Vous êtes sur la page 1sur 16

Anticoagulants

J e rro ld H . L e v y

Anticoagulants are drugs that delay or prevent the clotting of blood. In a perioperative setting,
patients receive anticoagulation for cardiovascular procedures, thromboprophylaxis, or for
cardiovascular disease and/or atrial fibrillation. Th e therapeutic potential of anticoagulation must
be considered against risks for increased bleeding. Many agents are also used in the perioperative
setting that may not be routinely monitored, including drugs such as low-molecular-weight heparin,
new oral anticoagulants that include direct thrombin inhibitors (dabigatran [Pradaxa] and factor Xa
inhibitors rivaroxaban [Xarelto] and apixaban), or newer platelet inhibitors. Th is chapter will
review the different anticoagulation agents, including antiplatelet agents, and considerations for
their use in the perioperative use. Th e agents most commonly used will be considered in detail.
Guidelines for management are published about every 4 years by the American College of Chest
Physicians (ACCP) and should be referred to for more detail.1–9

H e p a r in

Unfractionated heparin (UFH) is an extract of porcine intestine or bovine lung, where heparin is
stored in the mast cells. It is a mixture of highly sulfated glycosaminoglycans with molecular weights
ranging from 3,000 to 30,000 daltons that produce their anticoagulant effects by binding to
antithrombin (AT) (previously known as antithrombin III), a circulating serine protease. Heparin
acts as an anticoagulant by binding to AT, enhancing the rate of thrombin–AT complex formation
by 1,000 to 10,000 times. Other factors in the clotting cascade, including factor Xa but also XII, XI,
and IX are also inhibited by AT.10 Anticoagulation thus depends on the presence of adequate
amounts of circulating AT as shown in the Figure 30-1.
Standardization of heparin potency is based on in vitro comparison with a known standard. A
unit of heparin is defined as the volume of heparin-containing solution that will prevent 1 mL of
citrated sheep blood from clotting
648
for 1 hour aft er the addition of 0.2 mL of 1:100 calcium chloride. Heparin must contain at least 120
United States Pharmacopeia (USP) units per milliliter. Because the potency of different commercial
preparations of heparin may vary greatly, the heparin dosing should always be prescribed in units,
and most heparin is porcine in origin.

P h a r m a c o k in e t ic s
Heparin is a highly charged acidic molecule administered by intravenous (IV) or subcutaneous (SC)
injection. Th e pharmacokinetics of heparin are based on measurements of its biologic activity using
an anti-Xa assay. Over the range of heparin concentrations used clinically, the doseresponse
relationship is not linear for multiple reasons, including the need for AT to potentiate its effect, the
effects of temperature, its highly charged nature that causes protein binding, and the variability of
anticoagulation responses. Th e precise pathway of heparin elimination is uncertain, and the
influence of renal and hepatic disease on its pharmacokinetics is less than with other anticoagulants.
Heparin binds to many different proteins, which can affect its anticoagulant activity and contributes
to heparin resistance.11
C h a p te r 3 0 • A n tic o a g u la n ts 649

L a b o ra t o r y E v a lu a t io n o f C o a g u la t io n
Th e anticoagulant response to heparin varies widely especially in critically ill patients with
alterations in AT and other plasma proteins. Different tests are used to monitor UFH and other
anticoagulants as follows.2

A c t iv a t e d P a r t ia l T h ro m b o p la s t in T im e
Heparin treatment is usually monitored to maintain the ratio of the activated partial thromboplastin
time (aPTT) within a defined range of approximately 1.5 to 2.5 times normal values, typically 30 to
35 seconds. An excessively prolonged aPTT (. 120 seconds) is readily shortened by omitting a dose
because heparin has a brief elimination half-time. When low-dose heparin is used, laboratory tests
may not be required to monitor treatment because the dosage and schedule are well known.
TF/VIIa

X IX

IXa
VIIIa

Va
Rivaroxaban LMWH
AT
Apixaban Xa Fondaparinux
Endoxaban UFH

II
Argatroban AT UFH
Bivalirudin
Dabigatran IIa
Lepirudin
Fibrinogen Fibrin
However, some hospital laboratories have changed to anti-Xa assays instead of aPTT monitoring
because of the variability of responses, with low-dose regimens targeting levels of 0.3 to
0.5 unit/mL and high-dose regimens targeting levels
0.5 to 0.8 unit/mL.

A c t iv a t e d C lo t t in g T im e
At higher heparin concentrations like those typically used during cardiopulmonary bypass, the
activated clotting time is used to monitor anticoagulation. Th e activated clotting time (ACT) is
performed by mixing whole blood with an activating substance that has a large surface area, such
as celite (diatomaceous earth—silicon dioxide) or kaolin (clay—aluminum silicate). Th is is a
contact activation through the classic intrinsic pathway where factor XII initiates activation of the
clotting cascade. Th e activator speeds up the clotting time to normal values of approximately 100
to 150 seconds, depending on the device. Several commercially available timing systems used
clinically to measure the ACT are based on detecting the onset of clot formation. Nevertheless,
results between different commercial devices to measure the ACT may not be interchangeable,
especially if the type of activator (celite or kaolin) is different.
Heparin effect and its antagonism by protamine are commonly monitored in patients
undergoing cardiovascular procedures by measuring the ACT. Because the ACT is easy to use and
reliable for high heparin concentrations (. 1.0 unit/mL), it has become the mainstay of heparin
anticoagulation monitoring in perioperative management and for cardiac catheterization. In
addition to the presence of a heparin effect, the ACT may be influenced by hypothermia,
thrombocytopenia, presence of contact activation inhibitors (aprotinin), and preexisting
coagulation deficiencies (fibrinogen, factor XII, factor VII). With apro-
FIGURE 30-1 The major targets for anticoagulants in the coagulation pathway are directed against either factor X a or thrombin
(IIa). Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) require circulating AT as a cofactor, and only UFH
will inhibit thrombin. Fondaparinux is a synthetic pentasachharide and, like LMWH, indirectly inhibit factor X a, requiring AT as
a cofactor. The direct factor X a inhibitors are AT- independent and include rivaroxaban, apixaban, and endoxaban. Both oral
direct thrombin inhibitors (dabigatran) and IV agents directly inhibit thrombin. Vitamin K antagonists, such as warfarin, inhibit
the activation of factors II, VII, IX , X , as factors are made but are not activated by the posttranslational carboxylation that is
inhibited (mechanism not shown). (From Levy J H, Key NS , Azran MS . Novel oral anticoagulants: implications in the perioperative
setting. Anesthesiology. 2010;113:726–745.)
C h a p te r 3 0 • A n tic o a g u la n ts 650

tinin therapy, the recommendation is to use kaolin-ACT rather than a celite-ACT determination as
kaolin binds to aprotinin to minimize its effect.
For cardiac surgery, a baseline value for the ACT is determined (a) before the IV administration of
heparin, (b) 3 to 5 minutes aft er administration, and (c) at 30-minute intervals, thereaft er. Th e ACT
response to heparin is not linear for multiple reasons, including the need for AT for its effectiveness
and because of several other factors that affect ACT. During cardiopulmonary bypass, the target ACT
value is still controversial but oft en considered adequate if the ACT is longer than 350 seconds,
although most cardiac surgical centers target an ACT of longer than 400 seconds. Th e need to measure
ACT repeatedly is emphasized by the fourfold variation in heparin sensitivity between patients and
the threefold variation in the rate at which heparin is metabolized. Furthermore, ACT values can be
misleading during cardiopulmonary bypass with respect to heparin-induced anticoagulation because
of the effects of hypothermia and hemodilution on the measurement system.12

C lin ic a l U s e s
Heparin is used extensively for multiple purposes including the prevention and treatment of venous
thrombosis and pulmonary embolism, for acute coronary syndromes, and for perioperative
anticoagulation for extracorporeal circulation and hemodialysis. When administered intravenously,
heparin has an immediate onset of action, whereas SC administration results in variable
bioavailability with an onset of action in 1 to 2 hours.

H e p a r in -In d u c e d T h ro m b o c y t o p e n ia
Th rombocytopenia due to UFH is common and can begin within hours in patients exposed to heparin.
However, a more severe and even life-threatening syndrome develops in 0.5% to 6.0% of patients,
manifesting as severe thrombocytopenia (50% drop in platelet count or , 100,000 cells/mm3), that
can be associated with thrombotic events (heparin-induced thrombocytopenia with thrombosis). Th
is severe response typically develops aft er 4 to 5 days of heparin therapy and is caused by heparin-
dependent antibodies to platelet factor IV that trigger platelet aggregation and result in
thrombocytopenia (see the more detailed discussion in Physiology of Hemostasis, Chapter 27
Physiology of Hemostasis).13

A lle rg ic R e a c t io n s
Heparin can cause allergic reactions, but these are rare and present in a manner typical of other
hypersensitivity reactions. In patients that do experience immediate reactions, heparin-induced
thrombocytopenia (HIT) should also be suspected due to the presence of preformed antibodies. Rapid
IV infusion of large doses of heparin usually causes minimal hemodynamic changes.13

R e v e rs a l o f H e p a r in -In d u c e d A n t ic o a g u la t io n w it h P ro t a m in e
Protamine is one of the few agents available for reversing anticoagulation. Protamine is a strongly
alkaline (nearly two-thirds of the amino acid composition is arginine), polycationic, low-molecular-
weight protein found in salmon sperm. Th e positively charged alkaline protamine combines with the
negatively charged acidic heparin to form a stable complex that is devoid of anticoagulant activity. Th
ese heparin–protamine complexes are removed by the reticuloendothelial system. Clearance of
protamine by the reticuloendothelial system (within 20 minutes) is more rapid than heparin
clearance and that may explain, in part, the phenomenon of heparin rebound. The dose of protamine
required to antagonize heparin is typically 1 mg for every 100 units of circulating heparin activity. A
more specific dose of protamine is calculated by heparin-protamine titration. Most clinicians give too
much protamine because they reverse based on the total dose or heparin administered without
accounting for heparin elimination prior to the administration of protamine. Heparin has a half life of
approximately one hour, so determinations of protamine dosing should include considerations of the
circulating heparin level for reversal. (See also “Protamine” in Chapter 29, Procoagulants.)

L o w -M o le c u la r-W e ig h t H e p a r in s
C h a p te r 3 0 • A n tic o a g u la n ts 651

Enoxaparin and dalteparin are two commonly administered low-molecular-weight heparins


(LMWHs) derived from standard commercial-grade UFH by chemical depolymerization to yield
fragments with a mean molecular weight of 4,000 to 5,000 daltons. Depolymerization of heparin
results in a change in its anticoagulant profile, pharmacokinetics, and effects on platelet function.
Compared with heparin, which has an anti-Xa to anti-IIa activity of about 1:1, enoxaparin has a
corresponding ratio that varies between 4:1 and 2:1.14 The pharmacokinetics of enoxaparin and
dalteparin between patients are more consistent than heparin because these drugs bind less avidly to
proteins than heparin. Th is contributes to better bioavailability at low doses. Although protection
against venous thromboembolism (VTE) in high-risk medical and surgical patients is oft en thought
to be better with LMWH than with heparin, LMWH’s effect is greatly prolonged with renal failure and
anticoagulants such as UFH should be used in this population. Th erefore, care should be taken to
delay surgery for 12 hours aft er the last dose of LMWH in patients with normal renal function and
longer with renal dysfunction. Protamine does not neutralize LMWH.2,14

S p in a l a n d E p id u ra l H e m a t o m a s
Th e risk of spontaneous hematoma formation may be increased in the presence of LMWH and
indwelling epidural catheters for administration of postoperative analgesia and by concomitant use
of other drugs that affect hemostasis (nonsteroidal antiinflammatory drugs, platelet inhibitors) and
by traumatic or repeated attempts to accomplish entry into the epidural or subarachnoid space. Th
is increased risk of hematoma formation is a consideration when selecting regional anesthesia in
patients being treated with LMWH preparations. Recommendations for management of patients for
regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy are reported in
American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Th ird
Edition).15

F o n d a p a r in u x

Fondaparinux is a synthetic anticoagulant composed of the five saccharide units that make up the
active site of heparin that binds AT, such as LMWH, to inhibit factor Xa but has no direct activity
against thrombin. Administered subcutaneously, fondaparinux is rapidly absorbed and has an
elimination half-time of 15 hours, allowing for once daily administration. Metabolism does not occur
and the drug is eliminated by the kidneys and should not be used in patients with renal failure.
Clinical uses of fondaparinux include prevention of deep vein thrombosis (DVT) and pulmonary
embolism and as an alternate anticoagulant in patients with HIT. Because of its long duration of
action, it is used primarily in patients with HIT or concerns about sensitization.16
D a n a p a ro id

Danaparoid is a glycosaminoglycuronan that is derived from porcine intestinal mucosa and consists
of a mixture mostly of dermatan sulfate, and chondroitin sulfate. Th is low-molecular-weight
heparinoid compound attenuates fibrin formation principally by binding AT. Elimination of
danaparoid is predominately through the kidneys. Danaparoid is effective in decreasing the
incidence of DVT following total hip arthroplasty and was used for the treatment of HIT; this agent
is no longer available in the United States (it was removed from the U.S. market in 2002 due to a
shortage in drug substance) but is still in use in other countries.

P ro p h y la x is a g a in s t V e n o u s T h ro m b o e m b o lis m
Surgical procedures have been associated with a 20-fold increase in risk for VTE, which is
understandable considering that the majority of surgical patients have one or more risk factors for
developing VTE.17 The incidence of DVT is 10% to 40% among general surgery patients, and higher
still in high-risk surgery patient populations (e.g., orthopedic, thoracic, cardiac, and vascular
surgery).2,3 Fortunately, thromboprophylaxis is known to effectively reduce VTE in a cost-effective
C h a p te r 3 0 • A n tic o a g u la n ts 652

manner.2 However, despite their effectiveness, there are specific challenges regarding the use of
currently recommended anticoagulants.7
To prevent VTE, patients are treated with anticoagulants. Although SC heparin and LMWH are
commonly used, multiple novel agents are also approved for different indications including
fondaparinux, rivaroxaban, and dabigatran with different indications depending on the country.
Enoxaparin and dalteparin are commonly used LMWHs. Before the availability of LMWH, low-dose
heparin, 5,000 units subcutaneously every 8 to 12 hours, was a common regimen. In those with
renal failure or renal dysfunction, heparin and warfarin are the only drugs minimally affected
because of nonrenal clearance.
Among surgical patients, those undergoing total hip replacement are at unique risk for
developing DVT and many of the studies for approval of new anticoagulants have focused on this
group and other orthopedic patients. Th e risk of DVT is more protracted aft er hip surgery than aft
er general surgery, when it usually develops during the first few postoperative days. Th e surgical
technique for hip surgery, which kinks the femoral vein, seems to stimulate proximal DVT in the
operated leg, whereas calf vein thrombosis is more likely to develop in either leg. Another effect
unique to hip surgery is impairment of venous hemodynamics, which may last several weeks in the
operated leg. Indeed, there are significantly fewer venous thromboembolic complications in
patients undergoing elective hip replacement when prophylaxis with LMWH is given for 1 month
rather than only during the hospitalization. VTE is also a common, life-threatening complication of
major trauma. Pulmonary embolism has been observed to occur in 2% to 22% of patients with
major trauma, and fatal pulmonary embolism is the third most common cause of death in patients
who survive the first 24 hours.7,17

D ire c t T h ro m b in In h ib it o rs : P a re n t e ra l A g e n t s

An important class of anticoagulants that high-risk surgery patients at risk for HIT may receive are
the direct thrombin inhibitors, including bivalirudin, argatroban, lepirudin, and desirudin (Table 30-
1). Bivalirudin is also commonly used for cardiac interventional procedures. Th e direct thrombin
inhibitors also vary in their binding affinities for thrombin. Desirudin, lepirudin, and bivalirudin bond
in a bivalent manner to thrombin by interacting with both the catalytic site and fibrinogen-binding
site. Bivalent direct thrombin inhibitors show higher affinity and specificity for thrombin compared
with univalent direct thrombin inhibitors, which bind to the catalytic site only. Direct thrombin
inhibitors vary substantially in their pharmacokinetic properties in terms of half life and metabolism.
Th ere are also differences in immunogenicity between the direct thrombin inhibitors and with 40%
to 70% of patients developing antihirudin antibodies aft er 4 or more days of treatment.18

B iv a lir u d in
Bivalirudin, a synthetic analog of hirudin with a half-life of 25 minutes, has been widely studied in
patients with and without acute coronary syndromes undergoing percutaneous coronary
intervention (PCI). Th is agent is indicated for use in patients with unstable angina undergoing
percutaneous transluminal coronary angioplasty (PTCA); in patients with or at risk for HIT or HIT
with thrombosis syndrome (HITTS) undergoing PCI; and with provisional use of glycoprotein (GP)
IIb/IIIa inhibitors in patients undergoing PCI. Although it is a polypeptide, bivalirudin is considered a
safe anticoagulant in patients with HIT. In patients with HIT antibodies undergoing cardiopulmonary
bypass, bivalirudin provided safe and effective anticoagulation, with a 94% success rate for the
procedures.19 Further, multiple studies have demonstrated its application as a heparin replacement
in patients who are HIT positive and require on or off pump cardiac surgery, although this is an off-
label use for the drug.19–21

A rg a t ro b a n
Argatroban is an injectable, synthetic, univalent direct thrombin inhibitor indicated for prophylaxis
or treatment
C h a p te r 3 0 • A n tic o a g u la n ts 653

Indications Recommended Time to Stop before


Drug Dose Clinical Status Current (Future) Monitoring Surgery

Bivalirudin Intravenous Available in • PCI in patients ACT 4–6 h


United States, with HIT
Europe, and • PTCA
Canada • Cardiac surgery
(Canada)
• Acute coronary
syndromes
(Europe)
Argatroban Intravenous Available in United • Prophylaxis and aPTT 4–6 h States and Europe treatment
of ACT (PCI)
thrombosis in
HIT
• PCI in patients
with HIT
Lepirudin Intravenous Available in United • HIT and aPTT 24 h: Lepirudin
States and Europe prevention of and desirudin are
further VTE irreversible thrombin
inhibitors.
Desirudin Subcutaneous Available in United • Total hip aPTT 24 h
States and arthroplasty Europe
for hip • (HIT)
arthroplasty
Ximelagatran Oral No longer in clinical None
development
Dabigatran Oral Available in United • Total hip Thrombin 48 hours with noretexilate States for stroke or knee
times, aPTT mal renal function;
prevention for arthroplasty 72–96 h or more if atrial fibrilla- • VTE abnormal
renal function; approved • Atrial tion. Drug effects can in Europe and fibrillation
actually be measured
Canada for hip as noted and potenand knee arthro- tially can be used
plasty. to guide decision
making.

Table 30-1

ACT, activated clotting time; aPTT, activated partial thromboplastin time; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary
intervention; PTCA, percutaneous transluminal coronary angioplasty; VTE, venous thromboembolism.
of thrombosis in patients with or at risk of HIT undergoing PCI. It has a relatively short half-life of 40
to 50 minutes, and anticoagulation returns to baseline when stopping it aft er approximatrly 4
hours.22 Patients with HIT are likely to have renal dysfunction and most of the agents used for HIT are
all primarily renally eliminated. Argatroban is hepatically eliminated, thus no dose adjustments are
required in patients with renal impairment. As lepirudin is renally eliminated and bivalirudin is
partially ( 20%) renally eliminated, their use may require dose adjustment in renally impaired
patients to avoid accumulation. Antibodies to argatroban have not been detected
aft er prolonged or repeated use due to its low molecular weight.23

L e p ir u d in a n d D e s ir u d in
Lepirudin and desirudin are recombinant hirudins, synthetic analogs of hirudin, the direct thrombin
inhibitor first isolated from leeches as Hirudo medicinalis is the name of the leech. Th ese proteins
C h a p te r 3 0 • A n tic o a g u la n ts 654

are manufactured by recombinant methods. Lepirudin is approved for use in patients with HIT and
associated thromboembolic disease to prevent further thromboembolic complications.
Lepirudin was initially reported for cardiac surgical patients; however, bleeding was a major
problem due to its ability to irreversibly inhibit thrombin. HIT patients receiving lepirudin generate
antibodies and require close monitoring (using aPTT) to avoid bleeding complications. In patients
with renal dysfunction the drug may have a prolonged half-life.16,23
Desirudin (another recombinant hirudin) is approved for use in Europe and now in the United
States for the prevention of VTE aft er total hip or knee replacement surgery and has been studied
extensively in patients with stable angina or acute coronary syndromes undergoing PTCA.
Antigenicity and anaphylaxis are also reported, although the risk of hypersensitivity to desirudin
appears relatively low. Because desirudin is primarily eliminated by the kidneys, patients with renal
impairment require monitoring and the aPTT can be used.16

O ra l A n t ic o a g u la n t s

V it a m in K A n t a g o n is t s —W a r f a r in
Oral anticoagulants are derivatives of 4- hydroxycoumarin (coumarin). Warfarin is the most
frequently used anticoagulant because of its predictable onset and duration of action and its
excellent bioavailability aft er oral administration (Table 30-2). Treatment usually begins with an
oral warfarin dose of 5 to 10 mg, and the average maintenance dose is 5 mg; however, the dose
varies widely among individuals due to pharmacogenetic differences. Warfarin has been the only
oral agent available until the recent approval of new agents that are described in the sections that
follow. Disadvantages of warfarin include delayed onset of action, the need for regular laboratory
monitoring, and difficulty in reversal should a surgical procedure create concern about bleeding.3

Mechanism of Action
Warfarin inhibits vitamin K epoxide reductase that converts the vitamin K–dependent coagulation
proteins ( factors II [prothrombin], VII, IX, and X) to their active form, a posttranslational
modification. Th e anticoagulant effect of oral or IV warfarin is delayed for 8 to 12 hours, reflecting
the onset of inhibition of clotting factor synthesis and the elimination half-time of previously formed
clotting factors that are not altered by the oral anticoagulant. Peak effects of warfarin do not occur
for 36 to 72 hours.3

P h a r m a c o k in e t ic s
Warfarin is rapidly and completely absorbed, with peak concentrations occurring within 1 hour aft
er ingestion. It is 97% bound to albumin, and this contributes to its negligible renal excretion and
long elimination half-time of 24 to 36 hours aft er oral administration. Warfarin, however, does
cross the placenta and produces exaggerated effects in the fetus, who has limited ability to
synthesize clotting factors. Warfarin is metabolized to inactive metabolites that are conjugated with
glucuronic acid and ultimately excreted in bile (enterohepatic circulation) and urine.

L a b o ra t o r y E v a lu a t io n
Treatment with oral anticoagulants is best guided by measurement of the prothrombin time. The
prothrombin time is particularly sensitive to three of the four vitamin K– dependent clotting factors
(prothrombin and factors VII and X). Commercial prothrombin time reagents vary markedly in their
responsiveness to warfarin-induced decreases in clotting factors. Therefore, prothrombin time
results obtained with different reagents are not interchangeable between laboratories. Th is problem
of variability in the responsiveness of prothrombin time reagents has been overcome by the
introduction of a standardized system of reporting known as the international normalized ratio (INR).
Each manufacturer assigns a specific value that indicates how a particular batch of tissue factor
compares to an international reference tissue. Th e INR is the ratio of a patient’s prothrombin time to
a normal (control) sample, adjusted by the factor assigned by the manufacturer for the batch of factor
being used in the assay. For most indications, a moderate anticoagulant effect with a targeted INR of
2.0 to 3.0 is appropriate, including prosthetic valve prophylaxis. An excessively prolonged
prothrombin time is not readily shortened by omitting a dose because of the long elimination half-
C h a p te r 3 0 • A n tic o a g u la n ts 655

time of oral anticoagulants. Likewise, an inadequate therapeutic effect is not readily corrected by
increasing the dose because of the delayed onset of therapeutic effect.
Unexpected fluctuations in the dose response to warfarin may reflect changes in diet, undisclosed
drug use, poor patient compliance, surreptitious self-medication, or intermittent alcohol
consumption. Concomitant medication with over-the-counter and prescription drugs can augment or
inhibit the anticoagulant effect of coumarin drugs on hemostasis or interfere with platelet function.
Patients receiving coumarin drugs are sensitive to fluctuating levels of dietary vitamin K, which is
obtained predominantly from leafy green vegetables. Th e effect of coumarin can be potentiated in
sick patients with poor vitamin K intake, particularly if they are treated with antibiotics and IV fluids
without vitamin K supplementation. Preexisting liver disease and advanced age are associated with
enhanced effects of oral anticoagulants.3,24

C lin ic a l U s e s
Vitamin K antagonists (VKAs) are effective in the prevention of VTE, the prevention of systemic
embolization and resultant stroke in patients with prosthetic heart valves or atrial fibrillation, and for
treatment of patients with thrombophilia who are hypercoagulable. Because of the extensive new
range of oral anticoagulants for
C hto
Indications: Time a pStop
te r 3before
0 • A n tic
Drug u la n ts 656
o a gAdministration
Clinical Status Current (Future) Monitoring Elective Surgery

Apixaban Oral Phase III


(Atrial fibrillation) None Not yet approved;
(DVT) should be similar
(Acute coronary to rivaroxaban; syndrome) half-life
12 h
(Total knee
arthroplasty)
Danaparoid Intravenous or No longer Treatment of HIT; Calibrated No longer
available subcutaneous available thrombopro- plasma
phylaxis in HIT anti-Xa
patients activity
Low-molecular- Intravenous or Available in Multiple: throm- Plasma anti-Xa At least 12 h before weight heparin
subcutaneous Canada, boprophylaxis, activity surgery; longer if
(LMWH) Europe, and acute coronary renal dysfunction United States
syndromes as elimination is
prolonged, not
reversible
Fondaparinux Intravenous or Available in Thrombopro- Calibrated Long half-life of
subcutaneous Canada, phylaxis and plasma 17–21 h, should
Europe, and treatment of anti-Xa be stopped at least
United States pulmonary activity 2 d, longer if renal
embolism dysfunction
Rivaroxaban Oral Available in Total hip or knee None current At least 24 h based
Canada, arthroplasty on prescribing
Europe, and (Treatment of information, but
United States DVT and PE) drug half-life may
(Atrial fibrillation) be prolonged with
(Acute coronary renal dysfunction syndromes) and
recommend
holding 48 h
preoperatively
with normal renal
function and
longer if
abnormal.
Unfractionated Intravenous or aPTT, hepa- 4–6 h before the proheparin subcutaneous rin levels cedure if possible
(plasma but may need to
anti-Xa) continue for cardio-
vascular surgery;
also reversible
with protamine
Warfarin Oral and intra- Anticoagulation Prothrombin 5 days before venous for multiple
time/INR procedure to allow reasons and INR , 1.5; patients treatment of
may require bridgthrombophilia ing with heparin

Table 30-2

aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; HIT, heparin-induced thrombocytopenia; INR,
international normalized ratio; PE, pulmonary embolism.
C h a p te r 3 0 • A n tic o a g u la n ts 657

perioperative VTE prophylaxis, these agents are used less and less for this indication.

M a n a g e m e n t b e f o re E le c t iv e S u rg e r y
In patients receiving a VKA, the INR should be checked preoperatively. Although minor surgical
procedures can be safely performed in patients receiving oral anticoagulants, for major surgery,
discontinuation of oral anticoagulants 1 to 3 days preoperatively is recommended to permit the
prothrombin time to return to within 20% of its normal range. Th is approach, followed by reinstitution
of the oral anticoagulant regimen 1 to 7 days postoperatively, is not accompanied by an increased
incidence of thromboembolic complications in vulnerable patients. However, patients at high risk, such
as those with prosthetic heart valves, may require bridging with UFH.3
Bleeding is the main complication of any anticoagulant therapy, including the VKAs. Th e risk of
bleeding is influenced by the intensity of the anticoagulant therapy, the patient’s underlying disorder,
and the concomitant use of aspirin. Bleeding that occurs when the INR is less than 3.0 are frequently
associated with an obvious underlying cause (neoplasm, peptic ulcer). Th ese drugs may increase the
incidence of intracranial hemorrhage aft er a cerebrovascular accident. Compression neuropathy has
been observed in treated patients aft er brachial artery puncture to obtain a sample for blood gas
analysis. Treatment of bleeding depends on the severity and underlying patient and location. In
emergency situations, oral or IV administration of vitamin K is used but will not immediately reverse
the anticoagulant effect. If immediate reversal is needed, for performance of high-risk surgical
procedures such as craniotomy, administration of prothrombin complex concentrates (PCCs) is needed
if available or other reversal strategies as defined in Chapter 29 (Procoagulants). 3,25 Guidelines for
perioperative management are available.1

N e w O ra l A g e n t s
For many years, warfarin has been the only oral anticoagulant available but has variabilities regarding
dosing and effects and requires frequent monitoring and may take up to 5 days before therapeutic
levels can be obtained. Th e newer therapeutic agents have a rapid onset with therapeutic
anticoagulation within hours of administration and do not need routine monitoring. Dabigatran is an
oral direct thrombin inhibitor, and rivaroxaban is a direct factor Xa inhibitor similar to LMWH. 16 Both
of the newer agents require dose adjustments for renal failure and will be considered separately, along
with agents still under investigation.9,16 (Table 30-2)

D ire c t F a c t o r X a In h ib it o rs
Rivaroxaban (Xarelto)
Rivaroxaban is an oral, direct factor Xa inhibitor with . 10,000-fold greater selectivity for factor Xa than
for other related serine proteases. In contrast to LMWH and similar agents, rivaroxaban does not
require AT as a cofactor. Direct factor Xa inhibitors, including rivaroxaban, can inhibit free factor Xa,
clot-bound factor Xa, and factor Xa bound to the prothrombinase complex unlike indirect factor Xa
inhibitors, such as fondaparinux, which are unable to inhibit factor Xa within the prothrombinase
complex. Rivaroxaban is also a non-heparin-like molecule that may be suitable for the management of
patients with HIT. Rivaroxaban has been approved for the reduction of risk of stroke and systemic
embolism in nonvalvular atrial fibrillation, prophylaxis of deep vein thrombosis following hip or knee
replacement surgery, treatment of DVTs, treatment of pulmonary embolism (PE), and reducing the risk
of recurrence of DVTs and PE.9,16
When used with neuraxial anesthesia, an epidural catheter should not be removed earlier than 18
hours aft er the last administration of rivaroxaban, and the next rivaroxaban dose should be administered
no earlier than 6 hours aft er the removal of the catheter and as noted in the manufacturer’s package
insert.

Apixaban
Apixaban is another oral, direct factor Xa inhibitor administered twice daily. Like rivaroxaban, apixiban
is approved for the reduction of risk of stroke and systemic embolism in nonvalvular atrial fibrillation,
C h a p te r 3 0 • A n tic o a g u la n ts 658

prophylaxis of deep vein thrombosis following hip or knee replacement surgery, treatment of DVTs,
treatment of pulmonary embolism (PE), and reducing the risk of recurrence of DVTs and PE.

Other Direct Factor Xa Inhibitors under Investigation Several other direct factor Xa inhibitors are under
investigation and are approved in certain countries. Edoxaban is being evaluated for atrial fibrillation and
DVT prophylaxis.

D ire c t T h ro m b in In h ib it o rs
Ximelagatran
Ximelagatran is an oral, direct thrombin inhibitor that was approved in Europe for the VTE prophylaxis
but later withdrawn from the market in 2006 due to concerns over potential liver toxicity. However,
ximelagatran provided proof of principle that oral agents that act via direct inhibition of thrombin were
an effective mode of action for new anticoagulants.16

Dabigatran Etexilate (Pradaxa)


Dabigatran etexilate is an oral, direct thrombin inhibitor approved to reduce the risk of stroke and
systemic embolism in patients with non-valvular atrial fibrillation, for the treatment of DVT and PE in
patients who have been treated with a parenteral anticoagulant for 5-10 days, and to reduce the risk of
recurrence of DVT and PE in patients who have been previously treated. Dabigatran’s effects can be
measured best by thrombin times and also by aPTT values, although thrombin times are preferred. 9
Administration of the first dose should occur a minimum of 2 hours aft er the catheter is removed, and
patients should be observed for neurologic signs and symptoms.9,16 Dosing should also be adjusted for
patients with renal dysfunction.

P e r io p e ra t iv e M a n a g e m e n t o f t h e N e w O ra l A n t ic o a g u la n t s
Th e newer therapeutic agents have a rapid onset with therapeutic anticoagulation within hours of
administration and do not need routine monitoring. Dabigatran is an oral direct thrombin inhibitor, and
rivaroxaban is a direct factor Xa inhibitor similar to LMWH.16 Both of the newer agents require dose
adjustments for renal failure.16 One of the new challenges with use of these agents is how to manage
patients perioperatively. In the United States, warfarin is still a problem for clinicians because the PCCs
effective for immediate INR reversal are not available.25 Vitamin K takes days to work; use of 4 units of
fresh frozen plasma (FFP) is oft en used, but associated with transfusion risk and volume overload, and
FFP never restores the INR to baseline, but usually to approximately 1.4 to 1.6 which is the baseline INR
for FFP.25
Th e French Study Group on thrombosis and hemostasis has proposed perioperative management
strategies regarding the risk of bleeding and thrombosis for the new agents. Th e newer oral
anticoagulants may increase surgical bleeding, they have no validated antagonists, they cannot be
monitored by simple standardized laboratory assays, and their pharmacokinetics vary significantly
between patients.26 For procedures with low hemorrhagic risk, a therapeutic window of 48 hours (last
administration 24 hours before surgery, restart 24 hours aft er) is proposed. For procedures with medium
or high hemorrhagic risk, they suggest stopping therapy 5 days before surgery to ensure complete
elimination in all patients. Treatment should be resumed only when the risk of bleeding subsides. In
patients at high thrombotic risk (e.g., those in atrial fibrillation with a history of stroke), bridging with
heparin (LMWH, or UFH, if the former is contraindicated) is proposed. In an emergency, the procedure
should be postponed for as long as possible (minimum 1 to 2 half-lives) and nonspecific antihemorrhagic
agents, such as recombinant human activated factor VIIa or PCCs should not be given for prophylactic
reversal due to their uncertain benefit-risk.26
Although routine monitoring of the new anticoagulants is not standard, if needed they are best
evaluated with specialized tests. For dabigatran, thrombin clotting time (TT), ecarin clotting time (ECT),
and activated partial thromboplastin time (aPTT) can measure its effects.27 Prothrombin time (INR) is
not recommended. Th e aPTT, a standard test, can provide a useful qualitative assessment of
anticoagulant activity but is less sensitive at supratherapeutic dabigatran levels and limited data exists
for activated clotting time (ACT). Overall, the aPTT and TT are the most accessible qualitative methods
for determining the presence or absence of anticoagulant effect. Although there is no specific antidote to
C h a p te r 3 0 • A n tic o a g u la n ts 659

antagonize the anticoagulant effect of dabigatran, because of its short duration of effect, drug
discontinuation should be considered as previously noted. With overdose, dabigatran can also be dialyzed
in patients with renal impairment. In instances of life- threatening bleeding, where conventional
measures have failed or are unavailable, other prohemostatic agents such as recombinant activated factor
VII and PCCs can be considered.27 For rivaroxaban, prolongation of most standard hemostatic tests are
too variable and specialized tests evaluating anti-Xa are required.28 Recent data also suggests PCCs
completely reverse the anticoagulant effect of rivaroxaban in healthy subjects but have minimal effects
on dabigatran at the PCC doses of 50 IU/kg used in the study.29
In summary, for those who require urgent surgery, managing patients who receive dabigatran,
rivaroxaban, and other novel oral anticoagulants is still not well defined. Risk versus benefit should be
considered in logical decision making. It is important to note the therapies for reversal are off-label uses
from the literature as referenced but provide important perspective for perioperative management for
the clinician faced with managing patients receiving these agents.

P la t e le t In h ib it o rs

A s p ir in
Antiplatelet agents are the mainstay therapy for patients with atherosclerotic vascular disease and
coronary artery disease, therapy consistent with the role of platelets in atherosclerosis. 30 Treatment
with aspirin reduces the incidence of occlusive arterial vascular events. Aspirin irreversibly acetylates
cyclooxygenase and thereby prevents formation of thromboxane A2. Despite rapid clearance from the
body, the effects of aspirin on platelets are irreversible and last for the life of the platelet, 7 to 10 days.
Th e ACCP’s widely quoted guidelines suggest in patients who require temporary interruption of
aspirin- or clopidogrelcontaining drugs before surgery or a procedure, stopping this treatment 7 to 10
days before the procedure is recommended over stopping this treatment closer to surgery. In patients
who have had temporary interruption of aspirin therapy because of surgery or a procedure, resuming
aspirin approximately 24 hours (or the next morning) aft er surgery when there is adequate hemostasis
is recommended instead of resuming aspirin closer to surgery.1

T h ie n o p y r id in e s : C lo p id o g re l, P ra s u g re l, a n d T ic a g re lo r

Clopidogrel Prasugrel Ticagrelor Aspirin

Drug Class Th ienopyridine Thienopyridine Thienopyridine Acetylsalicylate


Mechanism of Selective, irreversible Selective, irrevers- Selective, reversible Cyclooxygenase
Action binding to and inhibi- ible binding to and binding to and inhibition tion of P2Y12 receptor inhibition
of P2Y12 inhibition of P2Y12 on platelets receptor on platelets receptor on platelets
Comments Prodrug, metabolized Prodrug, metabolized Direct-acting agent Active drug but to
active form by two to active form one resistance can different metabolic
metabolic step, occur, likely due steps, resistance due to more potent and to
absorption and
metabolism resistance rare other factors
C h a p te r 3 0 • A n tic o a g u la n ts 660

Currently approved thienopyridines include clopidogrel (Plavix), prasugrel (Effient), and ticagrelor. Th
e first two agents are prodrugs requiring in vivo metabolism each to an active metabolite as shown in
Table 30-3. Ticlopidine is now rarely used clinically and will not be considered. Th ienopyridines
irreversibly bind to P2Y12 receptors thereby blocking adenosine diphosphate (ADP) binding. Th is P2Y12
Table 30-3

receptor antagonism inhibits ADP-mediated platelet activation and aggregation due to the critical role
ADP plays in platelet function. When ADP is secreted from internal stores, it amplifies platelet responses
induced by other platelet agonists to increase activation, an internal to external signaling mechanism.31
Th e ADP-induced signal is again mediated by P2Y receptors, which are G-coupled 7-membrane-
spanning proteins that are present in many different cells.31 Th ere are multiple other P2Y receptor
subgroups, but the Gi-coupled P2Y12 receptor mediates inhibition of adenylyl cyclase and amplifies the
platelet aggregation response.31
Dual antiplatelet therapy—a thienopyridine (ADP P2Y12 receptor antagonist) coadministered with
aspirin— is commonly used for improving clinical outcomes in patients with acute coronary syndrome
and undergoing percutaneous intervention. New agents include prasugrel and ticagrelor. Ticagrelor is
a reversible, direct-acting P2Y12 receptor antagonist. Th e P2Y12 is a Gi-coupled platelet receptor for
ADP that plays a central role in platelet function. Drugs that inhibit P2Y12 are potent antithrombotic
drugs. Clopidogrel is the most widely used agent, but resistance, as defined as its inability to inhibit
adequately P2Y12-dependent platelet function, occurs in 20% to 30% of patients. Prasugrel and
ticagrelor appear to be more effective than clopidogrel in preventing thrombosis, although they
increase the incidence of major bleeding, a problem with the efficacy of all anticoagulants.
Current recommendations are to discontinue thienopyridines 7 days before elective surgery and to
avoid regional anesthesia until the effects of these drugs have dissipated. Guidelines for management
of patients with coronary stents on antiplatelet agents have been proposed and are oft en elaborate
(Table 30-4). Th e guidelines take in to consideration the type of coronary stent used and the interval
since the stent was placed as well as the urgency of need for surgery in decision making.
D ip y r id a m o le
Dipyridamole is an agent that increases cyclic adenosine monophosphate in platelets to inhibit their
function. Th is agent was also used for cardiac stress testing because of its coronary vasodilatory effects
(dipyridamole- thallium stress test). Currently, it is most frequently administered in combination with
aspirin to prevent stroke in patients who cannot take a thienopyridine. It can increase bleeding and
should be stopped preoperatively, but the aspirin component has a longer half life than dipyridamole.

D e x t ra n
Dextran-70 (70,000 daltons) binds to platelets and inhibits their function. Th is agent was used clinically
to reduce thrombosis aft er carotid surgery and a few other indications but is now rarely used for this
indication.

P la t e le t G ly c o p ro t e in IIb /IIIa A n t a g o n is t s
An important advance in managing ischemic cardiovascular disease was the development of platelet GP
IIb/IIIa receptor inhibitors, although these agents are now oft en replaced with newer therapies. Th e
IIb/IIIa receptor antagonists (abciximab, tirofiban, eptifibatide) either bind or competitively inhibit the
corresponding fibrinogen receptor that is important for platelet aggregation. Th ese drugs block
fibrinogen binding to platelet GP IIb/IIIa receptors that are a common pathway of platelet aggregation. In
multiple clinical trials, they have provided proof of concept on the critical role that platelet inhibition has
in reducing ischemic events associated with acute coronary syndrome and PCIs. In recent years,
thienopyridines and direct thrombin inhibitor (bivalirudin) in addition to PCIs including stenting have
had a significant impact; nonetheless, inhibiting platelet function has been critical
C h a p te r 3 0 • A n tic o a g u la n ts 661

Table 30-4
A n tip la telet T h era p y fo llo w in g S ten t P la c em en t: A 2 0 0 7 A H A /A C C R ec o m m en d a tio n s
1. Before implantation of a stent, the physician should discuss the need for dual-antiplatelet therapy. In patients
not expected to comply with 12 months of thienopyridine therapy, whether for economic or other reasons,
strong consideration should be given to avoiding a DES.
2. In patients who are undergoing preparation for PCI and who are likely to require invasive or surgical
procedures within the next 12 months, consideration should be given to implantation of a bare-metal stent or
performance of balloon angioplasty with provisional stent implantation instead of the routine use of a DES.
3. A greater effort by healthcare professionals must be made before patient discharge to ensure that patients are
properly and thoroughly educated about the reasons they are prescribed thienopyridines and the significant
risks associated with prematurely discontinuing such therapy.
4. Patients should be specifically instructed before hospital discharge to contact their treating cardiologist before
stopping any antiplatelet therapy, even if instructed to stop such therapy by another healthcare provider.
5. Healthcare providers who perform invasive or surgical procedures and who are concerned about
periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of
premature discontinuation of thienopyridine therapy. Such professionals who perform these procedures should
contact the patient’s cardiologist if issues regarding the patient’s antiplatelet therapy are unclear, to discuss
optimal patient management strategy.
6. Elective procedures for which there is significant risk of perioperative or postoperative bleeding should be
deferred until patients have completed an appropriate course of thienopyridine therapy (12 months aft er DES
implantation if they are not at high risk of bleeding and a minimum of 1 month for bare-metal stent
implantation).
For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of
thienopyridine therapy, aspirin should be continued if at all possible and the thienopyridine restarted as soon as
possible aft er the procedure because of concerns about late stent thrombosis.
ACC, American College of Cardiology; AHA, American Heart Association; DES, drug-eluting stent; PCI, percutaneous coronary intervention.
From Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on perioperative cardiovascular evaluation and care for noncardiac
surgery: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in
collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of
Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and
Society for Vascular Surgery. Circulation. 2007;116:
1971–1996.

to prevent platelet responses to vascular injury and clot formation. These agents prevent thrombus
formation initiated by platelets is in the pathogenesis of acute coronary syndrome (unstable angina,
myocardial infarction), angioplasty failure, and stent thrombosis.32,33 A summary of these agents is given
in Table 30-5.
C h a p te r 3 0 • A n tic o a g u la n ts 662

Various antagonists of GP IIb/IIIa are available. Th e first of these agents, the monoclonal antibody
abciximab (ReoPro), was been approved for use in PCI. Tirofiban (Aggrastat), a nonpeptide, for
treatment of acute coronary syndromes (unstable angina or non–Q-wave myocardial infarction) and
eptifibatide (Integrelin), a peptide, for
use both in PCI and acute coronary syndromes. New nonpeptide oral antagonists of GP IIb/IIIa intended
for long-term use are in various stages of clinical development and may find application in a broad
spectrum of atherothrombotic disease. Although GP IIb/IIIa antagonists are indicated for the acute
coronary syndrome and in patients undergoing interventional cardiology procedures, thienopyridines
have largely replaced these agents due to cost and increasing clinical data favoring the thienopyridines.
Abciximab has the longest half-life of all these agents as a monoclonal antibody, whereas the other
agents have shorter half-lives. All of three agents can cause thrombocytopenia.33

P e r io p e ra t iv e M a n a g e m e n t o f P a t ie n t s o n P la t e le t In h ib it o rs
Perioperative management of patients on various platelet inhibitors is complex and requires careful
coordinated care with multiple specialties. Th e risks and benefits of discontinuing antiplatelet therapy
must be carefully considered for each individual patient, especially prior to elective surgery. Th e most
recent guidelines by Fleisher et al.34 are listed in Table 30-4.

T h ro m b o ly t ic D r u g s

Stop
Elimination before
Route of Half-Time Clinical Surgery Prolong
Drug Structure Administration (h) Excretion Uses (h) PT/PTT Antidote

Abciximab Monoclonal Intravenous 12–24 Plasma proteases ACS 72 No/No


Dialysis antibodies PCI
Eptifibatide Peptide Intravenous 2–4 Renal ACS 24 No/No Dialysis
PCI
Tirofiban Nonpeptide Intravenous 2–4 Renal (30%–60%) ACS 24 No/No Dialysis
Biliary (40%–70%)

Table 30-5

ACS, acute coronary syndrome; PCI, percutaneous coronary intervention; PT, prothrombin time; PTT, partial thromboplastin time.
Pharmacologic thrombolysis is produced by drugs that act as plasminogen activators to convert the
endogenous proenzyme plasminogen to the fibrinolytic enzyme plasmin that lysis clot and other
proteins. Th e goal of thrombolytic therapy is to restore circulation through a previously occluded
artery or vein, most oft en a coronary artery. Fibrinolytic therapy was used previously in the treatment
of acute coronary syndrome but current American College of Cardiology and American Heart
Association published evidence-based guidelines for the management of patients depend on whether a
conservative (i.e., noninvasive) approach or an invasive strategy (i.e., PCI with possible angioplasty or
coronary artery bypass graft [CABG] surgery) is possible, specifically whether cardiac catheterization
is available.
Acute interventions with fibrinolytic agents can be lifesaving in patients with pulmonary emboli,35
ischemic stroke (e.g., middle cerebral arterial occlusion),6,36 and in patients suffering acute myocardial
infraction without immediate access to PCIs.37 Bleeding complications (5% to 30%) may occur whether
fibrinolytics are injected systemically or directly into the affected arterial lesion.38 Currently available
C h a p te r 3 0 • A n tic o a g u la n ts 663

fibrinolytics include streptokinase, urokinase, and tissue plasminogen activator (tPA). Th ese agents
activate plasminogen to plasmin, the major enzyme responsible for clot breakdown. Plasmin is a serine
protease that degrades fibrin (ogen) and factors V and VIII. In clinical practice, tPA is most commonly
used because of its localized catalytic effect on plasminogen activation in the presence of fibrin.39 Blood
flow to the thrombus is vital for the delivery of tPA, and thus localized activation of fibrinolysis via
catheter-directed drug delivery is theoretically more favorable than systemic administration.
Th rombolytic agents have an associated risk of bleeding (particularly intracranial hemorrhage) and
hemorrhagic complications occur more oft en in trauma, surgery, or following invasive diagnostic
procedures. Intracranial hemorrhage occurs in 1.7% to 8.0% of treated patients.40 Following lytic therapy,
hemorrhagic transformation of ischemic infarcts can occur. Th e recommended treatment of intracranial
or serious systemic bleeding aft er thrombolytic therapy is administration of cryoprecipitate and
platelets, although evidence-based guidelines for such an approach are lacking.40 Angioedema occurs in
1% to 5% of patients receiving IV rt-PA, and the use of angiotensinconverting enzyme inhibitors is
strongly associated with this complication.

Vous aimerez peut-être aussi