Novel Anticoagulants: Anesthetic Implications

Christine Rinder
OF THE role of pathologic ombosis in cardiovascular and cerebrovascular events and a better understanding of procoagulant states has spurred the development of new anticoagulants and new indications for their use] In fact, some therapies, such as coronary stents, are critically dependent on successful anticoagulation. Although numerous clinical trials have defined the safety of new anticoagulants in uncomplicated patients, their impact on surgical hemostasis is unclear. The surgical team must weigh the risks of excess surgical bleeding against the potential for thrombosis in a vital location. Understanding the pharmacokinetics of each anticoagulant is key to minimizing the window of time during which the patient is vulnerable to thrombosis. In addition, for the patient requiring emergent surgery, knowledge of the anticoagulant's mechanism of action may allow the anesthesiologist to reverse anticoagulation or tailor appropriate blood product use. This review briefly examines how these newer anticoagulants work and their relevance to perioperative anesthetic care. basic building block of the platelet aggregate is a platelet-ligand-platelet matrix with fibrinogen, von Willebrand factor, or fibronectin serving as the linking ligand. On the resting platelet, GPIIb/IIIa is maintained in an inactive form. On activation, the receptor undergoes a calcium-dependent conformational change that makes it capable of binding to an amino acid sequence, arginine-glycine-aspartate, in at least two sites found on fibrinogen, von Willebrand factor, and fibronectin (Fig 1A). GPIIb! IIIa is the most abundant glycoprotein on the platelet surface, with approximately 50,000 copies on the resting platelet, and additional receptors within a cytoplasmic pool that are mobilized to the surface with activation. Different platelet agonists use different activation pathways, but all of these culminate in GPIIb/IIIa conformational change. By targeting the interaction of the GPIIb/IIIa receptor with any of its arginine-glycine-aspartate-containing ligands, this class of antiplatelet agents blocks the final common step leading to formation of a platelet-ligand-pIatelet matrix (Fig 1B). The efficacy of these agents seems to be largely a function of the percentage receptor occupancy; the aggregation response of platelets is significantly inhibited at -->80% blockade of surface GPIIb/IIIa, whereas at 50% blockade, platelet function is essentially normal. In addition, some of the antiGPIIb/IIIa agents inhibit platelets in ways that go beyond simple receptor blockade. Occupancy of GPIIb/llIa by one of its bridging ligands produces transmembrane-signaling events that facilitate granule release, recruitment of additional platelets, and surface expression of negatively charged phospholipids that facilitate coagulation cascade assembly. Blockade of GPIlb/IIIa inhibits this transmemFrom the Department of Anesthesiology, Yale University School of Medicine, New Haven, CT. Address reprint requests to Christine Rinder, MD, Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, PO 208051, New Haven, CT 06520-8051. Emaih christine, rinder@yale.edu Copyright 9 2001 by W.B. Saunders Company 0277-0326/01/2002-0003535.00/0 doi: 10.1053/sane. 2001.23384

NOVEL ANTIPLATELET AGENTS (Table 1) Anti-llb/llla Agents

Platelet adhesion to a bleeding site is accomplished by different mechanisms depending in part on the nature of the injured vessel (artery v vein) and the blood velocity through that vessel. Once an initial layer of platelets is securely adherent to the bleeding site, the platelets undergo a coordinate array of processes that together are referred to as "activation." Platelet activation has multiple goals: (1) local release of ligands essential to a stable platelet-platelet matrix; (2) recruitment of additional platelets; (3) vasoconstriction of smaller arteries to slow bleeding; (4) localization and acceleration of the coagulation cascade resulting in fibrin formation; and (5) clot protection from fibrinolysis. One fundamental consequence of platelet activation is a conformational change in gtycoprotein IIb/IIIa (GPIIb/IIIa), the platelet receptor which is the target of a number of antiplatelet agents. 2 The

Seminars in Anesthesia, Periaperative Medicine and Pain, Vol 20, No 2 (June), 2001: pp 101-109

101

102
o

CHRISTINE RINDER

o
V~
0

~
E
>"

.'~
~
"E

'~
o

":5

o
~

o |

=~
~
E

~
.o

~E
~ '.~

=--

8 ~

2 .o_ ~o 9 =

O._

-=

-~s

o~8_

& &
L.u o._

0 "E |

"~
_

,.-

z
E o "-=

1=
;'-: o "-=

~
~

0
o

~-~o
~-~

._o ~
~ 8-8
~ 9 ,,"-0 =

--o

~=
,~
'--

~
.~ E

_oO

E s
u

,o -6

o
0

~-.~

.,,, >u

o.~Z'l

0 ._Q

o_~=~176176 ~-~_~~176176 ~a~ ~ ~ ~I o = ~ ~o P' 0" ~-~= ~o

0 0 9

~ --;= ~' 6 :'>~'~.~

E o

'g

=.~-o

~
o_~

.e~

o:~

,- o . " = - y - . 9 o 5 5

=.-~

,-'~"o

o._= =o o..$ .E .'- u- o o o o - o o o

~ =--o ,,, 0 - o ~--o

"-o , ~
oo=

'o

o o

2
0

'-0
o ..

o -8
o_ o_ |
E ~

o
.p
0
Z 0

.-o_

8 =
o

"-o

~6
. . . . 0 C

<

._-a
_ u

~._
~
,~

<
_

-~

<

-~

o ~_ ._
~
"g _ "~,
. . Ol~

"=A o=x
~__o 0

-0 0 0_

-I--

~ E ~o,.~

o._ ~

__ o.. ~
. .

.- o 0 _ ~ = =~.,-~

9 =u --~_'- "~
"~ ~ 0

=o
E o

e~.an

o
.m
._J

-g_
--o
0

"g_
"o
0

o._" - . o - u_~ m
~

~
_~m
--

_~
"~"

"-o
0

"11,3 A ua ~-

-~ x "

~8

do"
06--0 9 ~'~

go

o emo

.~ 9

~==%~

55

.~_

o'~

.~

.=~_

8-~

~55<

~o
e'., 0 0

,0 8 -

=..~
_=|
0

9 .- m._ --o0

9. 0 ~

c 9

"E.%_-

&~_

~, ~ 5 5 ~ . - =
o o'~-

=020--

u~

._

._=~-~ "- o o ~ " - ~ 0

u

NOVEL ANTICOAGULANTS

103

Resting Platelets

FIBRINOGEN

i,~~~tActivatedPiatelet s
inactive GPIIb/IIIa

Conformationally

_.

~"

active

GPIIb/IIIa

- - -

~FIBRINOGEN~

Fig 1. Schematic of the role of GPIIb/llla in forming a platelet-fibrinogen-platelet matrix and the ability of anti-GPIIb/ Ilia agents to block this action. On resting platelets (A), conformationally inactive GPllb/llla is unable to bind soluble fibrinogen; after stimulation by a platelet agonist, the resulting GPIIb/llla confarmational change allows fibrinogen binding in a bridging fashion, linking the activated platelets together. Independent of the plate]et activation pathway, GPIIb/llla inhibitors (B) block activated GPIIb/llla binding to fibrinogen, inhibiting thrombus formation.

mbinT~

Collagen

GPIIb/IIIa inhibition

FIBRINOGEN

brane signaling, thus extending the antiplatelet activity of these blockers beyond interference with platelet-platelet cohesion. Several different classes of anti-GPIIb/IIIa inhibitors have been developed, 3 each with unique pharmacokinetic and pharmacodynamic profiles. These agents have already carved out a sufficiently pervasive clinical niche such that many anesthesiologists will encounter them in patients presenting for urgent surgery. Abciximab (Reopro, Lilly, Indianapolis, IN) is a Fab fragment of a chimeric murine-human mono-

clonal antibody directed against GPIIb/IIIa. Abciximab binds with high affinity to GPIIb/IIIa independent of the receptors' conformational state.4 Because of this high receptor avidity, abciximab may persist for hours to days, although the plasma half-life of free drug is short (15 to 30 minutes). After bolus administration in doses producing 80% receptor blockade at 30 minutes, 50% to 60% of receptors may still be blocked after 24 hours, and traces of drug have been detected on circulating platelets for up to 1 week after

bound

platelet-

104
administration. In addition, small amounts of the antibody can be internalized by the platelet, blocking a portion of the intracellular stores of GPIIb! Ilia receptors and further extending the functional half-life of the drug. This latter property causes abciximab's antiplatelet activity to slowly wane after drug cessation and may, in fact, smooth the transition off the drug for the hypercoagulable patient. However, such lingering effects have the potential to contribute to perioperative bleeding well after stopping the drug. Because of the extreme longevity of the plateletbound form of abciximab, well beyond its plasma half-life, delaying urgent revascularization surgery for a few hours accomplishes little in the way of improved hemostatic potential. Platelet transfusions are effective in correcting the hemostatic defect, and the absence of free drug in the plasma ensures that the function of transfused platelets will not be inhibited. Platelet counts should routinely be checked before surgery, because abciximab-induced thrombocytopenia (<50,000 platelet/ram 3 in 2% of patients) may mandate platelet transfusion for surgery. Eptifibatide (Integrilin, COR Therapeutics, San Francisco, CA) is a synthetic cyclic peptide GPIIb/ Ilia receptor antagonist approved for use in acute coronary syndromes and after angioplasty or stent placement) Eptifibatide is almost two orders of magnitude smaller than abciximab, and rapidly binds to GPIIb/IIIa after intravenous administration. However, its affinity for the platelet receptor is less than that of abciximab, and the drug must therefore be administered in molar excess of the number of GPIIb/IIIa-binding sites. Eptifibatide has a 2.5-hour half-life and, unlike abciximab, platelet-associated drug levels decrease in tandem with plasma levels. For this reason and in contrast to abciximab, a delay in surgery for a few hours can restore platelet aggregability without the need for platelet transfusion. Furthermore, given the plasma excess of eptifibatide required to ensure 80% receptor blockade of endogenous platelets, 4 some inhibition of GPIIb/IIIa on the transfused platelets would be expected until plasma levels have decreased. Tirofiban (Aggrastat, Merck, West Point, PA) is a peptidometic GPIIb/IIIa inhibitor similar in size to eptifibatide. Like eptifibatide, tirofiban has shown efficacy in inhibiting coronary thrombosis in association with acute coronary syndromes and

CHRISTINE RINDER
percutaneous coronary interventions. 3 Tirofiban is somewhat slower than eptifibatide to produce platelet inhibition after administration, but tirofiban is also rapidly cleared from the plasma (TI! 2 = 2.5 hours), with no residual antiplatelet effects. With both high- and low-dose tirofiban, inhibition of adenosine diphosphate (ADP)-induced aggregation diminishes to <50% 4 hours after stopping the drug infusion and approaches baseline platelet function by 8 hours. 4 Tirofiban is not metabolized and is eliminated nearly entirely by renal clearance; thus, the dosage should be reduced in patients with severe renal insufficiency. Of the GPIIb/IIIa blockers noted in this article, abciximab has received the greatest attention with respect to bleeding complications. Some of these complications have been attributed to the dosage of adjuvant heparin used in one of the first trials (Evaluation of C7E3 for Prevention of Ischemic Complications, 1994), in which the heparin was not weight-adjusted. Subsequent abciximab trials and trials of other antiplatelet agents of its class have been more circumspect in heparin dosing, and the incidence of spontaneous hemorrhagic events has decreased accordingly. Abciximab also has been attributed with causing major bleeding complications during cardiopulmonary bypass surgery. 5 For urgent revascularization surgery, the markedly longer functional half-life of abciximab compared with the smaller blockers, eptifibatide and tirofiban, unquestionably contributes to its greater association with perioperative bleeding. Indeed, one cardiac surgeon has recommended that cardiologists choose one of the shorter-acting GPIIb/IIIa blockers instead of abciximab in any patient they consider at significant risk for urgent surgical revascularization. 6 However, the greater magnitude of risk reduction and better long-term survival in abciximab trials may bias cardiologists toward using abciximab for more seriously ill patients. 7 To date, no major head-to-head clinical trials have been conducted that would clarify the relative risk-benefit ratios of these anti-GPIIb/IIIa agents. A number of oral anti-GPIIbfllIa agents (eg, xemilofiban, sibrafiban, orbofiban) have been tested in the outpatient management of patients who underwent percutaneous transluminal coronary angioplasty, s Compared with the striking success of the intravenous GPIIb/IIIa blockers, oral inhibitors have been somewhat disappointing for antithrombotic ef-

NOVEL ANTICOAGULANTS
ficacy, and even potentially prothrombotic. 9 It is possible that the relatively subtherapeutic trough drug levels, by stabilizing the active receptor conformation, render GPIIb/Illa hyperresponsive to weak agonists without sufficient receptor occupancy to effectively block aggregation.l~The fact that the increased thrombotic tendency was observed principally at the lower dose of the oral GPIIb/llIa blocker supports this hypothesis. Better dosing strategies may help find a market for the oral folvns of these potent parenteral antiplatelet agents.

105
thrombus. In the presence of highly potent platelet agonists, such as thrombin, the influence of platelet-released products is minor, accounting for breakthrough thrombosis despite the use of effective platelet blockers such as aspirin. Ticlopidine (Ticlid, Roche Labs, Nutley, NJ) and clopidogrel (Plavix, Bristol-Meyers Squibb, Princeton, N J), the latter the acetate derivative of ticlopidine, are oral agents that are metabolized to compounds that block the ptatelet ADP receptor and prevent the ADP-induced amplification of ptatelet activation. 11 In clinical trials, both ticlopidine and clopidogret have been modestly superior to aspirin in the secondary prevention of heart attacks and strokes, and both have been approved by the Food and Drug Administration for this indication. Neither tictopidine nor clopidogrel affect platelet thromboxane A e synthesis or release and, thus, both drugs may be given in conjunction with aspirin for greater clinical potency. For example, in the first few months after coronary stenting when more robust antiplatelet activity is required, aspirin is often combined with either ticlopidine or clopidogrel to maintain stent pa-

ADP Receptor Antagonists

Dense granule release caused by platelet activation provides a local source of the platelet agonists, ADP, and serotonin (Fig 2). Platelet activation also stimulates synthesis and release of thromboxane As, another platelet agonist, from the platelet cytosol. These three agents are relatively weak agonists, but in the microenvironment of ongoing platelet activation, they can amplify the effects of other moderate platelet agonists. Such amplification may convert an otherwise reversible plateletplatelet conjugate into an irreversible platelet-rich

Weak Agonists

Strong Aaonists

Partial GPllbfllla Activation

Full GPIIb/Ina Activation

Threshold for Irreversible

Aggregation

II

Fig 2. Illustration of the different activation pathways used by weak versus strong platelet agonists. Weak platelet agonists and low doses of more potent agonists (collagen) are sufficiently stimulating to produce both granule and thromboxane A 2 (TXA2) release from a minority of platelets, forming reversible platelet-platelet aggregates. With augmentation by plateletreleased ADP, serotonin, and thromboxane A2, full GPIIb/llla activation in the majority of platelets causes platelet-platelet aggregate formation to become irreversible. Potent platelet agonists such as thrombin and high-dose collagen are sufficiently stimulating that they easily surpass threshold platelet activation levels, bypassing the need for supplementation by plateletreleased agonists. Abbreviations: EPI, epinephrine; ADP, adenosine diphosphate; PAF, platelet activating factor.

106
tency, and this combined therapy is being explored in a number of other clinical settings requiring potent antiplatelet activity. Because of the high frequency of neutropenia or thrombocytopenia observed with ticlopidine (2% to 3% of patients receiving the drug, with profound and even fatal outcomes in one-third of those), as well as a high incidence of thrombotic thrombocytopenic purpura (1 case per 1,600 to 3,000 patients), clinical use of ticlopidine has declined significantly. Clopidogrel has thus far proven to be as effective as ticlopidine in its antithrombotic action, 12 without the marrow suppressive potential and with, so far, a lower frequency of thrombocytopenic purpura associated with its use (11 known cases in approximately 3 million patients started on the drug). 13 Like ticlopidine, clopidogrel is inactive in vitro and is dependent on hepatic biotransformation in vivo. Steady-state platelet inhibition is reached between days 4 and 7 of treatment. In addition to its short-term use in patients with stented coronary artery disease, clopidogrel has been approved for more long-term use in patients with peripheral vascular disease, as well as those with stroke risk. Increasingly, ADP receptor blockers are perceived as making a critical difference in preserving vessel patency, and the decision to stop these agents before surgery should be made with caution. The perioperative team must compare the relative risk of increased blood loss and transfusion requirements with the potential for the individual patient to experience a catastrophic thrombotic event. Clinical experience with perioperative patients receiving clopidogrel has largely been anecdotal. Despite an elimination half-life of 8 hours, residual anti-aggregating activity can be observed for up to 5 days after discontinuation of treatment, particularly in elderly patients. The manufacturers have recommended that, like aspirin, clopidogrel use be stopped a full 7 days before surgery. When restarting the drug after surgery, the 4 to 7 days needed for full antiplatelet activity adds to the time window in which platelet function will be incompletely inhibited. Cilostazol (Pletal, Pharmacia & Upjohn, Peapack, NJ), another oral antiplatelet agent, has been approved for intermittent claudication in the peripheral vascular population. 14 Cilostazol is a potent selective inhibitor of phosphodiesterase 3, thereby slowing the breakdown of platelet cAMP, one of the intracellular second-messengers that

CHRISTINE RINDER
suppress platelet responsiveness. Cilostazol blunts platelet aggregation induced by ADP, low-dose collagen, epinephrine, arachidonic acid, and even low-dose thrombin, and in early trials, cilostazol seems to have somewhat more potent antiplatelet activity than aspirin. It has been compared with milrinone in vitro, and cilostazol was found to exert relatively greater antiplatelet effects with minimal enhancement of myocardial contractility, although the drug is contraindicated in patients with congestive heart failure. Its phosphodiesterase-inhibitory effects also produce a modest relaxation of vascular smooth muscle, likely contributing to its clinical ability to improve symptoms such as walking distance in patients with intermittent claudication. The elimination half-life of the drug and its active metabolites is 11 to 13 hours, and the drug accumulates approximately twofold with chronic administration (>2 days use). The optimum time for drug discontinuation before elective surgery has not been studied.
N e w Variations on Old Themes

The Food and Drug Administration has recently approved a combination drug consisting of an extended-release form of dipyridamole together with aspirin, marketed under the name of Aggrenox (Boehringer Ingelheiml Ridgefield, CT). In a large series of patients with a history of stroke or transient ischemic attack, this fixed-dose combination of drug was twice as effective in stroke prevention as either aspirin or dipyridamole alone. 15 The antiplatelet activity of this combination drug in vitro is also greater than that of aspirin alone, but its potential to contribute to perioperative bleeding is unknown. Its long duration of action suggests that if normal platelet function is desirable, patients will need at least 5 to 7 drug-free days to ensure return of platelet activity. Aspirin and other nonsteroidal anti-inflammatory drugs inhibit the action of the enzyme, cyclooxygenase (COX), which is found in many cells including platelets. 16 In platelets, COX inhibition blocks formation and release of the platelet activator/vasoconstrictor, thromboxane A 2 for the lifetime of the platelet (5 to 7 days) in the case of aspirin, and for the lifetime of circulating drug for the nonsteroidal anti-inflammatory drugs. Currently, two isoforms of the COX enzyme have been identified, COX-1 and COX-2, having similar amino acid sequences and enzymatic functions, but

NOVEL ANTICOAGULANTS
encoded by distinct genes and with very different tissue and cellular distributions. COX-1 is the isoform constitutively expressed jn platelets, whereas COX-2 is an inducible form expressed in macrophages and other cell types after stimulation by inflammatory mediators. Aspirin and nonsteroidal anti-inflammatory drugs inhibit both COX-1 and COX-2; however, a number of agents recently introduced to the market for the treatment of inflammatory diseases are more selective COX-2 inhibitors. By predominantly blocking the COX-2 isoform, these inhibitors retain potent anti-inflammatory effects with little or no antiplatelet activity. Experience with these agents in the perioperative setting is still being garnered, but if their antiplatelet activity is truly minimal, COX-2 inhibitors have the potential to be a valuable adjunct to opioid analgesics in the treatment of postoperative pain.
"6 . , "~, ._

107
a

8 ,o

~ 0

oo

~a

z~
.b_" f,

> -O

~ R-cZ.~

8 ", o. _ 8 . " |
o> o

<

o~

s
_.Q

'r-

=o

.,_~

~-o~

8 l '~ 8 E

._

.g
..Iz -1-

o,-~ Eo--.-'2 x o~15 ~ o ~oO_== ~ ~ 0 0

E
t-_o 9
. -

ANTITHROMBINS (Table 2) Low Molecular Weight Heparin (LMWH)

Unfractionated heparin (UFH) has been a mainstay of anticoagulant therapy for more than 50 years. Clinicians have managed to deal with the serious limitations of UFH, including poor bioavailability, variable activity between preparations, need for frequent partial thromboplastin time monitoring, bleeding risk, rebound after heparinization, osteoporosis, and heparin-induced thrombocytopenia and thrombosis] 7 When studies showed that the success of subcutaneous heparin in post-surgical deep vein thrombosis prophylaxis could be attributed to the preferential absorption of the low-molecular-weight UFH components exerting predominantly anti-Xa activity, the pharmaceutical industry worked aggressively develop effective smaller-chain heparins. Presently, tinzaparin sodium (Innohep, Dupont, Wilmington, DE), dalteparin (Fragmin, Pharmacia & Upjohn, Peapack, N J), and enoxaparin (Lovenox, Aventis Pharm, Parsippany, NJ) are approved in the United States for deep vein thrombosis prophylaxis, and the latter two are also approved for treatment of acute coronary syndromes, with some evidence that these agents are the treatment of choice for coronary events. LMWH products are produced by chemical, enzymatic, or physical depolymerization of UFH, using porcine heparin to avoid any risk of mad cow disease. Despite their relative size homogeneity, LMWH preparations can still be regarded as

"IT:
O O_

o_ "E

a-

--o

r~ O ..Q

8 r
"-6
o

"g
o~ u ~ o'~.E

"-6

E E

~LS~E
*E
O "B

,~ E
O

"6

o-~x

='--'a

g~

~g 8
. ~
> O

='-

N
_0

E
.r-

"-~

>.

"I-

-
o

J
O

E
D

2}
~:~ o C1- 0
0 = '-E

=~ ==~
.--

m-

z ~
-0

otA

O'-~

E 9

E P
[3

..

I1~

.E

<. ~

E 4',

o~"

L)

2
_ ~5

108
polypharmacy in terms of their mechanisms of action, some of which are not fully understood. 17 Where UFH have equivalent activity against thrombin and factor Xa, the main anticoagulant effects of LMWHs stem from potentiation of antithrombin's anti-Xa activity, a size-independent property of the polysaccharide. LMWHs do retain a variable portion of the parent UFH's ability to accelerate antithrombin-mediated inactivation of thrombin (IIa), depending on the proportion of higher-length polysaccharide chains in the particular LMWH preparation. In addition to its antithrombin-potentiating ability, LMWHs also induce release of endogenous anticoagulants, tissue plasminogen activator and tissue-factor pathway inhibitor, from endothelial cell stores, a property also observed with UFH. Unlike UFH, however, LMWH shows such reliable bioavailability after either intravenous or subcutaneous administration that many studies deny any need for laboratory monitoring of its activity. Indeed, given its multiplicity of actions, no single laboratory measurement could give an accurate representation of its anticoagulant activity. Attempts by manufacturers to standardize LMWHs on the basis of their anti-Xa potency or their ratio of anti-IIa/anti-Xa activity have failed, and for this reason as well as their different bioavailability properties, is the safety and efficacy profiles for one LMWH cannot readily be applied to another. Anesthetic implications of LMWHs have received a great deal of Food and Drug Administration and media attention, 19 and warnings regarding the hematoma risk associated with spinal or epidural anesthesia lead off enoxaparin's package insert. In point of fact, many of the reported hematoma cases occurred in patients who were also receiving other anticoagulants such as antiplatelet agents. Whether the association of this complication with LMWHs reflects the increased use of LMWHs in general, the growing tendency to combine LMWHs with antiplatelet drugs, or whether LMWHs uniquely predispose to bleeding in the epidural space is not known. Further complicating the decision regarding the choice of anesthetic is the uncertainty over LMWHs duration of anticoagulant action. The plasma half-life of these agents after intravenous administration is very reliable, albeit agent-specific. However, after subcutaneous administration, LMWH anticoagulant activity can persist as long as 12 hours, even when blood sam-

CHRISTINE RINDER
ples have no demonstrable anti-Xa activity. The minimum drug-free interval after which regional anesthesia becomes safe cannot be known with any certainty. Likewise, the potential of these drugs to contribute to perioperative blood loss is also unpredictable 2~ and likely to vary among the different formulations. With the growing attention to thrombotic risk together with their ease of administration, new LMWHs with unique pharmacokinetic profiles can be expected to become available, and oral heparin preparations are in development.
Direct Thrombin Inhibitors

These agents function independently of the action of antithrombin. Direct thrombin inhibitors do not bind to plasma proteins and are less immunogenic than standard heparin. One of their greatest advantages over UFH is their greater activity against clot-bound thrombin, theoretically making them the anticoagulant of choice during thrombolysis or procedures like percutaneous transluminal coronary angioplasty in which plaque-associated thrombin can be exposed. Lepirudin (Refludan, Aventis Pharmaceuticals, Parsippany, NJ) is the recombinant version of the leech anticoagulant, hirudin, which is approved for use in patients with heparin-induced thrombocytopenia and thrombosis requiring anticoagulation. 1 Lepirudin has a half-life on the order of 30 to 60 minutes after intravenous administration in patients with a normal creatinine clearance, and has been shown to be at least as effective as UFH in patients with unstable angina. There is no agent capable of reversing lepirudin anticoagulation, but lepirudin has been substituted for heparin during cardiopulmonary bypass with some success, although the dosing was largely empiric. 21 In doses used for the treatment of unstable angina, the activated partial thromboplastin time is adequate for anticoagulation monitoring. For use during cardiopulmonary bypass, the ecarin clotting time is the best monitoring modality because the activated partial thromboplastin time and the activated clotting time do not seem sufficiently sensitive to lepirudin levels at this dose range. Argatroban (Novastan, Texas Biotechnology Corp, Houston, TX) is another direct thrombin inhibitor that has been used extensively in Japan and is approved in the United States in patients in whom UFH is contraindicated. 22 It is a small molecule given by intravenous infusion that binds to

NOVEL ANTICOAGULANTS
the active site of thrombin and has superior activity against clot-bound thrombin than either heparin or hirudin. A recent trial of argatroban together with tissue plasminogen activator in patients with acute myocardial infarction 23 showed enhanced thrombolysis and reperfusion compared with UFH, although the 30-day composite outcome of death/ reinfarction/congestive heart failure was not significantly improved. Its relatively short half-life ( < 1 hour) makes it a potential alternative to heparin for cardiopulmonary bypass, although there have been no reports of its use in North America that might guide a dosing strategy. New anticoagulants are making their way into the clinical arena almost weekly, many with unique targets in the coagulation process and all with distinct pharmacokinetic properties, making them difficult to compare with one another. As these anticoagulants become more pervasive in the outpatient setting, anesthesiologists will be faced with increasingly complex questions. How soon after surgery should a patient be restarted on their agent? Can intravenous agents be substituted for oral ones to shorten the time window in which the patient is unanticoagulated? Are there unique surgical situations that would benefit from these novel agents? As new agents are developed and new indications for their use are identified, these issues will become more and more commonplace in the perioperative arena.

109
5. Gammie JS, Zenati M, Kormos RL, et al: Abciximab and excessive bleeding in patients undergoing emergency cardiac operations. Ann Thorac Surg 65:465-469, 1998 6. Dyke CM: Safety of glycoprotein IIb/IIIa inhibitors: A heart surgeon's perspective. Am Heart J 138:$307-316, 1999 (suppl) 7. Kereiakes DJ, Runyon JP, Broderick TM, et al: IIb's are not IIb's. Am J Cardiol 85:23C-3tC, 2000 8. Verstraete M: Synthetic inhibitors of platelet glycoprotein IIb/IIIa in clinical development. Circulation 101:76-81, 2000 9. Heeschen C, Hamm CW: Difficulties with oral' platelet glycoprotein IIbBIIa receptor antagonists. Lancet 355:330-331, 2000 10. Holmes MB, Sobel BE, Cannon CP, et at: Increased platelet reactivity in patients given Orofiban after and acute coronary syndrome: An OPUS-TIMI 16 substudy. Am J Cardiol 85:491-493, 2000 11. Zussman RM, Chesebro JH, Comerota A, et al: Antiplatelet therapy in the prevention of ischemic vascular events: Literature review and evidence-based guidelines for drug selection. Clin Cardiol 22:559-573, 1999 12. Easton JD: Clinical aspects of the use of clopidogrel, a new antiplatelet agent. Semin Thromb Hemost 25:77-82, 1999 13. Bennett CL, Connors JM, Carwile JM, et al: Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342:1773-1777, 2000 14. Beebe HM, Dawson DL, Cutler BS, et al: A new pharmacological treatment for intermittent claudication. Arch Intern Med 159:2041-2050, 1999 15. Sacco RL, Elkind MS: Update on antiplatelet therapy for stroke prevention. Arch Int Med 160:1579-1582, 2000 16. Schafer AI: Effects of nonsteroidal anti-inflammatory therapy on platelets. A m J Med 106:25S-36S, 1999 (suppl) 17. Fareed J, Hoppensteadt DA, Bick RL: An update on heparins at the beginning of the new millennium. Semin Thromb Hemost 26:5-21, 2000 18. Samam MM, Gerotziafas GT: Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost 26:31-38, 2000 19. Lumpkin MM: FDA public health advisory. Anesthesiology 88:27A-28A, 1998 20. Skubas NJ, Despoils GJ, Vlasnic JJ, et al: Preoperative use of enoxaparin and tirofiban: Possible association with increased bleeding postbypass. Anesthesiology 91:869, 1999 21. Latham P, Revelis AF, Joshi GP, et al: Use of recombinant hirudin in patients with heparin-induced thrombocytopenia with thrombosis requiring CPB. Anesthesiology 91:263-264, 2000 22. Hursfing MJ, Alford KL, Becket CP, et al: Novastan| (Brand of Argatroban): A small-molecule direct tbrombin inhibitor. Semin Thromb Hemost 23:503-516, 1997 23. Jang IK, Brown DF, Losordo D, et al: A multicenter, randomized study of argatroban versus heparin as adjunct to TPA in acute myocardial infarction: MINT study. J A m Coll Cardiol 33:1878-1885, 1999

REFERENCES
1. Weitz JI, Bates SM: Beyond heparin and aspirin. New treatments for unstable angina and non-Q-wave myocardial infarction. Arch Intern Med 160:740-758, 2000 2. Nurden AT, Poujol C, Ddurrieu-Jais C, et al: Platelet glycoprotein IIb/IIIa inhibitors: Basic and clinical aspects. Arterioscler Thromb Vasc Biol 19:2835-2840, 1999 3. Harrington RA: Overview of clinical trials of glycoprotein IIb-IIta inhibitors in acute coronary syndromes. A m Heart J 138:$276-286, 1999 (suppl) 4. Tcheng JE: Clinical challenges of platelet glycoprotein IIb/llIa receptor inhibitor therapy: Bleeding, reversal, tbrombocytopenia, and retreatment. Am Heart J 139:$38-45, 2000 (suppl)