Outpatients Using the Average Daily Dosing Method
Nonsensitive Patients Sensitive Patients
Initial dose 5 mg daily 2.5 mg daily
<1.5 7.5–10 mg daily 5–7.5 mg daily
1.5–1.9 5 mg daily 2.5 mg daily
2.0–3.0 2.5 mg daily 1.25 mg daily
3.1–4.0 1.25 mg daily 0.5 mg daily
Subsequent dosing and monitoring Continue dose escalation and
frequent monitoring until lower limit
of therapeutic range is reached.
aSee Table 11-17 on factors that increase sensitivity to warfarin.
Flexible Initiation Dosing Protocol for Warfarin Dosing, Including 10-mg and 5-
INR, international normalized ratio.
Source: Crowther MA et al. Warfarin: less may be better. Ann Intern Med. 1997;127:332.
Intensity and Duration of Therapy
CASE 11-5, QUESTION 5: What is the goal INR for A.W. and how long should anticoagulation be
In patients with DVT or PE, warfarin doses that prolong the PT to an INR of 2.0 to
3.0 are defined as regular intensity therapy. This therapeutic range is recommended
to maximize the antithrombotic effect of warfarin while minimizing potential bleeding
complications associated with excessive anticoagulation.
adhere to the blood vessel wall. Thus, the first step in resolution of a thrombus
involves covering the clot with a layer of endothelial cells to prevent additional
platelet aggregation at the site of vessel injury. This endothelialization process
generally takes 7 to 10 days to be completed. Initial anticoagulant treatment is used to
prevent clot extension while allowing adequate endothelialization to occur.
Continued anticoagulation prevents further clotting.
The appropriate duration of warfarin therapy is based on the likelihood of a
recurrent venous thromboembolic event and the risk of bleeding in each patient
(Table 11-9). Patients with unprovoked (idiopathic) DVT or PE should be treated for
at least 3 months, but considered for indefinite therapy as their likelihood of having a
recurrent event can be as high as 30% over 5 years.
associated with transient or reversible risk factors
(provoked VTE) are usually treated for 3 months, as in the case of A.W., whose
VTE provoking risk factor was a prolonged car ride, as the risk of recurrence is
lower (approximately 10% over 5 years). In cancer-associated thrombosis, first-line
treatment consists of long-term LMWH based on improved clinical outcomes over
warfarin; however, this needs to consider individual patient bleeding risk, patient
preferences, tolerability, and drug costs.
80–86 The use of DOACs in patients with
cancer is not currently endorsed; however, current data support its safety compared
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