Beyond Unfractionated Heparin and Warfarin Current and Future Advances

Article (PDF Available)inCirculation 116(5):552-60 · August 2007with31 Reads
DOI: 10.1161/CIRCULATIONAHA.106.685974 · Source: PubMed
Jack Hirsh, Martin O'Donnell and John W. Eikelboom
Beyond Unfractionated Heparin and Warfarin : Current and Future Advances
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Beyond Unfractionated Heparin and Warfarin
Current and Future Advances
Jack Hirsh, MD; Martin O’Donnell, MB; John W. Eikelboom, MBBS
nticoagulants are widely used by cardiologists. Unfrac-
tionated heparin (UFH) and coumarins were discovered
more than 60 years ago, and for more than 40 years, they have
been the sole anticoagulant drugs available to clinicians.
Now, in 2007, several new anticoagulants have been intro-
duced, and many more are under clinical development. Will
these new anticoagulants replace the established drugs, and if
so, how will these new anticoagulants fit into the therapeutic
armamentarium of the practicing cardiologist?
Both UFH and coumarins were in clinical use long before
their mechanism of action was completely understood. Both
were also discovered by chance: UFH from extracts of dog
liver and coumarins from extracts of vegetable matter
(spoiled sweet clover). Low-molecular-weight heparin
(LMWH) was also discovered by chance in the late 1970s and
early 1980s and was in clinical use for at least a decade before
its mechanistic advantages over UFH were identified.
In the
quest for new anticoagulants, scientists often turned to
extracting natural anticoagulants from hemophagic animals
and insects and from snake venoms.
Defibrinating enzymes,
factor Xa inhibitors, and thrombin inhibitors were isolated,
purified, and in some cases synthesized by recombinant
techniques. Of these anticoagulants, recombinant hirudin
(from leeches) and recombinant NAPC2 (from hookworm)
have been tested clinically. A few new anticoagulants (throm-
bomodulin, activated protein C) are synthesized by recombi-
nant techniques, but with advances in structure-based design,
most new anticoagulants are small molecules designed spe-
cifically to block the activity of coagulation enzymes either
by fitting into their catalytic pockets, like a key into a lock, or
by interacting with and activating anticoagulant proteins such
as antithrombin (AT; eg, fondaparinux). On the basis of these
technological advances, it is now possible to modulate the
coagulation process at almost every step.
The first wave of new anticoagulants was not orally active,
thereby limiting their value for long-term treatment. These
new parenteral anticoagulants (LMWH, bivalirudin, and
fondaparinux) are effective and, because of their advantages
over UFH, have replaced or are likely to replace UFH for
many acute cardiac indications. As a result, the need for
additional parenteral anticoagulants is less pressing than for
new oral anticoagulants to replace warfarin. Initially, devel-
opment of orally active agents was stalled because of tech-
nical difficulties; however, with advances in techniques for
oral absorption, several new site-specific oral anticoagulants
have now been developed and are undergoing clinical testing.
Drug developers have focused mainly on 2 key targets: factor
Xa and factor IIa (thrombin). The cost of developing a new
anticoagulant is high. Added to these development costs,
trials evaluating novel anticoagulant therapies for the preven-
tion of major vascular events for cardiac indications are
particularly expensive, because the required sample size is
large, and the duration of follow-up is long. Consequently, drug
development often starts with less expensive studies in the
prevention of venous thrombosis, based on the premise that
success in this indication predicts success for other indications.
Drugs currently under development or recently introduced
into clinical practice are listed in Table 1. In the remainder of
the present review, we emphasize those agents that have been
or are likely to be introduced into clinical practice in
cardiology. Several new parenteral compounds but no new
oral agents have been approved clinically. Before discussing
the new antithrombotic drugs, we briefly review the limita-
tions and advantages of UFH and LMWH, because it is these
limitations that provide opportunities for new parenteral
anticoagulants. The limitations of warfarin have been re-
viewed extensively elsewhere
and will not be discussed here.
Limitations and Advantages of UFH
and LMWH
In addition to its well-known bleeding complications, UFH
has biological and pharmacokinetic limitations.
The biolog-
ical limitations are immune-mediated platelet activation,
which leads to heparin-induced thrombocytopenia (HIT), and
an effect on bone cells that leads to heparin-induced osteo-
porosis. These side effects are chain length– dependent and
charge-dependent. Pharmacokinetic limitations are caused by
AT-independent binding of UFH to plasma proteins and to
proteins released from platelets, which results in the variable
anticoagulant response and, therefore, a need for anticoagu-
lant monitoring.
Is UFH likely to become obsolete? The answer is not yet.
UFH has 3 major advantages over LMWH.
The first is that
the anticoagulant effects of UFH can be rapidly and com-
pletely neutralized by protamine. On the basis of this advan-
tage, UFH remains the anticoagulant of choice during cardio-
From the Henderson Research Centre, Hamilton Health Sciences Corporation (J.H.), Department of Medicine, McMaster University (J.H., M.O.,
J.W.E.), and Thrombosis Service, Hamilton General Hospital, Hamilton Health Sciences Corporation (J.W.E.), Hamilton, Ontario, Canada.
Correspondence to John W Eikelboom, Thrombosis Service, Hamilton General Hospital, Hamilton Health Sciences Corporation and McMaster
University, Hamilton, Ontario L8L 2X2, Canada. E-mail
(Circulation. 2007;116:552-560.)
© 2007 American Heart Association, Inc.
Circulation is available at DOI: 10.1161/CIRCULATIONAHA.106.685974
Contemporary Reviews in Cardiovascular Medicine
at MCMASTER UNIV on May 14, 2013 from
pulmonary bypass. Second, when used in clinical doses, UFH
is not cleared by the kidneys and therefore is potentially safer
than LMWH in patients with renal insufficiency. The third
advantage, although theoretical, is potentially important in
cardiology. UFH is effective in modulating the contact
activation pathway by inactivating factor XIa and, to a lesser
extent, factor XIIa through an AT-dependent mechanism
(Figure). In contrast, the shorter chain length of LMWH is
less effective, and pentasaccharide is ineffective in blocking
these contact activation steps.
The contact activation path-
TABLE 1. New Anticoagulants
Target Parenteral Oral
Factor IIa (thrombin)† Hirudin (desirudin, lepirudin) Ximelagatran
Bivalirudin* Dabigatran*
Argatroban* Odiparcil*
Factor Xa† Fondaparinux* Rivaroxaban*
Idraparinux‡ Apixaban*
SSR126517 (biotinylated idraparinux) LY517717*
DX-9056a YM150*
Otamixaban* Du-176b*
Factor VIIa/TF
Tifacogin (recombinant TFPI)
Recombinant NAPc2
Factor VIIai
Factor IXa Factor IXa aptamer* TTP889
Protein C pathway Protein C
Drotrecogin (recombinant activated protein C)
ART123 (soluble thrombomodulin)
Factor Xa/factor IIa Hexadecasaccharide (SR123781A)*
Bemiparin (ultra-LMWH)
TF indicates tissue factor; TFPI, tissue factor pathway inhibitor; NAPc2, nematode anticoagulant
peptide; and Factor VIIai, active site blocked factor VIIa.
*Agents that are under evaluation or are approved for use for cardiology indications are identified
with an asterisk.
†Many other factor Xa and factor IIa inhibitors are currently in early stages of development.
‡A biotinylated formulation of idraparinux is currently undergoing clinical trials.
Inhibition of the contact activation and tissue factor pathways by UFH and inhibition of the tissue activation pathway by LMWH and
fondaparinux. Tissues factor pathway: initiation of coagulation is triggered by the tissue factor/factor VIIa complex (TF/VIIa), which acti-
vates factor IX (IX) and factor X (X). Contact activation pathway: initiation of coagulation is triggered by activation of factor XII (XIIa),
which activates factor XI (XIa). Factor XIa activates factor IX, and activated factor IX (IXa) propagates coagulation by activating factor X
in a reaction that utilizes activated factor VIII (VIIIa) as a cofactor. Activated factor X (Xa), with activated factor V (Va) as a cofactor,
converts prothrombin (II) to thrombin (IIa). Thrombin then converts fibrinogen to fibrin. UFH targets steps in both the contact activation
pathway (inactivates XIa and XIIa) and tissue factor pathway (inactivates IXa, Xa, and IIa). Fondaparinux modulates the tissue factor
pathway by inactivating factor Xa. LMWH also modulates the tissue factor pathway by inactivating factor Xa and, to a lesser degree,
factor IIa. LMWH exerts weak activity against the contact activation pathway. P indicates phospholipid surface; TF, tissue factor.
Hirsh et al Beyond Unfractionated Heparin and Warfarin 553
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way contributes to thrombosis on catheter tips, stents, and
filters. Most clinically relevant thrombogenic stimuli trigger
coagulation through activation of the tissue factor pathway,
which is blocked by inhibitors of factor Xa and thrombin.
Hemostasis is also triggered by activation of the tissue factor
pathway, and anticoagulant-mediated bleeding occurs as a
consequence of inhibition of this pathway. In contrast, the
contact activation pathway contributes to thrombosis medi-
ated by contact with a foreign surface, and this pathway has
minimal involvement in hemostasis. Therefore, by directly
inhibiting the contact activation pathway (in addition to the
tissue factor pathway through inhibition of factor Xa and
thrombin), UFH has the potential advantage of modulating
coagulation triggered by this pathway, at doses that are less
likely to produce bleeding than other anticoagulants. These
theoretical considerations might explain in part why early
attempts to use LMWH to prevent clotting in cardiac bypass
circuits were unpromising and why the risk of thrombosis of
cardiac catheters is higher with fondaparinux than with UFH.
LMWHs are prepared by depolymerization of UFH; they
have a more predictable dose response and a longer-half life
than UFH and are cleared principally by the renal route.
LMWH has replaced UFH for many indications, including the
management of patients with acute coronary syndromes (ACS).
UFH and LMWH are contraindicated in patients with a
recent history of HIT, and LMWH is contraindicated in
patients with severe renal insufficiency. The new parenteral
anticoagulants can be used safely in HIT, and some are partially
or entirely cleared by nonrenal mechanisms (Table 2).
New Anticoagulants
Thrombin Inhibitors
Direct thrombin inhibitors bind to thrombin and block its
interaction with substrates.
Unlike UFH, direct thrombin
inhibitors inactivate fibrin-bound thrombin and fluid-phase
thrombin, a theoretical advantage that is of uncertain clinical
importance. Direct thrombin inhibitors lack an antidote.
Three parenteral direct thrombin inhibitors have been
licensed in North America for limited indications: hirudin is
approved for treatment of patients with HIT; argatroban is
approved for the treatment of HIT and for patients with or at
risk of HIT who are undergoing percutaneous coronary
intervention (PCI); and bivalirudin is licensed as an alterna-
tive to UFH in patients undergoing PCI.
Bivalirudin is a 20 –amino acid synthetic polypeptide
analog of hirudin.
Once bound, bivalirudin is cleaved by
thrombin, thereby reducing its antithrombotic activity. Biva-
lirudin has a plasma half-life of 25 minutes after intravenous
injection and is partially cleared renally; there is no antidote
for bivalirudin.
Bivalirudin has been evaluated in patients
with non–ST-segment elevation ACS who are undergoing
in patients with ST-segment elevation myocardial
infarction (MI) treated with streptokinase,
and in urgent or
elective PCI.
10 –12
Ximelagatran, the first orally active thrombin inhibitor,
a prodrug of the active site-directed thrombin inhibitor
melagatran. After ingestion and absorption, ximelagatran
undergoes rapid biotransformation to melagatran, the active
agent. Melagatran is eliminated via the kidneys. Ximelagat-
ran has a plasma half-life of 4 to 5 hours and is administered
orally twice daily.
Ximelagatran has been evaluated exten-
sively for the prevention of stroke and systemic embolism in
patients with atrial fibrillation (AF)
and in patients with
Despite favorable efficacy results, ximelagatran was
not approved for use in North America because of concerns
regarding liver toxicity and issues related to the claim that it
is noninferior to warfarin in AF patients. Nevertheless, the
results of the ximelagatran studies are important because they
provide solid evidence that an oral anticoagulant can be used
safely and effectively without coagulation monitoring.
Dabigatran etexilate is a prodrug of dabigatran, a specific,
competitive, and reversible inhibitor of thrombin.
ran etexilate is rapidly absorbed after oral administration and
converted to dabigatran. The plasma half-life is 8 hours
after a single dose and 14 to 17 hours after multiple doses.
Despite its long half-life, dabigatran etexilate is being given