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initial therapy with a parenteral anticoagulant
(e.g. LMWH) prior to the first dose.
If a VKA is chosen, it should be initiated on
the same day as parenteral therapy is started, and
the parenteral anticoagulant must be continued
for a minimum of 5 days and until the international normalized ratio (INR) is 2.0 or above
for at least 24 hours.
41
Because of this critical
requirement and the need to monitor therapy,
PE patients discharged on a VKA will need very
close follow-up with their outpatient physician or
with an anticoagulation clinic within 2–3 days.
For patients with PE and active cancer,
extended therapy for at least the first 3 months
of treatment with LMWH is preferred over VKA,
rivaroxaban, apixaban, edoxaban or dabigatran.
35
The advent of the direct-acting oral anticoagulants (DOACs) rivaroxaban, apixaban, edoxaban,
and dabigatran has markedly expanded the therapeutic choices for acute PE beyond LMWH and
VKA. Generally, the DOACs have comparable
efficacy to VKAs in terms of preventing recurrent
VTE, fatal PE and overall mortality, but with significantly lower risk of bleeding complications.
42
However, using DOACs does not eliminate the
need for observation stay since some patients
with low-risk PE may still require completion of
their diagnostic evaluation and risk stratification.
Also, devoting resources on effective patient education and ensuring access to medications prior to
disposition are just as important with these newer
agents.
References
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a prospective cohort study.
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D-dimer testing, and computed
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et al. Current diagnosis of
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of the prospective investigation
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22. Le Gal G, Righini M, Boehlen
F, et al. A positive compression
ultrasonography of the lower
limb veins is highly predictive
of pulmonary embolism on
computed tomography in
suspected patients. Thromb
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963–966.
23. Lankeit M, Konstantinides S.
Mortality risk assessment and
the role of thrombolysis in
pulmonary embolism.
Clin Chest Med 2010; 31(4):
759–769.
24. Becattini C, Vedovati MC,
Agnelli G. Prognostic value of
troponins in acute pulmonary
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Circulation 2007; 116(4):
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25. Wicki J, Perrier A, Pemeger
TV, et al. Predicting adverse
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pulmonary embolism: a risk
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26. Uresandi F, Otero R, Cayuela
A, et al. A clinical prediction
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thromboembolism. Arch
Bronconeumol 2007; 43(11):
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27. Murugappan M, Johnson JA,
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Management Exclusion
(HOME) criteria for initial
treatment of acute pulmonary
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Care Med 2008; 177: A182.
28. Nendaz MR, Bandelier P,
Aujesky D, et al. Validation of a
risk score identifying patients
with acute pulmonary
embolism, who are at low risk
of clinical adverse outcome.
Thromb Haemost 2004; 91(6):
1232–1236.
29. Aujesky D, LeManach CD,
et al. Validation of a model to
predict adverse outcomes in
patients with pulmonary
embolism. Eur Heart J 2006;
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30. Otero R, Jimenez D.
Pulmonary embolism at home.
Eur Respir J 2008; 31(3):
686–687; author reply 687.
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RA, et al. Derivation and
validation of a prognostic
model for pulmonary
embolism. Am J Respir Crit
Care Med 2005; 172(8):
1041–1046.
32. Venetz C, Jimenez D, Mean M,
et al. A comparison of the
original and simplified
Pulmonary Embolism Severity
Index. Thromb Haemost 2011;
106(3): 423–428.
33. Konstantinides S, Torkicki A,
Agnelli G, et al. 2014 ESC
Guidelines on the diagnosis
and management of acute
pulmonary embolism.
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35(43): 3033–3069.
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AJ, et al. Antithrombotic
Therapy for VTE Disease:
Antithrombotic Therapy and
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ed: American College of Chest
Physicians Evidence-Based
Clinical Practice Guidelines.
Chest 2012; 141(2 Suppl):
e419S–94S.
35. Kearon C, Akl EA, Ornelas J,
et al. Antithrombotic Therapy
for VTE Disease: CHEST
Guideline and Expert Panel
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36. FDA expands use of Xarelto to
treat, reduce recurrence of blood
clots. November 8, 2012;
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NewsEvents/Newsroom/
PressAnnouncements/
ucm326654.htm. (Accessed
March 2016)
37. Einstein PE Investigators:
Buller HR, Prins MH, Lensin
AW, et al. Oral rivaroxaban for
the treatment of Symptomatic
Pulmonary Embolism. N Engl
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38. Agnelli G, Buller HR, Cohen A,
et al. Oral Apixaban for the
treatment of Acute Venous
Thromboembolism. NEJM
2013; 369(9): 799–808.
39. Hokusai-VTE Investigators:
Buller HR, Decousus H, Gross
MA, et al. Edoxaban versus
Warfarin for the treatment of
Symptomatic Venous
Thromboembolism. NEJM
2013; 369: 1406–1415.
40. Schulman S, Kearon C,
Kakkar AK, et al. Re-Cover
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warfarin in the treatment of
acute venous
thromboembolism. N Engl
JMed2009; 361(24):2342–2352.
41. Kearon C, Akl EA, Comerota
AJ, et al. Antithrombotic
Therapy for VTE Disease:
Antithrombotic Therapy and
David G. Paje
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Prevention of Thrombosis, 9th
ed: American College of Chest
Physicians Evidence-Based
Clinical Practice Guidelines.
Chest 2012; 141(2 Suppl):
e419S–94S.
42. Van Der Hulle T, Kooiman J,
den Exter PL, et al.
Effectiveness and safety of
novel oral anticoagulants as
compared with vitamin
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systematic review and metaanalysis. Journal of Thrombosis
and Haemostasis 2014; 12:
320–328.
Acute Pulmonary Embolism (PE)
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20:59:16
Subpart IVC
Chapter
33
Clinical – Vascular
Anticoagulants
David G. Paje, MD, FACP, SFHM
Introduction
Since its discovery in the mid-1900s, warfarin has
been the predominant anticoagulant used for the
prevention and treatment of thromboembolism
in patients with atrial fibrillation, venous thromboembolic disease (VTE), mechanical heart valves
and other hypercoagulable states. It has a narrow
therapeutic window and highly variable dosing
requirements. Thus, patients must be monitored
closely with regular blood work and dose adjustments to ensure that the international normalized
ratio (INR) of the prothrombin time (PT) is in the
desired range. However, because the optimal INR
range for warfarin is not the same for all indications, rigorous investigations were performed to
establish the most appropriate INR target that
effectively reduces thromboembolic events for
each condition while at the same time minimizing
the risk of clinically significant bleeding. For the
most common indications, nonvalvular atrial
fibrillation (NVAF) and VTE, the target INR is
from 2.0 to 3.0.
Bleeding is the most feared complication
of oral anticoagulant therapy and it is directly
related to the intensity of treatment.
1
Clinical
studies show that warfarin increases the risk of
major bleeding by 0.3–0.5% per year and the risk
of intracranial hemo rrhage (ICH) by 0.2%.
2
Moreover, the rate of bleeding rises sharply as
the INR increases greater than 4.5,
3,4
a level that
is commonly seen in patients undergoing routine
outpatient monitoring of their anticoagulation.
5
In the emergency department (ED), among
patients whose INR values were obtained during
their visit, almost 1 in 10 (11%) had an INR above
5.0.
6
Many of these patients present with gross
bleeding.
6,7
Thus, patients with a supratherapeutic
INR are frequently admitted to the hospital and
are treated as inpatients.
7
However, this practice
may not always be necessary in the light of current evidence particularly on the efficacy and
outcomes of anticoagulation reversal strategies
using vitamin K.
8,9
In the absence of clinically
significant bleeding, patients with excessive anticoagulation due to warfarin may be managed safely
and effectively in the observation or outpatient
setting.
Pharmacology of Warfarin
Warfarin is the most commonly used vitamin
K antagonist (VKA), particularly in the United
States. It interferes with the final step in the hepatic synthesis of biologically active coagulation
proteins, the γ-carboxylation of glutamate residues on the N-terminal regions of vitamin Kdependent factors II, VII, IX, and X. This step is
necessary for the conformational change in the
clotting proteins that allows binding to cofactors
on phospholipid surfaces. The carboxylation process requires the reduced form of vitamin K,
which results from an oxidation-reduction reaction that involves eit her vitamin K epoxide reductase or vitamin K reductase; both of which are
directly inhibited by warfarin, the former more so
than the latter.
Commercially distributed warfarin is a
racemic mixture of two optically active isomers,
the more potent S-enantiomer and the less potent
R-enantiomer. It is highly water soluble and is
rapidly absorbed from the stomach and small
intestines, with a bioavailability of almost 100%.
Its maximal blood concentration is reached about
90 minutes after oral administration. Warfarin is
extensively protein-bound, mainly to albumin;
the free fraction that is pharmacologically active
varies among individuals and is independent of
the total serum concentration. The two isomers of
warfarin are processed in the liver through different pathways; the S-enanti omer is mostly metabolized by the p450 cytoc hrome enzyme CYP2C9,
while the R-enantiomer is primarily oxidized by
two cytochrome enzymes, CYP1A2 and CYP3A4.
037
20:59:38
The racemic mixture of warfarin has a half-life
of 36–42 hours.
10
The onset of warfarin’s anticoagulant effect is
based on the time it takes to sufficiently deplete
the levels of circulating clotting factors, particularly factors II and X. Although the INR may
increase during the first few days after starting
warfarin, this merely reflects a reduction in the
levels of factor VII, which has a shorter half-life of
about 6 hours. Since prothrombin (factor II) has a
longer half-life of about 60–72 hours, effective
anticoagulation may not be achieved until after
at least 5 days of treatment.
10
If higher doses were
used for initiating treatment with warfarin, the
INR may rise more rapidly because of a greater
reduction of factor VII but this will not alter the
time required to reach steady state.
11
The relationship between the dose of warfarin
and its anticoagulant effect is influenced by genetic
and environmental factors that affect its absorption
from the gastrointestinal tract, its metabolism in
the liver and the sensitivity of its pharmacologic
target, vitamin K oxide reductase (VKOR), to its
inhibitory action. Thus, warfarin dosing must be
individualized and periodic adjustments may
be required to keep the INR in the target range.
Among patients who are on long-term treatment
with warfarin, several factors may lead to fluctuations in the INR, including inaccuracies in
INR testing, variable dietary intake of vitamin K,
changesinvitaminKorwarfarinabsorption,
changes in warfarin metabolism, changes in vitamin K-dependent coagulation factor synthesis or
metabolism, effects of concomitant medications,
and patient noncompliance.
12
Because of these,
maintaining optimal anticoagulation with warfarin
may oftentimes be quite challenging. Even in the
ideal setting of a clinical trial, the time-in-therapeutic range (TTR) achieved ranged from 29%
to 75%.
13
Excessive Anticoagulation and
Bleeding Risk
For most clinical indications, the target INR is
either 2.5 or 3.0, with acceptable ranges of
2.0–3.0 or 2.5–3.5, respectively.
14–16
Although
the annual incidence of major bleeding associated
with warfarin is estimated to be only about 1% to
3%,
2
the rate of significant bleeding events rises
steeply when the INR exceeds 4.5.
3,4
In a case-
control analysis of adu lts who suffered ICH while
on warfarin, the rate of ICH was found to double
for every 1-point increase in INR.
17
In addition to the intensity of anticoagulation, other factors may contribute to the bleeding
risk, including the concomitant use of other
drugs that may interfere with hemostasis, prior
bleeding events and advanced age. Several clinical prediction rules have been developed to predict bleeding while taking warfarin for any
indication.
18
One of these, the Modified Outpatient Bleeding Risk Index (mOBRI), has been
independently validated and was found to perform better than physicians’ estimates of the
probability of major bleeding.
19
The mOBRI
includes four independent patient risk factors
for major bleed ing: age >
65 years, history of
gastrointestinal bleeding in the preceding 2
weeks, history of stroke, and at least one of the
following comorbid conditions: recent myocardial infarction, hematocrit < 30%, creatinine
> 1.5 mg/dL, or diabetes mellitus. One point is
counted for every risk factor category and highrisk is defined as >
3 points. For patients
on anti coag ulatio n specifically for NVAF, the
HAS-BLED (Hypertension, Abnormal Renal/
Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, E lderly, Drugs/Alcohol
Concomitantly) score is a well-validated and
widely used tool to assess the risk of major
bleeding.
20,21
Most authors classify bleeding events as either
major or minor (non-major). Major bleeding in
non-surgical patients is defined by the International Society of Thrombosis and Haemostasis
(ISTH) as fatal bleeding, and/or symptomatic
bleeding in a critical area or organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal,
intraarticular, pericardial, intramuscular with
compartment syndrome), and/or bleeding resulting in a drop in hemoglobin level of 2 g/dL or
more or requiring the transfusion of 2 or more
units of red blood cells.
22
The most prevalent site
of anticoagulant-related major bleeding is the gastrointestinal tract, followed by urinary tract, intracerebral, genital tract, and retroperitoneal.
23
Based on a retrospective study, the mortality rate
from major bleeding associated with warfarin was
9.5%.
23
Elderly patients (75 years and older) who
generally have a higher risk of fatal thrombotic
events were also found to have a higher rate of
fatal bleeding, almost exclusively from ICH.
24
Also, the risk of fatal ICH may be related to the
Anticoagulants
037
20:59:38
indication for anticoagulation; it is significantly
more frequent in those taking warfarin for atrial
fibrillation than in those who had VTE.
25–27
Anticoagulation Reversal Strategies
with Vitamin K
The anticoagulant effect of warfarin results from
its inhibition of the oxidation-reduction reaction
that produces the reduced vitamin-K, which is
necessary for the carboxylation of the clotting
factors. This involves a pair of enzymes: vitamin
K epoxide reductase, which is sensitive to warfarin, and vitamin K reductase, which is less
sensitive. Low doses of vitamin K (phytonadione)
can overcome warfarin’s inhibition of vitamin
K epoxide reductase and offset its anticoagulant
effect. Larger doses of vitamin K may in fact lead
to warfarin resistance that may last for 1 week or
more because the vitamin K that accumulates
in the liver becomes available to the warfarininsensitive reductase.
When anticoagulation becomes excessive, the
goal is to promptly reduce the risk of bleeding by
using strategies that will bring the INR down to
safe levels while at the same time avoiding overcorrection, which may lead to thromboembolic
complications. Simply withholding warfarin and
allowing the INR to fall into the desired range
is the most widely used approach and results in
low (0.8%) incidence of major bleeding among
patients with a moderate elevation of INR
(6.0–10.0).
28
On the other hand, administration
of either oral or intravenous vitamin K is more
likely to reverse excessive anticoagulation at
24 hours compared to simply withholding warfarin.
29
However, when four randomized controlled trials (RCT) compared vitamin K to
placebo for patients with INR of 4.5–10.0, the
rates of major bleeding (0.8% vs. 2.0%) and
thromboembolism (1.2% vs. 0.9%) were similar
in both groups.
30–33
Therefore, for patients
with an INR of 4.5–10.0 who are not bleeding,
administration of vitamin K may lead to a more
rapid correction of the INR but there is no evidence of benefit in terms of bleeding and thromboembolic outcomes.
When patients with INR values above 9.0 were
studied separately, the 30-day risk of major bleeding was high (9.6%) when vitamin K was not
given routinely.
34
But when 2.5 mg of oral vita-
min K was given to 107 warfarin-treated patients
with INR > 10 but without evidence of bleeding,
the rate of major bleeding by 90 days was low
(3.7%).
9
Also, patients who are administered oral
vitamin K are more likely to have an INR < 5by
day 3 compared to those who only withheld warfarin.
35
Thus, while there are no RCTs to guide
the management of patients with INR > 10.0
without bleeding, using vitamin K may be a prudent option considering the substantial risk
of bleeding.
Oral administration is the most preferred
route of giving vitamin K to reverse anticoagulation in patients w ho are not bleeding. Although
intravenous administration resulted in a more
rapid decline in INR at 6 hours and at 12 hours,
the INR values achieved at 24 hours were similar
for both oral and intravenous routes.
36
Oral
vitamin K at doses of 1–2.5 mg reliably corrects
excessive anticoagulation without causing
warfarin resistance, or anaphylactoid or skin
reactions.
31,37
Intravenous vitamin K is often used in
patients who are bleeding and who need urgent
reversal of anticoagulation. The suggested dose
for serious or life threatening bleeding is 5–10
mg, diluted in a minimum of 50 mL of intravenous fluid and administered over a minimum of 20
minutes.
10,38
This may be repeated if necessary at
12–24 hour intervals because of the long half-life
of warfarin. Anaphylactoid reactions to intravenous vitamin K have been described but are rare,
and are associated with large doses, administered
rapidly and with little dilution.
39
Subcutaneous administration of vitamin K is
less effective when compared to either the oral or
intravenous routes; its absorption is variable and
its effect on INR is unpredictable.
40,41
Finally, the management of excessive anticoagulation in patients with mechanical heart valves
who are not bleeding may be quite challenging.
These patients have a high thromboembolic risk,
particularly with prosthetic valves in the mitral
position or with older valves in either the mitral
or aortic positions. It may be pruden t to adopt an
approach that will minimize the likelihood of
overcorrection and of warfarin resistance.
Direct Oral Anticoagulants
After about half a century of vitamin-K antagonists
as the only available oral anticoagulants, two new
classes of effective alternative oral medications
David G. Paje
037
20:59:38
have emerged. Collectively known as direct oral
anticoagulants (DOACs), these new agents are
rapidly acting, target-specific and have predictable
anticoagulant effects, thus eliminating the need
for routine monitoring. Dabigatran is a direct
prothrombin inhibitor and has been approved to
reduce the risk of stroke and systemic embolism
in NVAF, to treat and prevent recurrence of VTE,
and to prevent VTE after hip arthroplasty. Rivaroxaban, apixaban, and edoxaban are direct Factor
Xa (FXa) inhibitors and are all indicated in
patients with NVAF and VTE. In addition, both
rivaroxaban and apixaban are approved for VTE
prevention after hip or knee arthroplasty.
The DOACs are now the preferred anticoagulant of choice for most patients. Compared to
warfarin, DOACs showed significant reductions
in the risk of stroke, ICH and mortality in
patients with NVAF, with similar risk of major
bleeding and increased risk of gastrointestinal
bleeding.
42
Among those with VTE, DOACs
are at least as effective as VKAs in preventing
recurrent VTE, fatal PE and overall mortality
but with significantly lower rates of bleeding
complications.
43
When bleeding occurs in patients taking
DOACs, the severity of bleeding and the timing
of the last dose taken are the key considerations in
initial management. If the bleeding is non-major
and is adequately controlled without using reversal agents, the patient may be placed in observation for continued monitoring. The DOACs have
relatively short half-lives and with normal renal
function, their anticoagulant effect should resolve
24–48 hours after the last dose.
44
Patient Selection
Most warfarin-treated patients with excessive
anticoagulation who are not bleeding may be
managed in the outpatient setting (Figure 33.1)
with either dose adjustments alone (for INR
< 4.5), simp ly withholding warfarin (for INR
4.5–10.0), or administering low-dose oral vitamin
K (for INR > 10.0). Observation care may be a
reasonable alternative for those who have an
unacceptably high bleeding risk from a combination of a high INR > 10.0 and the presence of
other independent risk factors for major bleeding.
Although clinical prediction tools have been
developed to estimate bleeding risk in patients
receiving anticoagulants, none has been proposed
to predict bleeding specifically in patients with
excessive anticoagulation.
Patients on DOACs who experience nonmajor bleeding that is adequately controlled without using reversal agents are also appropriate
candidates for observation care. On the other
Patient with excessive anticoagulation or
supratherapeutic INR while on warfarin
INR < 4.5
NO BLEEDING
4.5 < INR < 10
NO BLEEDING
INR > 10
NO BLEEDING
ANY INR
W/ SIGNIFICANT
BLEEDING
· Adjust dose or hold
warfarin
· Resume warfarin at a
lower dose once
INR is in therapeutic
range
· Hold warfarin
· Resume warfarin at a
lower dose once
INR is in therapeutic
range
· Hold warfarin
· Give oral vitamin K
2.5 mg
· INR should
substantially drop
within 24 hours
· Resume warfarin at a
lower dose once
INR is in therapeutic
range
· Hold warfarin
· Give intravenous
vitamin K 10 mg
by slow infusion
· Give Fresh Frozen
Plasma (FFP) or
Prothrombin
Complex
Concentrate (PCC)
· Resume warfarin at a
lower dose once
INR is in therapeutic
range
Figure 33.1 Algorithm for Managing Excessive Anticoagulation
Anticoagulants
037
20:59:38
hand, DOAC patients who present with major
bleeding or who require the use of reversal agents
should be managed in the inpatient setting.
Observation Care
Patients on warfarin treatment with an INR > 10
and without evidence of bleeding should have
their dose withheld until after their INR is back
in the therapeutic range. Also, they should be
given oral vitamin K at a dose of 2.5 mg preferably while in the ED. Because there is a delay in
clotting factor synthesis following oral vitamin
K replacement, those patients who have other risk
factors for major bleeding in addition to the elevated INR may be monitored closely so that more
aggressive reversal measures can be instituted
promptly when signs and symptoms of significant
bleeding develop. Their INR may be repeated at
24 hours, at which time it is expected to fall to
safer levels if hepatic function is normal, but not
necessarily to the ideal therapeutic range. After
discharge from observation care, patients should
be followed very closely within a couple of days
by their anticoagulation physician, particularly
those with challenging issues such as mechanical
heart valves.
A non-major bleeding episode in a patient
taking a DOAC should be controlled promptly
without the need for any reversal agent. Initial
observation management includes hol ding or discontinuing succeeding doses of the anticoagulant,
reviewing concomitant medications that may also
affect hemostasis, evaluating renal function and
managing hydration status. There is currently no
readily available laboratory test that can specifically measure the anticoagulant activity of DOACs.
However, common coagulation assays may be
used to roughly gauge the anticoagulant effect of
DOACs. The activated partial thromboplastin
time (aPTT) is prolonged when there is an anticoagulant effect of dabigatran, but the aPTT may
be normal even when the plasma level of dabigatran is elevated. Similarly, the PT is prolonged
when there is an anticoagulant effect of FXa
inhibitors, but a normal PT does not rule out
elevated levels of FXa inhibitors.
45
Since all the DOACs are at least partially
eliminated through the kidneys, assessing the
renal function (using Cockcroft-Gault method)
is necessary in approxim ating the resolution
of their anticoagulant effect. In patients with
normal renal function, dabigatran and FXa
inhibitors should be eliminated 2–3daysand
1–2 days, respectively, after the last dose. Thus,
patients may be di scharged from observation care
if they remain clinically stable after 24–48 hours
of monitoring.
Finally, patients who are seen in observation
for complications related to anticoagulation
should have an individualized reassessment of
the benefits of continued treatment versus the risk
of bleeding. This is also a good time to reconsider
their options for anticoagulant therapy.
Collaborating with the primary care provider or
the physician responsible for managing their
anticoagulation may be necessary when discussing these issues with the patient.
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