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Antithrombotic Therapy: October 2014
Antithrombotic Therapy: October 2014
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Antithrombotic Therapy
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CWR 35
CHAPTER 35
35-1
Plaque disruption
Vascular injury
Collagen vWF
Collagen and vWF Tissue factor
TXA2
Platelet recruitment and activation Thrombin
ADP Clopidogrel
Prasugrel
Platelet aggregation Fibrin formation
X Ticagrelor
Cangrelor
Platelet recruitment and activation
Platelet-fibrin thrombus
f0015
Figure 35-2 Coordinated role of platelets and the coagulation GP-IIb/IIIa activation
system in thrombogenesis. Vascular injury simultaneously triggers Abciximab
platelet activation and aggregation, as well as activation of the coagu- X Eptifibatide
lation system. Platelet activation is initiated by exposure of subendo- Tirofiban
thelial collagen and von Willebrand factor (vWF) onto which platelets Platelet aggregation
adhere. Adherent platelets become activated and release ADP and f0020
TXA2, platelet agonists that activate ambient platelets and recruit Figure 35-3 Site of action of antiplatelet drugs. Aspirin inhibits TXA2
them to the site of injury. When platelets are activated, glycoprotein synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1).
IIb/IIIa on their surface undergoes a conformational change that Reduced TXA2 release attenuates platelet activation and recruitment
enables it to ligate fibrinogen and mediate platelet aggregation. to the site of vascular injury. Ticlopidine, clopidogrel, and prasugrel
Coagulation is triggered by tissue factor exposed at the site of injury. irreversibly block P2Y12, a key ADP receptor on the platelet surface,
Tissue factor triggers thrombin generation. As a potent platelet whereas ticagrelor acts as a reversible inhibitor of P2Y12. Therefore
agonist, thrombin amplifies platelet recruitment to the site of injury. these agents also attenuate platelet recruitment. Abciximab, eptifiba-
Thrombin also converts fibrinogen to fibrin; the fibrin strands then tide, and tirofiban inhibit the final common pathway of platelet aggre-
weave the platelet aggregates together to form a platelet/fibrin gation by blocking fibrinogen binding to activated glycoprotein (GP)
F thrombus. IIb/IIIa.
synthesis of prostacyclin, a potent vasodilator and inhibitor Aspirin resistance has also been described biochemically p0085
of platelet aggregation. as failure of the drug to produce its expected inhibitory
effects on platelet TXA2 synthesis16 or arachidonic acid-
s0035 Indications induced platelet aggregation.17 However, the tests used for
p0060 Aspirin is widely used for secondary prevention in patients diagnosis of biochemical aspirin resistance have not been
with established coronary, cerebrovascular, or peripheral arte- well standardized,15 and there is no definitive evidence that
rial disease. In such patients, aspirin produces a 25% reduc- the tests identify patients at risk for recurrent vascular events
tion in the risk for cardiovascular death, MI, or stroke.10 The or that resistance can be reversed by giving higher doses of
use of aspirin for primary prevention is more controversial. aspirin or by adding other antiplatelet drugs.15 Until this
Recent studies have questioned whether the benefits of daily information is available, testing for aspirin resistance remains
aspirin for primary cardiac protection outweigh its associated a research tool.
risks for gastrointestinal and intracerebral hemorrhage.11,12
Consequently, aspirin is no longer recommended for primary Perioperative Aspirin Management s0055
cardiac prevention unless the baseline cardiovascular risk is Aspirin does not need to be stopped before diagnostic tests p0090
higher than 10% at 10 years. or surgical procedures associated with a low risk for bleeding.
These include dental procedures, such as tooth extraction or
s0040 Dosages root canal surgery, dermatologic procedures, such as excision
p0065 Aspirin is usually administered at doses of 75 to 325 mg once of basal or squamous cell cancers or malignant or premalig-
daily. There is no evidence that higher-dose aspirin is more nant nevi, or ophthalmologic procedures, such as cataract
effective than lower aspirin doses, and some analyses suggest surgery. Although continuation of aspirin during major
reduced efficacy with higher doses.13 Because the side effects surgery increases the risk for bleeding, discontinuation of
of aspirin are dose related, daily aspirin doses of 75 to 150 mg aspirin is associated with about a threefold increased risk for
are recommended for most indications. When rapid platelet cardiovascular events in patients undergoing noncardiac
inhibition is required, an initial aspirin dose of at least 160 mg surgery.18,19 Therefore, benefit-to-risk assessments must weigh
should be given.13 the benefit of continued aspirin for reduction of cardiac
events against the risk for increased bleeding at the time of
s0045 Side Effects surgery. In general, therefore, aspirin is discontinued 7 to 10
p0070 Most common side effects are gastrointestinal and range from days before noncardiac surgery or diagnostic or therapeutic
dyspepsia to erosive gastritis or peptic ulcers with bleeding interventions associated with a moderate or high risk for
and perforation.13 These side effects are dose related, and use bleeding, provided that the risk for cardiovascular events off
of enteric-coated or buffered aspirin in place of plain aspirin aspirin is low. If the risk for cardiovascular events is high,
does not eliminate them. The overall risk for major bleeding aspirin can be continued because even though aspirin
with aspirin ranges from 1% to 3% per year,13 and the risk increases the risk for bleeding, the bleeding rarely requires
increases when aspirin is given in conjunction with other medical intervention. Patients undergoing coronary artery
antiplatelet drugs, such as clopidogrel, or with anticoagulants, bypass grafting (CABG) should continue aspirin up to the
such as warfarin. When dual therapy is used, low-dose aspirin time of surgery because aspirin use within 5 days of CABG
should be given (75 to 100 mg daily). Eradication of Helico- lowers the risk for postoperative death without increasing
Metabolic activation of clopidogrel is inefficient, because given clopidogrel and in 9.9% of those randomized to prasu-
only 15% of absorbed drug undergoes activation through two grel. This 19% relative risk reduction and 2.2% absolute
oxidative steps. In addition, varying absorption, and loss-of- reduction was mainly due to a reduction in nonfatal MI. The
function polymorphisms in the enzymes responsible for clopi- rate of major bleeding was higher with prasugrel than with
dogrel activation or drug-drug competition for these enzymes clopidogrel (1.4% and 0.9%, respectively), as was the rate of
may delay and decrease the antiplatelet effects of clopido- fatal bleeding (0.4% and 0.1%, respectively). When com-
grel.21 Although prasugrel, a third-generation thienopyridine, pared with clopidogrel in 7243 acute coronary syndrome
also requires metabolic activation, the process is more effi- patients who were managed medically and did not undergo
cient and predictable than the activation of clopidogrel. cardiac revascularization, prasugrel did not significantly
Consequently, prasugrel has a faster onset of action than reduce the risk for cardiovascular death, MI, or stroke; rates
clopidogrel and produces greater inhibition of ADP-induced of major bleeding were similar with prasugrel and clopido-
platelet aggregation.22 grel.33 Based on the results of this study, prasugrel should not
p0105 Ticagrelor has a mechanism of action distinct from that of be used in place of clopidogrel in acute coronary syndrome
the thienopyridines. In contrast to clopidogrel and prasugrel, patients who are medically managed, but is an option in
ticagrelor does not require metabolic activation and serves as higher-risk patients undergoing PCI.
a reversible inhibitor of P2Y12. Without a requirement for Ticagrelor was compared with clopidogrel in 18,624 p0125
activation, ticagrelor has a more rapid onset of action than patients with acute coronary syndrome all of whom also
clopidogrel and a more rapid offset of action than either received aspirin.34 At 12 months, ticagrelor produced a 16%
clopidogrel or prasugrel. reduction in the primary efficacy outcome; a composite of
vascular death, MI, or stroke (from 11.7% to 9.8%). Ticagre-
s0070 Indications lor also was associated with a 21% reduction in the rate of
p0110 When compared with aspirin in patients with recent isch- cardiovascular death (from 5.1% to 4.0%) and all-cause mor-
emic stroke, MI, or peripheral arterial disease, clopidogrel tality (from 5.9% to 4.5%). Although ticagrelor did not
reduced the risk for cardiovascular death, MI, and stroke increase the overall rate of major bleeding as defined in the
by 8.7%.23 Therefore clopidogrel is marginally more effective trial, it was associated with a 19% increase in non-CABG
than aspirin, but it also is more expensive. In some patients, surgery related major bleeding (from 3.8% to 4.5%). Based
clopidogrel and aspirin are combined to capitalize on their on these results, current guidelines recommend ticagrelor as
capacity to block complementary pathways of platelet acti- a potential alternative to clopidogrel in acute coronary syn-
vation. For example, the combination of aspirin plus clopi- drome patients regardless of whether they are managed medi-
dogrel is recommended for at least 4 weeks after implantation cally or with PCI.
of a bare metal stent in a coronary artery and for 1 year
in those with a drug-eluting stent.24 Concerns about late Dosing s0075
in-stent thrombosis with drug-eluting stents25,26 have led Clopidogrel is given once daily at a dose of 75 mg.24 Because p0130
some experts to recommend long-term use of clopidogrel its onset of action is delayed for several days, loading doses
plus aspirin for this indication, provided that the risk for of clopidogrel are given when rapid ADP receptor blockade
bleeding is low.27 is desired. For example, patients undergoing coronary stent-
p0115 The combination of clopidogrel and aspirin also is effec- ing are often given a loading dose of 300 to 600 mg, which
tive in medically managed patients with unstable angina. produces inhibition of ADP-induced platelet aggregation in
Thus in 12,562 such patients, the risk for cardiovascular about 4 to 6 hours.24
death, MI, or stroke was 9.3% in those randomized to the Prasugrel is initiated with a loading dose of 60 mg followed p0135
combination of clopidogrel and aspirin and 11.4% in those by a maintenance dose of 10 mg once daily. A dose of 5 mg
given aspirin alone. This 20% relative risk reduction with once daily is used for those over the age of 75 years or those
combination therapy was highly statistically significant.28 with a body weight less than 60 kg. Prasugrel should be
However, combining clopidogrel with aspirin increases the avoided in patients with a history of stroke or transient isch-
risk for major bleeding to about 2% per year. This bleeding emic attack.
risk persists even if the daily dose of aspirin is 100 mg or less.29 In contrast to the thienopyridines, which produce irrevers- p0140
Therefore the combination of clopidogrel and aspirin should ible inhibition of P2Y12, ticagrelor inhibits the receptor in a
only be used when there is a clear benefit. For example, this reversible fashion. With a half-life of only about 8 hours,
combination has not proven to be superior to clopidogrel ticagrelor must be administered twice daily. Ticagrelor is initi-
alone in patients with acute ischemic stroke,30 or to aspirin ated with a loading dose of 180 mg followed by a mainte-
alone for primary prevention in those at risk for cardiovascu- nance dose of 90 mg twice daily.
lar events.31
p0120 Prasugrel was compared with clopidogrel in 13,608 patients Side Effects s0080
with moderate-risk to high-risk acute coronary syndrome The major side effect of clopidogrel, prasugrel, and ticagrelor p0145
scheduled for PCI.32 All patients received aspirin. The is bleeding. Gastrointestinal and hematologic side effects are
primary efficacy endpoint, a composite of cardiovascular rare with the thienopyridines.35 Side effects of ticagrelor
F death, nonfatal MI, or stroke, occurred in 12.1% of patients include dyspnea, which is usually mild and dose-related,
asymptomatic bradycardia with ventricular pauses, and a receiving clopidogrel or ticagrelor should discontinue the
modest increase in the levels of uric acid.36,37 medication 7 to 10 days (minimum of 5 days) before surgery.
Because of its shorter offset of action, ticagrelor needs to be
s0085 Clopidogrel Resistance held for only 5 days before surgery, although even 3 days is
p0150 The capacity of clopidogrel to inhibit ADP-induced platelet likely to be sufficient. Whenever possible, elective surgery in
aggregation varies among patients.38 This variability reflects, patients receiving dual antiplatelet therapy for coronary stent
at least in part, genetic polymorphisms in the CYP isoen- implantation should be deferred for at least 6 weeks after bare
zymes involved in its metabolic activation. Most important metal stent implantation and 12 months after drug-eluting
of these isoenzymes is CYP2C19. Clopidogrel-treated patients stent implantation. If such patients require urgent surgery
with the loss-of-function CYP2C19*2 allele exhibit reduced within 6 weeks of stent placement, dual antiplatelet therapy
platelet inhibition compared with those with the wild-type should be continued during the perioperative period. Clopi-
CYP2C19*1 allele; they also experience a higher rate of dogrel is safer than prasugrel or ticagrelor in this setting.
cardiovascular events.34,39,40 This is important because esti- Patients receiving dual antiplatelet therapy who are at risk p0170
mates suggest that up to 25% of whites, 30% of blacks, and for cardiovascular events should continue aspirin up to the
50% of Asians carry the loss-of-function allele, which would time of surgery, but they should discontinue their thienopyri-
render them resistant to clopidogrel. Even patients with the dine 7 to 10 days before surgery. Ticagrelor can be stopped 5
reduced-function CYP2C19*3, *4, or *5 alleles may derive days before surgery.
less benefit from clopidogrel than those with the full-function
CYP2C19*1 allele. Patients with polymorphisms in ABCB1
Dipyridamole s0095
may exhibit reduced clopidogrel absorption, and polymor-
phisms in CYP3A4 can also reduce the metabolic activation Dipyridamole is a relatively weak antiplatelet agent on its p0175
of clopidogrel. Polymorphisms in both of these enzymes have own,24 but an extended-release formulation of dipyridamole
been linked to adverse clinical outcomes.41 In contrast to combined with low-dose aspirin, a preparation known as
their effect on the metabolic activation of clopidogrel, Aggrenox, is used for prevention of stroke in patients with
CYP2C19 and CYP3A4 polymorphisms appear to be less transient ischemic attacks.48
important determinants of the activation of prasugrel.42 Thus
in the study that compared prasugrel with clopidogrel in Mechanism of Action s0100
patients with acute coronary syndrome, an association was By inhibiting phosphodiesterase, dipyridamole blocks the p0180
found between loss-of-function alleles and an increased rate breakdown of cAMP. Increased levels of cAMP reduce intra-
of cardiovascular events with clopidogrel, but not with pra- cellular calcium and inhibit platelet activation. Dipyridamole
sugrel.43 Similar results were observed when ticagrelor was also blocks the uptake of adenosine by platelets and other
compared with clopidogrel.44 Because of these observations, cells. With more extracellular adenosine, local cAMP levels
some guidelines recommend ticagrelor or prasugrel over clop- are increased further because the platelet adenosine A2 recep-
idogrel for patients with acute coronary syndrome. tor is coupled to adenylate cyclase.
p0155 Concomitant administration of clopidogrel with proton-
pump inhibitors, which are inhibitors of CYP2C19, may Dosing s0105
also produce a small reduction in the inhibitory effects of Aggrenox is given twice daily. Each capsule contains 200 mg p0185
prevention. However, when compared with clopidogrel in Table 35-1 Features of GP-IIb/IIIa Antagonists t0010
20,332 patients with ischemic stroke,51 the rate of recurrent
Feature Abciximab Eptifibatide Tirofiban
stroke with Aggrenox was similar to that with clopidogrel
(9.0% and 8.8%, respectively) and the rate of major bleeding Description Fab fragment of Cyclical Nonpeptidic
with Aggrenox was higher with apixaban than with clopido- humanized KGD- RGD
mouse containing mimetic
grel (4.1% and 3.6%, respectively). The results of this study monoclonal heptapeptide
dampened the enthusiasm for the use of Aggrenox. Because antibody
of its vasodilatory effects and the paucity of data supporting Specific for No Yes Yes
the use of dipyridamole in patients with symptomatic coro- GP-IIb/IIIa
nary artery disease, Aggrenox should not be used for stroke Plasma half-life Short (min) Long (2.5 h) Long (2.0 h)
prevention in such patients. Platelet-bound Long (days) Short (sec) Short (sec)
half-life
s0120 Perioperative Management Renal clearance No Yes Yes
p0200 Although dipyridamole has a rapid offset of action, the aspirin
component of Aggrenox produces irreversible inhibition of
COX-1. Consequently, as with aspirin, Aggrenox should be
discontinued 7 to 10 days before surgery.
s0160 ANTICOAGULANTS
p0250 Anticoagulants are available in parenteral and oral forms.
Currently available parenteral anticoagulants include heparin,
C f0025
low-molecular-weight heparin (LMWH), and fondaparinux,
a synthetic pentasaccharide. Currently available oral antico- Figure 35-4 Mechanism of action of heparin, low-molecular-weight
heparin (LMWH), and fondaparinux, a synthetic pentasaccharide.
agulants include warfarin, dabigatran etexilate (an oral A, Heparin binds to antithrombin via its pentasaccharide sequence.
thrombin inhibitor), and rivaroxaban and apixaban, which This induces a conformational change in the reactive center loop of
are oral factor Xa inhibitors. antithrombin that accelerates its interaction with factor Xa. To potenti-
ate thrombin inhibition, heparin must simultaneously bind to anti-
thrombin and thrombin. Only heparin chains composed of at least 18
s0165 Parenteral Anticoagulants
saccharide units (corresponding to a molecular weight of 5400) are of
s0170 Heparin sufficient length to perform this bridging function. With a mean
molecular weight of 15,000, all of the heparin chains are long enough
p0255 A sulfated polysaccharide, heparin is isolated from mamma- to do this. B, LMWH has greater capacity to potentiate factor Xa inhibi-
lian tissues rich in mast cells. Most commercial heparin is tion by antithrombin than by thrombin because, with a mean molecu-
range of 5000 to 30,000, almost all of the chains of unfrac- The interaction of heparin with plasma proteins also con- p0295
tionated heparin are long enough to affect this bridging func- tributes to the phenomenon of heparin rebound. Defined as
tion.67 Consequently, by definition, heparin has equal capacity the reappearance of anticoagulant activity after adequate
to promote the inhibition of thrombin and factor Xa by neutralization of heparin with protamine, heparin rebound
antithrombin and is assigned a 1 : 1 ratio of anti–factor Xa to may contribute to excessive postoperative bleeding after
anti–factor IIa (thrombin) activity.61 cardiac surgery. This phenomenon likely reflects the slow
p0270 Heparin causes the release of tissue factor pathway inhibi- release of protein-bound heparin after circulating heparin is
tor, a factor Xa–dependent inhibitor of tissue factor–bound neutralized by protamine and can be managed by administra-
factor VIIa,52 from the endothelium.67,68 Tissue factor pathway tion of additional protamine as boluses or as a low-dose con-
inhibitor may contribute to the antithrombotic activity of tinuous infusion.80
heparin. Longer heparin chains induce the release of more
tissue factor pathway inhibitor than do shorter chains.67,68 Monitoring the Anticoagulant Effect of Heparin. Heparin s0185
therapy can be monitored using the activated partial throm- p0300
s0180 Pharmacology of Heparin. Heparin must be given paren- boplastin time (aPTT) or anti–factor Xa level. Although the
p0275 terally. It is usually administered subcutaneously or by con- aPTT is the test most often employed for this purpose, there
tinuous intravenous infusion. When it is used for therapeutic are problems with this assay. aPTT reagents vary in their
purposes, the intravenous route is most often used. If sensitivity to heparin and the type of coagulometer used
heparin is given subcutaneously for treatment of thrombosis, for testing can influence the results.81 Consequently, labora-
the dose of heparin must be high enough to overcome tories must establish a therapeutic aPTT range with each
the limited bioavailability associated with this method of reagent-coagulometer combination by measuring the aPTT
delivery.61 and anti–factor Xa level in plasma samples collected from
p0280 In the circulation, heparin binds to the endothelium and heparin-treated patients. For most of the aPTT reagents and
to plasma proteins other than antithrombin. Heparin binding coagulometers in current use, therapeutic heparin levels are
to endothelial cells explains its dose-dependent clearance. At achieved with a two- to threefold prolongation of the aPTT.82
low doses, the half-life of heparin is short because it rapidly Anti–factor Xa levels also can be used to monitor heparin p0305
binds to the endothelium.61 With higher doses of heparin, the therapy. With this test, therapeutic heparin levels range from
half-life is longer because heparin is cleared more slowly once 0.3 to 0.7 units/mL. Although this test is gaining in popular-
the endothelium is saturated.61 Clearance is mainly extrare- ity, anti–factor Xa assays have yet to be standardized, and
nal; heparin binds to macrophages, which internalize and results can vary widely between laboratories.
depolymerize the long heparin chains and secrete shorter Up to 25% of heparin-treated patients with venous throm- p0310
chains back into the circulation. Because of its dose- boembolism require more than 35,000 units/day to achieve a
dependent clearance mechanism, the plasma half-life of therapeutic aPTT. These patients are considered heparin
heparin ranges from 30 to 60 minutes with bolus intravenous resistant.83 It is useful to measure anti–factor Xa levels in
doses of 25 and 100 units/kg, respectively.61 heparin-resistant patients because many will have a therapeu-
p0285 Once heparin enters the circulation, it binds to plasma tic anti–factor Xa level despite a subtherapeutic aPTT. This
proteins other than antithrombin, a phenomenon that dissociation in test results occurs because elevated plasma
reduces the anticoagulant activity of heparin.70 Some of the levels of fibrinogen and factor VIII, both of which are acute-
heparin-binding proteins found in plasma are acute-phase phase proteins, shorten the aPTT but have no effect on
reactants whose levels are elevated in ill patients.70,71 Others, anti–factor Xa levels.84 Heparin therapy in patients who
such as high-molecular-weight multimers of vWF, are released exhibit this phenomenon is best monitored using anti–factor
from activated platelets or endothelial cells.72,73 Activated Xa levels instead of the aPTT.83 Patients with congenital or
platelets also release platelet factor 4 (PF4), a highly cationic acquired antithrombin deficiency and those with elevated
protein that binds heparin with high affinity.74 The large levels of heparin-binding proteins also may need high doses
amounts of PF4 found in the vicinity of platelet-rich arterial of heparin to achieve a therapeutic aPTT or anti–factor Xa
thrombi can neutralize the anticoagulant activity of heparin.75 level. If there is good correlation between the aPTT and the
This phenomenon may attenuate heparin’s capacity to sup- anti–factor Xa levels, either test can be used to monitor
press thrombus growth. heparin therapy.
p0290 Because the levels of heparin-binding proteins in plasma
vary from person to person, the anticoagulant response to Dosing. For prophylaxis, heparin is usually given in fixed s0190
fixed or weight-adjusted doses of heparin is unpredictable. doses of 5000 units subcutaneously two or three times daily. p0315
Consequently, coagulation monitoring is essential to ensure With these low doses, coagulation monitoring is unneces-
that a therapeutic response is obtained. This is particularly sary.37 In contrast, monitoring is essential when the drug is
important when heparin is administered for treatment of given in therapeutic doses. Fixed-dose or weight-based heparin
established thrombosis because a subtherapeutic anticoagu- nomograms are used to standardize heparin dosing and to
lant response may render patients at risk for recurrent throm- shorten the time required to achieve a therapeutic anticoagu-
bosis,76,77 whereas excessive anticoagulation increases the risk lant response. At least two heparin nomograms have been
F for bleeding.78,79 validated in patients with venous thromboembolism and
t0015 Table 35-2 Pharmacokinetic and Biophysical potential for heparin neutralization by the high concentra-
Limitations of Heparin tions of PF4 released from activated platelets within the
platelet-rich thrombus.75
Limitations Mechanism
Poor bioavailability at low Binds to endothelial cells and Side Effects. The most common side effect of heparin is s0200
doses macrophages
bleeding. Other complications include thrombocytopenia, p0330
Dose-dependent clearance Binds to endothelial cells and
osteoporosis, and elevated levels of transaminases.
macrophages
Bleeding. The risk for heparin-induced bleeding increases s0205
Variable anticoagulant Binds to plasma proteins whose
response levels vary from patient to with higher heparin doses. Concomitant administration of p0335
patient drugs that affect hemostasis, such as antiplatelet or fibrino-
Reduced activity in the vicinity Neutralized by platelet factor 4 lytic agents, increases the risk for bleeding, as does recent
of platelet-rich thrombi released from activated surgery or trauma.96 Heparin-treated patients with serious
platelets bleeding can be given protamine sulfate to neutralize the
Limited activity against factor Reduced capacity of heparin- heparin. Protamine sulfate, a mixture of basic polypeptides
Xa incorporated in the antithrombin complex to inhibit
isolated from salmon sperm, binds heparin with high affinity,
prothrombinase complex factor Xa bound to activated
and thrombin bound to platelets and thrombin bound and the resultant protamine-heparin complexes are then
fibrin to fibrin cleared. Typically, 1 mg of protamine sulfate neutralizes 100
units of heparin. Protamine sulfate is given intravenously.
Anaphylactoid reactions to protamine sulfate97 can occur,
and drug administration by slow intravenous infusion is rec-
reduce the time required to achieve a therapeutic aPTT.85,86 ommended to reduce the risk for these problems.97,98
Weight-adjusted heparin nomograms also have been evalu- Thrombocytopenia. Heparin can cause thrombocy s0210
ated in patients with acute coronary syndromes. After an topenia. Heparin-induced thrombocytopenia (HIT) is an p0340
intravenous heparin bolus of 5000 units or 70 units/kg, a antibody-mediated process that is triggered by antibodies
heparin infusion rate of 12 to 15 units/kg/hour usually is directed against neoantigens on PF4 that are exposed when
administered.86,87 In contrast, weight-adjusted heparin nomo- heparin binds to this protein.99 These antibodies, which
grams for patients with venous thromboembolism use an usually are of the IgG subtype, bind simultaneously to the
initial bolus of 5000 units or 80 units/kg followed by an infu- heparin-PF4 complex and to platelet Fc receptors. Such
sion of 18 units/kg/hour.85 Thus patients with venous throm- binding activates the platelets and generates platelet mic-
boembolism appear to require higher doses of heparin to roparticles. Circulating microparticles are prothrombotic
achieve a therapeutic aPTT than do patients with acute coro- because they express anionic phospholipids on their surface
nary syndromes. This may reflect differences in the thrombus and can bind clotting factors, thereby promoting thrombin
burden. Heparin binds to fibrin, and the fibrin content of generation.100
extensive deep vein thrombi is greater than that of small coro- The clinical features of HIT are illustrated in Table 35-3. p0345
nary thrombi. Typically, HIT occurs 5 to 14 days after initiation of heparin
therapy, but it can manifest earlier if the patient has received
s0195 Limitations of Heparin. Heparin has pharmacokinetic heparin within the past 3 months.101 Even a 50% decrease in
b0010 BOX 35-1 given long-term heparin therapy,105-108 and symptomatic ver-
MANAGEMENT OF HEPARIN-INDUCED THROMBOCYTOPENIA tebral fractures occur in 2% to 3% of these individuals.
p0365 Stop all heparin. Studies in vitro109 and in laboratory animals110-112 have p0405
u0015 Give an alternative anticoagulant, such as lepirudin, argatroban, provided insights into the pathogenesis of heparin-induced
bivalirudin, or fondaparinux. osteoporosis. These investigations suggest that heparin causes
u0020 Do not give platelet transfusions. bone resorption both by decreasing bone formation and by
u0025 Do not give warfarin until the platelet count returns to its baseline enhancing bone resorption.109-112 Thus heparin affects the
level. If warfarin was administered, give vitamin K to restore the activity of both osteoblasts and osteoclasts.
INR to normal. Elevated Levels of Transaminases. Therapeutic doses of s0220
u0030 Evaluate for thrombosis, particularly deep vein thrombosis. heparin frequently cause modest elevation in the serum levels p0410
of hepatic transaminases, without a concomitant increase in
the level of bilirubin.113,114 The levels of transaminases rapidly
return to normal when the drug is stopped. The mechanism
responsible for this phenomenon is unknown.
and, like many autoimmune disorders, occurs more frequently
in females than in males. Perioperative Management. When given subcutaneously s0225
p0350 HIT can be associated with thrombosis, either arterial or for thromboprophylaxis, the last dose of heparin should be p0415
venous. Venous thrombosis, which manifests as deep vein administered no later than 2 hours before surgery. Full-dose
thrombosis and/or pulmonary embolism, is more common intravenous heparin should be stopped 4 to 6 hours before
than arterial thrombosis. Arterial thrombosis can manifest as surgery.115 When used for thromboprophylaxis, low-dose
ischemic stroke or acute MI. Rarely, platelet-rich thrombi in heparin can be started 12 to 24 hours after surgery. Resump-
the distal aorta or iliac arteries can cause critical limb tion of full-dose heparin should be delayed until hemostasis
ischemia.99 is secure. Often heparin is started as an infusion without a
p0355 The diagnosis of HIT is established using enzyme-linked loading dose in this setting.
assays to detect antibodies against heparin-PF4 complexes or
with platelet activation assays. Enzyme-linked assays are sen- Low-Molecular-Weight Heparin s0230
sitive, but can be positive in the absence of any clinical Consisting of smaller fragments of heparin, LMWH is pre- p0420
evidence of HIT.99 The most specific diagnostic test is the pared from unfractionated heparin by controlled enzymatic
serotonin release assay. This test is performed by quantifying or chemical depolymerization. The mean molecular weight
serotonin release when washed platelets loaded with labeled of LMWH is 5000, one third the mean molecular weight of
serotonin are exposed to patient serum in the absence or unfractionated heparin.116 LMWH has advantages over
presence of varying concentrations of heparin. If the patient heparin (Table 35-4) and has replaced heparin for most
serum contains the HIT antibody, heparin addition induces indications.
platelet activation and subsequent serotonin release.99
p0360 Management of HIT is outlined in Box 35-1. Heparin Mechanism of Action. Like heparin, LMWH exerts its s0235
should be stopped in patients with suspected or documented anticoagulant activity by activating antithrombin. With a p0425
HIT, and an alternative anticoagulant should be administered mean molecular weight of 5000, which corresponds to about
to prevent or treat thrombosis.102 The agents most often used 17 saccharide units, at least half of the pentasaccharide-
for this indication are parenteral direct thrombin inhibitors containing chains of LMWH are too short to bridge thrombin
(such as lepirudin, argatroban, or bivalirudin) or factor Xa to antithrombin (see Fig. 35-4). However, these chains
inhibitors (such as fondaparinux or danaparoid). retain the capacity to accelerate factor Xa inhibition by
p0395 Patients with HIT, particularly those with associated antithrombin because this activity is largely the result of
thrombosis, often have evidence of increased thrombin gen-
eration that can lead to consumption of protein C. If these
patients are given warfarin without a concomitant thrombin
Table 35-4 Advantages of LMWH Over Heparin t0025
parenteral anticoagulant, the further decrease in protein C
levels induced by the vitamin K antagonist can trigger skin Advantage Consequence
necrosis.103,104 To avoid this problem, patients with HIT Better bioavailability and longer Can be given subcutaneously
should be treated with a direct thrombin inhibitor or half-life after subcutaneous once or twice daily for both
fondaparinux until the platelet count returns to normal injection prophylaxis and treatment
levels. At this point, low-dose warfarin therapy can be intro- Dose-independent clearance Simplified dosing
duced, and the thrombin inhibitor can be discontinued when Predictable anticoagulant Coagulation monitoring is
the anticoagulant response to warfarin has been therapeutic response unnecessary in most patients
for at least 2 days.102 Lower risk for heparin-induced Safer than heparin for short or
thrombocytopenia long-term administration
s0215 Osteoporosis. Treatment with therapeutic doses of heparin
Lower risk for osteoporosis Safer than heparin for
p0400 for over a month can cause a reduction in bone density. This extended administration
F complication has been reported in up to 30% of patients
the conformational changes in antithrombin evoked by as in patients with mechanical heart valves who are given
pentasaccharide binding. Consequently, LMWH inhibits LMWH for prevention of valve thrombosis.
factor Xa more than thrombin.16 Depending on the unique
molecular weight distributions of various LMWH prepara- LMWH Dosing. The doses of LMWH recommended for pro- s0250
tions, their ratios of anti–factor Xa to anti–factor IIa activity phylaxis or treatment vary depending on the LMWH prepa- p0450
range from 2 : 1 to 4 : 1. ration. For prophylaxis, once-daily subcutaneous doses of
4000 to 5000 units are often used, whereas doses of 2500 to
s0240 Pharmacology of LMWH. Although usually given subcuta- 3000 units are given when the drug is administered twice
p0430 neously, LMWH also can be administered intravenously if a daily. For treatment of venous thromboembolism, a dose of
rapid anticoagulant response is needed. LMWH has pharma- 150 to 200 units/kg is given if the drug is administered once
cokinetic advantages over heparin.116,117 These advantages daily. If a twice-daily regimen is employed, a dose of 100
reflect the fact that shorter heparin chains bind less avidly to units/kg is given. In patients with unstable angina, LMWH
endothelial cells, macrophages, and heparin-binding plasma is given subcutaneously on a twice-daily basis at a dose of 100
proteins.118-120 Reduced binding to endothelial cells and mac- to 120 units/kg.116
rophages eliminates the rapid, dose-dependent, and saturable
mechanism of clearance characteristic of unfractionated Side Effects. The major complication of LMWH is bleeding. s0255
heparin. Instead, the clearance of LMWH is dose indepen- Recent metaanalyses suggest that the risk for major bleeding p0455
dent and its plasma half-life is longer.117 Based on measure- may be lower with LMWH than with unfractionated
ment of anti–factor Xa levels, LMWH has a plasma half-life heparin.125,126 HIT and osteoporosis are less common with
of about 4 hours. LMWH is cleared almost exclusively by the LMWH than with unfractionated heparin.116
kidneys, and the drug can accumulate in patients with renal Bleeding. As with heparin, bleeding with LMWH is more s0260
insufficiency.116,117 common in patients receiving concomitant therapy with p0460
p0435 LMWH exhibits about 90% bioavailability after subcuta- antiplatelet or fibrinolytic drugs. Recent surgery, trauma, or
neous injection.116,117 Because LMWH binds less avidly to underlying hemostatic defects also increase the risk for bleed-
heparin-binding proteins in plasma than heparin, LMWH ing with LMWH.96
produces a more predictable dose response and resistance to Although protamine sulfate can be used as an antidote p0465
LMWH is rare. With a longer half-life and more predictable for LMWH, it incompletely neutralizes the anticoagulant
anticoagulant response, LMWH can be given subcutaneously activity of LMWH because protamine sulfate binds only the
once or twice daily without coagulation monitoring, even longer chains of LMWH.110 Since longer chains are respon-
when the drug is given in treatment doses.116 These properties sible for catalysis of thrombin inhibition by antithrombin,
render LMWH more convenient than unfractionated heparin. protamine sulfate completely reverses the anti–factor IIa
Capitalizing on this feature, studies in patients with venous activity of LMWH. In contrast, protamine sulfate only par-
thromboembolism have shown that home treatment with tially reverses the anti–factor Xa activity of LMWH because
LMWH is as effective and safe as in-hospital treatment with the shorter pentasaccharide-containing chains of LMWH
continuous intravenous infusions of heparin.121-123 Out- do not bind to protamine sulfate. Consequently, patients
patient treatment with LMWH streamlines care, reduces at high risk for bleeding may be more safely treated with
health care costs, and increases patient satisfaction. continuous intravenous unfractionated heparin than with
drug should be held for 24 hours before surgery. Thrombopro- not bind to plasma proteins. The drug is given at a dose of
phylaxis with LMWH can be started 12 to 24 hours after 2.5 mg once daily for prevention of venous thromboembo-
surgery; if started 12 hours after major surgery, a half dose can lism. For initial treatment of established venous thromboem-
be given. Resumption of full-dose LMWH should be delayed bolism, fondaparinux is given at a dose of 7.5 mg once daily.
for 2 to 3 days. The dose can be reduced to 5 mg once daily for those weigh-
ing less than 50 kg and increased to 10 mg for those over
s0280 Fondaparinux 100 kg. When given in these doses, fondaparinux is as effec-
p0490 A synthetic analog of the antithrombin-binding pentasac- tive as heparin or LMWH for initial treatment of patients
charide sequence, fondaparinux differs from LMWH in with deep vein thrombosis or pulmonary embolism and pro-
several ways (Table 35-5). Fondaparinux is licensed for duces similar rates of bleeding.135,136
thromboprophylaxis in general surgical and high-risk ortho- Fondaparinux is used at a dose of 2.5 mg once daily p0510
pedic patients and as an alternative to heparin or LMWH for in patients with acute coronary syndromes. When this
initial treatment of patients with established venous throm- prophylactic dose of fondaparinux was compared with treat-
boembolism. Although approved as an alternative to heparin ment doses of enoxaparin in patients with non–ST-segment
or LMWH in patients with acute coronary syndrome in elevation acute coronary syndromes, no difference was
Europe and Canada, fondaparinux is not licensed for this seen in the rate of cardiovascular death, MI, or stroke at
indication in the United States. 9 days.137 However, the rate of major bleeding was 50%
lower with fondaparinux than with enoxaparin, a differ-
s0285 Mechanism of Action. As a synthetic analog of the ence that likely reflects the fact that the dose of fondaparinux
p0495 antithrombin-binding pentasaccharide sequence found in was lower than that of enoxaparin. In acute coronary
heparin and LMWH, fondaparinux has a molecular weight syndrome patients who require PCI, there is a risk for
of 1728. Fondaparinux binds only to antithrombin (see Fig. catheter thrombosis with fondaparinux unless adjunctive
35-4) and is too short to bridge thrombin to antithrombin. heparin is given.138
Consequently, fondaparinux catalyzes factor Xa inhibition by
antithrombin and does not enhance the rate of thrombin Side Effects. Although fondaparinux can induce the for- s0295
inhibition.133 mation of HIT antibodies, HIT is rare with thrombocy- p0515
topenia. In contrast to LMWH, there is no cross-reactivity
s0290 Pharmacology of Fondaparinux. Fondaparinux exhibits of fondaparinux with HIT antibodies. Consequently,
p0500 complete bioavailability after subcutaneous injection. With fondaparinux appears to be effective for treatment of HIT
no binding to endothelial cells or plasma proteins, the clear- patients,139 although large clinical trials supporting its use
ance of fondaparinux is dose independent and its plasma are lacking.
half-life is 17 hours.134 The drug is given subcutaneously once The major side effect of fondaparinux is bleeding. There p0520
daily. Because fondaparinux is cleared unchanged via the is no antidote for fondaparinux. Protamine sulfate has no
kidneys, it is contraindicated in patients with a creatinine effect on the anticoagulant activity of fondaparinux because
clearance less than 30 mL/min and it should be used it fails to bind to the drug. Recombinant activated factor VII
with caution in those with a creatinine clearance less than reverses the anticoagulant effects of fondaparinux in volun-
50 mL/min.133,134 teers,140 but it is unknown whether this agent will control
p0505 Fondaparinux produces a predictable anticoagulant fondaparinux-induced bleeding.
response after administration in fixed doses because it does
Perioperative Management. When used in prophylactic or s0300
treatment doses, the last dose of fondaparinux should be p0525
given at least 36 hours before major surgery.
t0035 Table 35-6 Comparison of the Properties of portion of bivalirudin interacts with the active site of throm-
Lepirudin, Bivalirudin, and Argatroban bin, whereas its COOH-terminal tail binds to exosite 1, the
substrate-binding domain on thrombin. Bivalirudin has a
Features Lepirudin Bivalirudin Argatroban
plasma half-life of 25 min, the shortest half-life of all the
Molecular mass 7000 1980 527 parenteral direct thrombin inhibitors.141 Bivalirudin is
Site(s) of interaction Active site and Active site and Active site degraded by peptidases and is partially excreted via the
with thrombin exosite 1 exosite 1
kidneys. When given in high doses in the cardiac catheteriza-
Renal clearance Yes Limited No
tion laboratory, the anticoagulant activity of bivalirudin is
Hepatic metabolism No No Yes
monitored using the activated clotting time. With lower
Plasma half-life 60 25 45
doses, its activity can be assessed using the aPTT.
(min)
Studies comparing bivalirudin with heparin suggest p0560
that bivalirudin produces less bleeding.145,146 This feature
plus its short half-life make bivalirudin an attractive alter-
s0310 Lepirudin
native to heparin in patients undergoing percutaneous
p0535 Lepirudin is a bivalent direct thrombin inhibitor that inter- coronary interventions.147 Bivalirudin also has been used
acts with both the active site and exosite 1, the substrate successfully in HIT patients who require percutaneous
binding site, on thrombin.141 For rapid anticoagulation, lepi- coronary interventions.148
rudin is given by continuous intravenous infusion, but the
drug can be given subcutaneously for thromboprophylaxis.
Oral Anticoagulants s0325
Lepirudin has a plasma half-life of 60 minutes after intrave-
nous infusion and is cleared by the kidneys. Consequently, Current oral anticoagulant practice dates back almost 60 p0565
lepirudin accumulates in patients with renal insufficiency.142 years to when the vitamin K antagonists were discovered as
A high proportion of lepirudin-treated patients develop anti- a result of investigations into the cause of hemorrhagic disease
bodies against the drug.143 Although these antibodies rarely in cattle. Characterized by a decrease in prothrombin levels,
cause problems, in a small subset of patients they can delay this disorder is caused by ingestion of hay containing spoiled
lepirudin clearance and enhance its anticoagulant activity. sweet clover. Hydroxycoumarin, which was isolated from bac-
Serious bleeding has been reported in some of these patients.143 terial contaminants in the hay, interferes with vitamin K
p0540 Lepirudin is usually monitored using the aPTT, and the metabolism, thereby causing a syndrome similar to vitamin
dose is adjusted to maintain an aPTT that is 1.5 to 2.5 times K deficiency.
the control. The aPTT is not an ideal test for monitoring
lepirudin therapy because the clotting time plateaus with Warfarin s0330
higher drug concentrations. Although the ecarin clotting A water-soluble vitamin K antagonist initially developed as p0570
time provides a better index of lepirudin dose than the aPTT a rodenticide, warfarin is the coumarin derivative most often
does, the ecarin clotting time has yet to be standardized. prescribed in North America. Like other vitamin K antago-
nists, warfarin interferes with the synthesis of the vitamin
s0315 Argatroban K–dependent clotting proteins, which include prothrombin
p0545 A univalent inhibitor that targets the active site of throm- (factor II) and factors VII, IX, and X. Vitamin K antagonists
prothrombin time with each new batch of thromboplastin withheld until the INR returns to the therapeutic range. If
reagent. To accomplish this, the prothrombin time must the INR is higher than 9, a therapeutic INR can be achieved
be measured in fresh plasma samples from at least 20 more rapidly by administration of low doses of sublingual
healthy volunteers using the same coagulometer that is vitamin K.160,161 A vitamin K dose of 2 to 5 mg usually
used for patient samples.155 is adequate, but higher doses can be administered if more
p0620 For most indications, warfarin is administered in doses rapid reversal of the INR is required, or if the INR is
that produce a target INR of 2.0 to 3.0. An exception is excessively high.
patients with mechanical heart valves in the mitral position, Patients with serious bleeding need more aggressive treat- p0650
in which case a target INR of 2.5 to 3.5 is recommended.155 ment. These patients should be given 10 mg of vitamin K
Studies in atrial fibrillation demonstrate an increased risk by slow intravenous infusion. Additional vitamin K should
for cardioembolic stroke when the INR falls below 1.7 and be given until the INR is in the normal range. Treatment
an increase in bleeding with INR values over 4.5.158 These with vitamin K should be supplemented with fresh frozen
findings highlight the fact that vitamin K antagonists have plasma as a source of the vitamin K–dependent clotting
a narrow therapeutic window. In support of this concept, a proteins. For life-threatening bleeds or for patients who
study in patients receiving long-term warfarin therapy for cannot tolerate the volume load, prothrombin complex con-
unprovoked venous thromboembolism demonstrated a centrates can be used. Derived from pooled human plasma,
higher rate of recurrent venous thromboembolism with a four-factor prothrombin complex concentrates contain all
target INR of 1.5 to 1.9 compared with a target INR of 2.0 of the vitamin K–dependent coagulation factors (factors II,
to 3.0.159 VII, IX, and X), whereas three-factor concentrates contain
little or no factor VII. It is unclear whether three-factor
s0350 Dosing. Warfarin is usually started at a dose of 5 to 10 mg. concentrates are as effective as four-factor concentrates for
p0625 The dose is then titrated to achieve the desired target INR. warfarin reversal.162 Consequently, fresh frozen plasma or
Because of its delayed onset of action, patients with estab- low-dose recombinant factor VIIa is sometimes administered
lished thrombosis or those at high risk for thrombosis are in conjunction with three-factor concentrates to supplement
given concomitant treatment with a rapidly acting parenteral the levels of factor VII. Recombinant factor VIIa should
anticoagulant, such as heparin, LMWH, or fondaparinux. not be used as the sole agent to reverse warfarin because it
Initial prolongation of the INR reflects reduction in the only supplements one of the missing factors. In support of
functional levels of factor VII. Consequently, concomitant this concept, factor VIIa failed to attenuate warfarin-induced
treatment with the parenteral anticoagulant should be con- bleeding from punch biopsy sites in volunteers, even though
tinued until the INR has been therapeutic for at least 2 it normalized the INR.163
consecutive days. A minimum 5-day course of parenteral Warfarin-treated patients who experience bleeding when p0655
anticoagulation is recommended to ensure that the levels of their INR is in the therapeutic range require investigation
prothrombin have been reduced into the therapeutic range into the cause of the bleeding. Those with gastrointestinal
with warfarin.155 bleeding often have underlying peptic ulcer disease or a
p0630 Because warfarin has a narrow therapeutic window, fre- tumor. Similarly, investigation of hematuria or uterine bleed-
quent coagulation monitoring is essential to ensure that a ing in patients with a therapeutic INR may unmask a tumor
therapeutic anticoagulant response is obtained. Even patients of the genitourinary tract.
with thrombosis. Protein C concentrates can be given to Table 35-7 Comparison of the Features of the New t0040
protein C–deficient patients to accelerate healing of the skin Oral Anticoagulants
lesions; fresh frozen plasma may be of value for those with
Dabigatran
protein S deficiency. Occasionally, when there is extensive Features Rivaroxaban Apixaban Etexilate
skin loss, grafting is necessary.
Target Xa Xa IIa
p0675 Because of the potential for skin necrosis, patients with
Molecular weight 436 460 628
known protein C or protein S deficiency require overlapping
Prodrug No No Yes
treatment with a parenteral anticoagulant when initiating
Bioavailability (%) 80 50 6
warfarin therapy. Warfarin should be started in low doses in
Time to peak (h) 3 3 2
these patients, and the parenteral anticoagulant should be
Half-life (h) 9 9-14 12-17
continued until the INR is therapeutic for at least 2 to 3
Renal excretion (%) 33* 25 80
consecutive days.
Antidote None None None
s0370 Pregnancy. Warfarin crosses the placenta and can cause
p0680 fetal abnormalities or bleeding. The fetal abnormalities *33% excreted as unchanged drug.
include a characteristic embryopathy, which consists of nasal
hypoplasia and stippled epiphyses. The risk for embryopathy
is highest if warfarin is given in the first trimester of preg-
New Oral Anticoagulants s0385
nancy.166 Central nervous system abnormalities also can occur
with exposure to coumarin drugs at any time during preg- New oral anticoagulants that target thrombin or factor Xa are p0700
nancy. Finally, maternal administration of warfarin produces available as alternatives to warfarin.169 These drugs have a
an anticoagulant effect in the fetus that can cause bleeding. rapid onset of action and have half-lives that permit once- or
This is of particular concern at delivery when trauma to the twice-daily administration (Table 35-7). Designed to produce
head during passage through the birth canal can lead to a predictable level of anticoagulation, the new oral agents are
intracranial bleeding. Because of these potential problems, more convenient than warfarin because they can be given in
warfarin is contraindicated in pregnancy, particularly in the fixed doses without coagulation monitoring.
first and third trimesters. Instead, heparin, LMWH, or
fondaparinux can be given during pregnancy for prevention Apixaban. An oral direct factor Xa inhibitor, apixaban is s0390
or treatment of thrombosis. licensed as an alternative to warfarin for stroke prevention p0705
p0685 Warfarin does not pass into the breast milk. Consequently, in atrial fibrillation in the United States, Europe, and
warfarin can safely be given to nursing mothers. Canada. Apixaban is an active drug with an oral bioavail-
ability over 50%. Apixaban inhibits both free and clot-
s0375 Special Problems. Patients with a lupus anticoagulant or associated factor Xa activity.170 In healthy males, levels of
p0690 those who need urgent or elective surgery present special apixaban in plasma peak about 3 hours after oral administra-
challenges. Although observational studies suggested that tion, and the drug is cleared with a terminal plasma half-life
patients with thrombosis complicating the antiphospholipid of 8 to 14 hours.171 Apixaban is eliminated via multiple
antibody syndrome required higher-intensity warfarin regi- pathways, including oxidative metabolism, renal, and intes-
mens to prevent recurrent thromboembolic events, two tinal routes; about 25% of the drug is excreted unchanged
recent randomized trial demonstrated that targeting an INR by the kidneys. Potent inhibitors of CYP3A4, such as
of 2.0 to 3.0 is as effective as higher-intensity treatment and ketoconazole or ritonavir, are contraindicated because they
produces less bleeding.167,168 Monitoring warfarin therapy can increase plasma drug concentrations.
be problematic in patients with antiphospholipid antibody Apixaban was compared with warfarin for stroke preven- p0710
syndrome if the lupus anticoagulant prolongs the baseline tion in 18,201 patients who had atrial fibrillation and at least
INR; factor X levels can be used in place of the INR to dose one additional risk factor for stroke.172 Compared with war-
warfarin in such patients. farin, apixaban reduced the rate of stroke or systemic embo-
lism from 1.60% to 1.27%. The rate of major bleeding was
s0380 Perioperative Management. Warfarin should be stopped lower with apixaban than with warfarin (2.13% and 3.09%,
p0695 5 days before surgery or invasive procedures to allow the respectively) as was the rate of all-cause mortality (3.52% and
INR to return to normal levels. The INR should be deter- 3.94%, respectively). Apixaban was also compared with
mined before surgery to ensure that it is less than 1.5. aspirin for stroke prevention in 5599 atrial fibrillation patients
Patients at high risk for thrombosis, such as those with who could not take warfarin.173 Compared with aspirin, apix-
mechanical heart valves, can be bridged with intravenous aban reduced the rate of stroke or systemic embolism from
heparin or once- or twice-daily subcutaneous injections of 3.7% to 1.6% without significantly increasing the rate of
LMWH when the INR falls below 2.0. Intravenous heparin major bleeding (1.4% and 1.2%, respectively).
should be stopped 4 to 6 hours before surgery, whereas
the last dose of LMWH should be given 24 hours before Rivaroxaban. An oral factor Xa inhibitor, rivaroxaban is s0395
surgery. Warfarin can be restarted 12 to 24 hours after approved in the United States, Europe, and Canada for p0715
F surgery. thromboprophylaxis after elective hip or knee replacement
surgery, for treatment of venous thromboembolism, and for Two doses of dabigatran (150 or 110 mg twice daily) were p0735
stroke prevention in patients with atrial fibrillation. Rivar- compared with warfarin in 18,113 patients with atrial fibril-
oxaban is an active compound with 80% oral bioavailability. lation.180 The annual rate of stroke or systemic embolism was
Plasma levels of rivaroxaban peak 2 to 3 hours after admin- significantly lower with dabigatran 150 mg than with warfa-
istration and the terminal half-life is 7 to 11 hours.174,175 One rin (1.69% and 1.11%, respectively), whereas the 110-mg
third of the administered drug is cleared as unchanged active dose of dabigatran was associated with a rate of 1.53% and
drug by the kidneys, one third is metabolized by the liver via was noninferior to warfarin. The rate of major bleeding was
CYP3A4-dependent and independent pathways and then significantly lower with the 110 mg of dabigatran than with
excreted in feces, and one third is metabolized to inactive warfarin (2.71% and 3.36%, respectively); the rate of bleed-
metabolites, which are then excreted by the kidneys. The ing with the 150-mg dose of dabigatran was similar to that
pharmacokinetic and pharmacodynamic profile of rivaroxa- with warfarin (3.11% and 3.36%, respectively). Both the
ban is predictable and dose dependent and is not influenced 110-mg and the 150-mg dose of dabigatran were associated
by age, gender, or body weight. Potent inhibitors of both with lower rates of hemorrhagic stroke than the rate with
CYP3A4 and P-glycoprotein, such as ketoconazole or ritona- warfarin (0.12%, 0.10%, and 0.38%, respectively).
vir, are contraindicated because they increase plasma drug
concentrations. Dosing. For stroke prevention in patients with nonvalvular s0405
p0720 A pooled analysis of studies that compared rivaroxaban atrial fibrillation, rivaroxaban is given at a dose of 20 mg once p0740
with LMWH followed by warfarin for treatment of deep daily with a dose reduction to 15 mg once daily in patients
vein thrombosis or pulmonary embolism,176,177 revealed with a creatinine clearance of 15 to 49 mL/min; dabigatran
similar efficacy with the two treatment regimens with rates is given at a dose of 150 mg twice daily with a dose reduction
of recurrence of 2.1% and 2.3%, respectively. The rate of to 75 mg twice daily in those with a creatinine clearance of
major or clinically relevant nonmajor bleeding with rivar- 15 to 30 mL/min; and apixaban is given at a dose of 5 mg
oxaban was similar to that with conventional treatment twice daily with a dose reduction to 2.5 mg twice daily for
(0.4% and 10.0%, respectively), whereas the rate of major patients with a creatinine higher than 1.5 g/dL, or for those
bleeding was lower with rivaroxaban (1.0% and 1.7%, respec- 80 years of age or older or who weigh less than 60 kg.
tively). Even in fragile patients—those over 75 years of age, For short-term thromboprophylaxis after elective hip or p0745
those with a body weight less than 60 kg, or those with a knee replacement surgery, rivaroxaban is given at a dose of
creatinine clearance less than 50 mL/min—rates of recurrent 10 mg once daily. When used for treatment of deep vein
thrombosis were similar with rivaroxaban and conventional thrombosis and/or pulmonary embolism, rivaroxaban is
treatment (2.7% and 3.8%, respectively), and the rate of started at a dose of 15 mg twice daily for 3 weeks and the dose
major bleeding was lower with rivaroxaban (1.3% and 4.5%, is then reduced to 20 mg once daily thereafter.
respectively).
p0725 Rivaroxaban was compared with warfarin for stroke pre- Monitoring. Although the new oral anticoagulants are s0410
vention in 14,264 patients with atrial fibrillation who had at administered without routine monitoring, certain situations p0750
least two risk factors for stroke.178 Rates of stroke or systemic justify monitoring to determine their anticoagulant activity.
embolism with rivaroxaban and warfarin were 2.1% and These include assessment of adherence, detection of accumu-
2.4%, respectively, and rates of major bleeding were 3.6% and lation or overdose, identification of bleeding mechanism, and
s0420 Periprocedural Management. Like warfarin, the new oral development of novel antithrombotic drugs. Based on the
p0760 anticoagulants must be stopped before procedures associated results of well-designed clinical trials, the choice of agents
with a moderate or high risk for bleeding. The drugs should has expanded and treatment has become more streamlined.
be held for 1 to 2 days—longer if renal function is impaired. Despite these advances, however, arterial and venous throm-
Assessment of residual anticoagulant activity before high-risk boembolic disorders remain a major cause of morbidity and
procedures is prudent. mortality. Consequently, the search for better targets and
more potent, safer, or more convenient antiplatelet and anti-
s0425 Management of Bleeding. There are no specific antidotes coagulant drugs continues.
p0765 for the new oral anticoagulants. With minor bleeding, holding
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