European Heart Journal Advance Access published online on April 10, 2007
European Heart Journal, doi:10.1093/eurheartj/ehl492
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Anticoagulants in heart disease: current status and perspectives
Italy
Denmark
Sweden
Italy
Switzerland
United Kingdom
Denmark
Denmark
France
Sweden
The Netherlands
Canada
* Corresponding author. Institute of Cardiology, ‘G. d'Annunzio’ University—Chieti, Ospedale S. Camillo de Lellis, Via Forlanini 50, 66100 Chieti, Italy. Tel: +39 0871 415 12; fax: +39 0871 402 817/498217. E-mail address: rdecater{at}unich.it
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Preamble: purposes and scope of the task force |
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Preamble: purposes and scope...
Blood coagulationDrugs interfering with blood coagulation are a mainstay of cardiovascular therapy. Despite their widespread use, there are a number of unmet needs for current parenteral and oral anticoagulants in cardiovascular diseases. This therapeutic area is undergoing unprecedented changes with the clinical introduction of new drugs. This document, initiated by a committee appointed by the European Society of Cardiology (ESC) Working Group on Thrombosis, intends therefore:
- to review the current mechanism of action, pharmacological properties, indications, side effects, ongoing trials, and areas of current investigations for drugs interfering with coagulation as applied to atherothrombosis and arterial thrombo-embolism in heart disease, namely:
- coronary heart disease and percutaneous coronary interventions (PCIs);
- atrial fibrillation (AF);
- artificial heart valves;
- chronic heart failure (CHF);
- coronary heart disease and percutaneous coronary interventions (PCIs);
- to do so with a ‘pharmacologically based’ approach rather than a ‘disease-oriented’ one, complementary with what other Guidelines Groups and Task Forces have done or are in the process of doing in indicating and recommending therapeutic options for specific cardiovascular diseases;
- to do so by putting together a group of coagulation experts and clinical cardiologists, mostly—but not exclusively—from Europe.
This document is intended to follow-up on the Task Force Document on the use of antiplatelet agents in cardiovascular disease, proposed by the committee of experts appointed similarly by the ESC Working Group on Thrombosis1 and is intended to be regularly updated. The Writing Committee of this document has decided against issuing graded recommendations on the use and dosing of drugs, because this might conflict with the task of guidelines, some of which are being finalized at the same time by the ESC.
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Blood coagulation |
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Haemostasis
When a blood vessel is damaged, the site of disruption must be rapidly sealed to prevent blood loss. Haemostasis requires the formation of an impermeable platelet and fibrin plug at the site of injury. Preventing clot propagation through the vascular tree also requires localizing platelets and coagulation at the site of injury. The clot is later dissolved by another protease reaction, fibrinolysis, which also prevents the vessel from being occluded by the clot during its formation. In order for the blood to stay fluid within the circulation, a delicate balance between the carefully regulated systems of coagulation and fibrinolysis is needed. Disturbances in either system will cause a tendency towards thrombosis or bleeding, respectively.2
Arterial thrombosis
Arterial thrombosis can occur from at least two main different mechanisms, endothelial erosion or plaque rupture.3–5 Superficial erosion or denudation of the endothelial cells lining the plaque accounts for about 25% of all cases of fatal coronary thromboses. Plaque rupture causes 
75% of major coronary thromboses. Plaque rupture results in the exposure of thrombogenic material, e.g. collagen and tissue factor (TF), to the flowing blood. Upon plaque rupture, the lipid gruel, containing TF, and the underlying connective tissue matrix are exposed to the blood, leading to the activation of platelets and the coagulation system as well as to the simultaneous release of vasoactive substances. This induces thrombus formation and vasoconstriction, which may cause myocardial ischaemia and acute coronary syndromes (ACS).
Tissue factor
Today coagulation is considered to be a highly regulated reaction that takes place on cell surfaces.6,7 The main initiator of coagulation is TF, a transmembrane glycoprotein (GP). TF is a member of the class II cytokine receptor superfamily, and functions both as the receptor and as the essential cofactor for factors (F) VII and VIIa. Assembly of the TF/FVIIa complex on cellular surfaces leads to the activation of FX and initiates coagulation. TF is constitutively expressed in cells surrounding blood vessels and large organs to form a haemostatic barrier, but can also be induced in vascular cells in response to a number of inflammatory stimuli, such as adhesion molecules [among which P-selectin and CD40 ligand (CD40L)], cytokines, and oxidized/modified low density lipoproteins (LDLs).8 Total lethality in homozygous TF knock-out mice embryos provides convincing evidence for TF to be indispensable for life. In addition to its role in haemostasis, the TF/FVIIa complex has been shown to elicit intracellular signalling resulting in the induction of various genes, thus explaining its role in various biological functions, such as embryonic development, cell migration, inflammation, apoptosis, and angiogenesis.9–11
Tissue factor pathway inhibitor
TF pathway inhibitor (TFPI) is a potent serine protease inhibitor of TF/FVIIa-induced coagulation. It functions by neutralizing the catalytic activity of FXa and, in the presence of FXa, by feedback inhibition of the TF/FVIIa complex.12 TFPI contains three Kunitz-type domains: the first domain binds to FVIIa and the second to FXa. The third domain is involved in binding of TFPI to lipoproteins. The C-terminal end of TFPI is required for the binding to cell surfaces (13 and references therein). The primary site of synthesis of TFPI is the vascular endothelium,14 but also a number of other cell types have been reported to be production sites, including platelets. In vivo, 80% of plasma TFPI circulates in complex with plasma lipoproteins. A major pool of TFPI, free TFPI, is associated with the endothelial surface and is released into circulating blood upon the intravenous (i.v.) administration of unfractionated heparin (UFH) as well as after the subcutaneous (s.c.) injection of low molecular weight heparins (LMWHs).15
Cellular control of coagulation
The cell surface-based coagulation process can be currently described in three overlapping phases: initiation, amplification, and propagation.7,16,17 The process starts on TF-exposing cells and continues on the surfaces of activated platelets.
The initiation phase is localized to TF-bearing cells that are exposed from the subendothelial tissue to flowing blood upon vascular injury. The proteolytic TF/FVIIa complex activates small amounts of FIX and FX. On TF-exposing cells, FXa then associates with FVa to form the prothrombinase complex (Figure 1). FVa derives from several sources, including activated platelets adhering at injury sites, as well as from plasma, where FV can be activated by FXa. The prothrombinase complex then cleaves prothrombin to generate small amounts of thrombin, the enzyme responsible for clot formation. The concentration of TF/FVIIa complex and of TFPI regulates the duration of this initiation phase. When a certain amount of FXa has been generated, it is bound by TFPI, and a quaternary complex with TF and FVIIa is formed.
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In contrast to FXa, FIXa is not inhibited by TFPI, and only slowly inhibited by antithrombin (AT). FIXa moves in the fluid phase from TF-bearing cells to nearby platelets at the injury site.
In the amplification phase, low concentrations of thrombin activate platelets adhering to the injury site to release FV from their 
-granules. A positive feedback loop is initiated, whereby thrombin activates released FV, and FVIII bound to von Willebrand factor. Such activated factors bind to platelet surfaces, which provide enough scaffolding for the large-scale thrombin generation that occurs during the propagation phase. Thrombin also activates FXI bound to platelets (Figure 1). The role of FXIa, a member of the intrinsic pathway of coagulation, can be considered as a booster of FIXa production on the platelet surface and thus increases thrombin generation.17
In the propagation phase, the phospholipid surface of activated platelets acts as a cofactor for the activation of the FVIIIa–FIXa complex (termed ‘Xase’) and of the FVa–FXa complex (‘prothrombinase’), which accelerate the generation of FXa and thrombin, respectively. In addition, FXIa bound to the platelet surface activates FIX to form more Xase. FXa, thus produced, associates rapidly with FVa on the platelet surface, resulting in a burst of thrombin, ultimately leading to the bulk cleavage of fibrinogen to fibrin. Soluble fibrin is finally stabilized by FXIIIa, also activated by thrombin, to form a fibrin network, i.e. a thrombus (Figure 1).
Thrombomodulin (TM), a transmembrane molecule expressed on endothelial cells, also binds thrombin, and the thrombin–TM complex activates the protein C anticoagulation system. Activated protein C limits the FXa/FVa activity on the endothelial surface of the injured vessel and thus the propagation of coagulation reactions.17 However, the burst of thrombin also induces activation of the carboxypeptidase thrombin-activatable fibrinolysis inhibitor (TAFI), which removes the plasmin(ogen)-binding C-terminal lysine residues, and thereby increases the resistance of the clot to lysis.
Possible targets of coagulation inhibitors (anticoagulants) are depicted in Figure 2.
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Classical targeting of coagulation is done with heparins and vitamin K antagonists (VKAs). To target the initiation phase of coagulation, a number of drugs that inhibit the activity of TF/FVIIa complex are under evaluation, including recombinant TFPI (tifagosin), recombinant nematode anticoagulant (NAPC2), and active site-inhibited FVIIa (ASIS). Under development are a number of novel drugs targeting TF-FVIIa (Figure 2).
Drugs directed to target coagulation proteases that drive the propagation phase include agents that block the coagulation proteases FIXa or FXa, directly or indirectly. These drugs decrease thrombin formation. On the other hand, activated protein C and soluble TM are aimed to inactivate the cofactors FVa and FVIIIa that are critical for the generation of thrombin. FIXa blockers include monoclonal antibodies and active site inhibitors. However, these new drugs have not yet (http://www.clinicaltrials.gov) reached phase III and will not be further reviewed here. The synthetic pentasaccharides mediate an indirect, AT-dependent, inhibitory effect on FXa. A number of orally active direct FXa inhibitors are under clinical testing in phase II studies. One advantage with these inhibitors is the capacity to block not only free FXa, but also FXa within the prothrombinase complex at the platelet surface. Other possible advantages of these inhibitors are that they target a molecule, FXa, which has fewer functions outside coagulation compared with thrombin, they have a wider therapeutic window than thrombin inhibitors, and they do not apparently lead, upon discontinuation, to the rebound hypercoagulability that is regularly observed upon stopping thrombin inhibitors.
New inhibitors of fibrin formation are direct thrombin inhibitors (DTIs) that bind to thrombin and block its interaction with substrates, preventing the formation of fibrin and activation of platelets and FV, FVIII, FXI, and FXIII. These drugs may also inhibit thrombin-induced intracellular signal transduction pathways, including thrombin-induced platelet activation. The DTIs also block thrombin bound to fibrin in addition to thrombin in plasma.18
Cross-talk between coagulation and inflammation
Coagulation and inflammation are integrated processes through a network of components.19–21 They contribute together to diseases, as illustrated by the thrombus formation on ruptured atherosclerotic plaques, which contain abundance of inflammatory cells. Coagulation proteases modulate inflammation by activation of protease-activated receptors (PARs) and also by TM and binding of activated protein C to endothelial protein C receptor.22,23 PARs are seven transmembrane domains, G protein-coupled receptors expressed on a variety of cells, such as platelets, endothelial cells, and leukocytes. Platelets express PAR1 and PAR4, to which thrombin binds and thereby induces the activation of platelets, the expression of P-selectin and CD40L, and the release of inflammatory cytokines and growth factors. Cross-talk between the cells in platelet–leukocyte complexes via P-selectin and CD40L leads to TF-expression and further cytokine release. PAR1 may also bind the ternary complex TF/FVIIa/FXa. PAR2 cannot bind thrombin, but TF/FVIIa complex and FXa can activate this receptor.24 Binding of the different coagulation proteases to the PARs results in the upregulation of a number of genes involved in inflammation, including interleukin (IL)-8 and tumor necrosis factor- (Figure 3). On the basis of these findings, new drugs that will prevent activation of these PARs are under development.
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Epidemiology of anticoagulant therapy in heart disease |
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Coronary heart disease
Population-based surveys conducted in Europe during 1999–2001 have shown that most (>90%) patients presenting with an ACS receive aspirin during hospital admission and that most (
80%) also receive either unfractionated heparin (UFH) or low molecular weight heparins (LMWHs), with the proportions receiving these two forms of heparin approximately equal.25–27 The frequency of use of heparin varies little according to the presence of ST-elevation on admission or by final diagnosis [Q-wave myocardial infarction (MI), non-Q-wave MI, or unstable angina], but there is considerable variation in usage between European countries. At hospital discharge, most patients (>90%) receive an antithrombotic agent, generally aspirin, but in one survey around 6% were prescribed warfarin and around 9% LMWHs.27 The most recent cardiological survey of European prescribing practice, the EUROASPIRE-II study, examined treatment of patients who had undergone a coronary procedure (coronary bypass surgery or PCIs) or who had been hospitalized with acute MI or myocardial ischaemia.28 On admission, around one half were taking an antiplatelet agent and 7% an anticoagulant (which must be supposed to have been oral in most instances). On discharge, 90% were taking an antiplatelet regimen and 12% an anticoagulant regimen [which could have been an oral anticoagulant or a subcutaneous (s.c.) LMWH]. There was evidence of variation in the frequency of use of anticoagulants between European countries.
Non-valvular atrial fibrillation
The Euro Heart Survey on Atrial Fibrillation examined prescribing patterns among European cardiology practices during 2003–04.29 Most patients surveyed had a risk factor for stroke, and hence an oral anticoagulant was indicated. Around 80% of those with persistent or permanent AF received an anticoagulant, and 50% of those with paroxysmal did so. Only around 4% of patients with persistent or permanent AF did not receive any antithrombotic therapy. These rates are likely to be an overestimate of the use of anticoagulants in general practice. In a survey of UK-based general practitioners in 2003, around 40–50% of patients were taking warfarin (which was up from around 20–25% in 1994), whereas the remainder were taking an antiplatelet regimen.30 However, only around one half of those at very high risk of stroke were taking warfarin, so there remains ample scope for better targeting of therapy.
Prosthetic heart valves
Oral anticoagulants are widely prescribed and used in patients with prosthetic heart valves and irregularly recommended and used in patients with rheumatic mitral stenosis in sinus rhythm, but there is little data on the consistency of use and on how closely available recommendations are followed in different countries31 (see http://americanheart.org/downloadable/heart/1150461625693ValvularHeartDisease2006.pdf).
Heart failure
In the PRIME-II trial of ibopamine in CHF [New York Heart Association (NYHA) functional classes III and IV], drug use was surveyed among 1825 patients in 13 participating countries.32 Overall, 43% of patients were taking anticoagulants, but the proportion varied from 19% in France to 70% in the Netherlands. There was indirect evidence that anticoagulants were being used instead of antiplatelet therapy, since in areas of high anticoagulant use there was lower-than-average use of antiplatelet therapy. These data suggest the need for further randomized trials to establish whether oral anticoagulant therapy is preferable to aspirin among suitable patients with heart failure.
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Parenteral anticoagulants: general pharmacology |
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Thrombin has an active site and two exosites, one of which, exosite 1, binds to its fibrin substrate, orientating it towards the active site. Figure 4 displays the mechanisms of action of the different thrombin inhibitors described here below.
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Heparin derivatives
The heparin derivatives in current use include UFH, LMWHs, and the synthetic pentasaccharide derivatives fondaparinux and idraparinux. These are all parenteral drugs that must be administered by i.v. or s.c. injection, and they are classified as indirect anticoagulants because they require a plasma cofactor (essentially AT) to exert their anticoagulant activity. Thus, heparin derivatives bind to AT in plasma, a naturally occurring serine protease inhibitor, and enhance its capacity to inhibit FXa and thrombin. Each of the heparin derivatives will be briefly described.
Unfractionated heparin
As an agent discovered almost 90 years ago, UFH is the prototype of its derivatives. It is a natural product that can be isolated from beef lung or porcine intestinal mucosa. Because of the danger of transmission of prion disease from bovine tissues, most of the heparin used today is from porcine intestinal tissue.33
Mechanism of action
Heparin consists of a family of highly sulfated polysaccharide chains ranging in molecular weight from 3000 to 30 000 with a mean of 15 000, which corresponds to about 45 saccharide units.33 Only one-third of the heparin chains possess a unique pentasaccharide sequence that exhibits high affinity for AT, and it is this fraction that is responsible for most of the anticoagulant activity of heparin.33 Heparin chains lacking this pentasaccharide sequence have minimal anticoagulant activity when heparin is given in the usual prophylactic or therapeutic doses. With higher doses, heparin chains with or without a pentasaccharide sequence activate heparin cofactor II, a second plasma cofactor.34 Unlike AT, however, heparin cofactor II only inhibits thrombin.34 At even higher concentrations, heparin attenuates FXa generation in an AT- and heparin cofactor II-independent fashion.35,36
Heparin catalyses thrombin inhibition by AT by simultaneously binding to both AT, via its pentasaccharide sequence, and thrombin, in a charge-dependent fashion. Formation of this ternary heparin/AT/thrombin complex bridges the inhibitor and the enzyme together, and accelerates their interaction.33 The arginine reactive centre of AT then binds covalently to the active site serine of thrombin to form a stable thrombin/AT complex. Heparin dissociates from this complex and is able to activate additional AT molecules (Figure 4A–C).
Only heparin chains consisting of 18 or more saccharide units, which correspond to a molecular weight of about 5400, are of sufficient length to bridge AT to thrombin. However, shorter pentasaccharide-containing heparin can catalyse FXa inhibition by AT because this reaction does not require bridging. Instead, to catalyse FXa inhibition, heparin needs only to bind to AT via its pentasaccharide sequence.33 This binding evokes conformational changes in the reactive centre arginine of AT that accelerate its interaction with FXa.
Pharmacokinetics
UFH must be given parenterally. The preferred routes are by continuous i.v. infusion or by s.c. injection. When given s.c. for treatment of thrombosis, higher doses of heparin than those administered by i.v. infusion are needed to overcome the fact that the bioavailability of heparin after s.c. injection is only about 30%.33 This is, however, highly variable among individuals.37 The committee therefore recommends against the use of s.c. UFH, even as a bridging therapy for the short-term use after interruption of VKAs.
In the circulation, a number of plasma proteins compete with AT for heparin binding, thereby reducing its anticoagulant activity. The levels of these heparin-binding proteins vary among patients. This phenomenon contributes to the variable anticoagulant response to heparin and to the phenomenon of heparin resistance.33 Heparin also binds to endothelial cells and macrophages, a property that further complicates its pharmacokinetics.
Heparin is cleared through a combination of a rapid saturable phase and a slower first-order mechanism.33 The saturable phase of clearance likely reflects heparin binding to endothelial cells, platelets, and macrophages. Once bound, heparin is internalized and depolymerized. When the cellular binding sites are saturated, heparin enters the circulation, from where it is cleared more slowly via the kidneys. At therapeutic doses, a large proportion of heparin is cleared through the rapid saturable mechanism.33
The complex kinetics of heparin clearance render the anticoagulant response to UFH non-linear at therapeutic doses, with both the peak activity and duration of effect increasing disproportionately with increasing doses. Thus, the apparent half-life of UFH increases from 30 min after an i.v. bolus of 25 U/kg to 60 min with a bolus of 100 U/kg and to 150 min with a 400 U/kg bolus.33
Dosing and monitoring
The efficacy of UFH for the initial treatment of venous thrombo-embolism (VTE) is critically dependent on the dose.38,39 Heparin can be given in fixed or weight-adjusted doses, and nomograms have been developed to facilitate dosing.39 The doses of UFH recommended for the treatment of ACS are lower than those typically used to treat VTE. Because heparin can bind to fibrin, this difference may reflect the smaller thrombus burden in arterial thrombosis compared with venous thrombosis.
Because the anticoagulant response to UFH varies among patients, UFH therapy is monitored and the dose is adjusted based on these results. The test most often used to monitor heparin is the activated partial thromboplastin time (aPTT). The activated clotting time (ACT) is used to monitor the higher doses of UFH given to patients undergoing PCIs or cardiopulmonary bypass surgery.
A retrospective study done many years ago suggested that an aPTT ratio between 1.5 and 2.5 was associated with a reduced risk for recurrent VTE.40 On the basis of this study, an aPTT ratio (calculated by dividing the reported therapeutic aPTT range by the control value for the reagent) of 1.5–2.5 was adopted as the therapeutic range for UFH. However, the clinical relevance of this therapeutic range is uncertain because it has never been validated in prospective studies and because the aPTT reagents and coagulometers have changed over the years. With most aPTT reagents and coagulometers in current use, therapeutic heparin levels correspond to an aPTT ratio of 2.0–3.0.41 The committee agrees with the ACCP statement that the therapeutic range should be adapted to the reagent used.33 The committee recommends against the use of a fixed aPTT target in seconds for any therapeutic indications of UFH.
Side effects
Bleeding is the major complication of heparin therapy and will be dealt with in a specific paragraph together with management of bleeding with other anticoagulants (discussed subsequently).
Other complications of heparin include heparin-induced thrombocytopenia (HIT) and osteoporosis. HIT is caused by antibodies that are directed against a neoepitope on platelet factor 4 (PF4) that is exposed with the formation of heparin/PF4 complexes. By binding to Fc receptors on the platelet, these antibodies, which are of the IgG subclass, can activate the platelets.42,43 Activated platelets are then removed from the circulation, which causes thrombocytopenia. In addition, activated platelets and microvesicles arising from them can provide a surface onto which clotting factors assemble to promote thrombin generation. This phenomenon likely explains why HIT is a prothrombotic condition.42,43
Osteoporosis is a complication of long-term treatment with therapeutic doses of heparin. This appears to be the result of heparin binding to osteoblasts with subsequent osteoclast activation.33 It is not clear whether heparin-induced osteoporosis is reversible when heparin treatment is stopped.
Low molecular weight heparins
LMWHs are gradually replacing UFH for most indications. Like UFH, LMWHs are natural products that are derived from UFH by chemical or enzymatic depolymerization.33 LMWHs have pharmacological and biological advantages over heparin that render them more convenient to administer and less likely to cause HIT.33,44
Mechanism of action
As fragments of heparin, the mean molecular weights of LMWH preparations are about one-third that of heparin and range from about 4000 to 5000, which corresponds to about 15 saccharide units. Like UFH, LMWHs are heterogeneous and consist of polysaccharide chains that range in molecular weight from 2000 to 9000. About one-fifth of the chains possess a pentasaccharide sequence, and the anticoagulant activity of LMWHs is restricted to this fraction33,44 (Figure 4).
A number of LMWH preparations are available for clinical use. Each is prepared using a different method of depolymerization, and each has a unique molecular weight profile that endows it, at least to some extent, with distinct pharmacokinetic and anticoagulant properties. Consequently, the various LMWH preparations are not interchangeable.
Like UFH, LMWHs produce their anticoagulant effects by activating AT and accelerating the rate at which it inhibits FXa and thrombin. Because only pentasaccharide-containing chains composed of at least 18 saccharide units are of sufficient length to bridge AT to thrombin, at least 50–75% of LMWH chains are too short to catalyse thrombin inhibition. However, these short chains retain the capacity to promote FXa inhibition because this reaction does not require bridging. Consequently, LMWH preparations have greater capacity to promote FXa inhibition than thrombin inhibition and have anti-Xa to anti-IIa ratios that range from 2:1 to 4:1 depending on their molecular weight profiles. In contrast, by definition, UFH has an anti-Xa to anti-IIa ratio of 133,44 (Table 1). LMWHs have been shown to reduce significantly the release of von Willebrand factor, which has been shown to be a predictor of outcome in non-ST-elevation ACS (NSTE-ACS) and in ST-elevation acute myocardial infarction (STEMI),47 when compared with UFH.48 LMWHs also produce enhanced release of TFPI, which inhibits the factor VIIa–TF complex.49 However, the clinical relevance of these properties is uncertain.
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Pharmacokinetics
LMWHs have pharmacokinetic advantages over UFH. The bioavailability of LMWHs after s.c. injection is over 90%, likely reflecting the better absorption of shorter heparin chains from the s.c. injection site. LMWHs produce a more predictable anticoagulant response than UFH because the shorter heparin chains exhibit reduced affinity for heparin binding proteins in the plasma. In addition, LMWHs have a longer half-life than UFH and the half-life is dose-independent. These phenomena reflect reduced binding of LMWHs to the endothelium.
LMWHs are cleared via the kidneys and the drug can accumulate in patients with impaired renal function.
Dosing and monitoring
Typically, LMWHs are given in fixed or weight-adjusted doses without monitoring. However, monitoring is recommended in obese patients, in those with renal insufficiency, and when therapeutic doses of LMWHs are required during pregnancy. When monitoring is required, the anti-Xa level is the recommended test.33 LMWHs also slightly prolong the aPTT, but this occurs to a much lesser extent than with UFH, and the aPTT cannot be used for monitoring.33
Recent studies suggest that LMWHs can be given in weight-based doses to obese patients and a meta-analysis that included data on 921 patients with a body mass index over 30 did not find any increase in major bleeding when LMWHs were administered in this fashion.50 Appropriate dosing of LMWHs in patients with renal sufficiency is less clear. There is an inverse relationship between creatinine clearance and anti-Xa levels51,52 and the risk of bleeding complications with LMWHs is higher in patients with impaired renal function.50,53 In patients with severe renal insufficiency, UFH may be a better choice than LMWHs.
Side effects
Like any anticoagulant, the major side effect of LMWH treatment is bleeding. This is dealt with below in a specific paragraph (discussed subsequently).
HIT is less common with LMWHs than with UFH.42,54 This reflects the fact that LMWHs have lower affinity for platelets and cause less PF4 release than UFH. In addition, if PF4 is released, the lower affinity of LMWHs for PF4 results in the formation of fewer heparin/PF4 complexes, the antigenic target of HIT antibodies.42 However, LMWHs can form complexes with PF4 that are capable of binding HIT antibodies. This phenomenon likely explains the cross-reactivity with LMWHs in patients with HIT. Therefore, LMWHs should not be used as an alternative to heparin in patients with suspected or established HIT.
The risk of osteoporosis is lower with LMWHs than with heparin. This probably reflects the lower affinity of LMWHs for bone cells. In small clinical trials, LMWHs did not appear to reduce bone density when given in prophylactic or treatment doses.55–57
Pentasaccharides: fondaparinux and idraparinux
A new heparin derivative is fondaparinux, a synthetic analogue of the pentasaccharide sequence present in UFH and LMWHs that mediates their interaction with AT.58,59 Fondaparinux shares all the pharmacological and biological advantages of LMWHs over UFH. However, compared with LMWHs, fondaparinux selectively inhibits FXa, without specific inhibition of thrombin activity. As a synthetic molecule, fondaparinux is highly standardized and has no antigenic properties. A derivative of fondaparinux, termed idraparinux, is a synthetic, long-acting, highly sulfated analogue of fondaparinux, with prolonged half-life.
Mechanism of action
Fondaparinux has a molecular weight of 1728.58,59 Compared with the natural heparin-derived pentasaccharide, its structure has been modified so as to enhance its affinity for AT. The specific anti-Xa activity of fondaparinux is about seven-fold higher than that of LMWHs (about 700 anti-Xa U/mg and 100 anti-Xa U/mg, respectively). Fondaparinux reversibly binds to AT, producing irreversible conformational changes at the reactive centre loop of AT that enhance its reactivity with FXa by at least two orders of magnitude. As the molecule is too short to bridge AT to thrombin, fondaparinux has no effect on AT-mediated thrombin inhibition (Figure 4).
The bioavailability of fondaparinux after s.c. injection is 100%, higher than LMWHs and much higher than UFH. The drug is rapidly absorbed and has a half-life of about 17 h in young subjects and 21 h in the elderly. This difference in half-life likely reflects the reduced renal function in the elderly. Fondaparinux is excreted unchanged in the urine58,60 and should therefore not be given to patients with a creatinine clearance of <30 mL/min.
Fondaparinux produces a predictable anticoagulant response and exhibits linear pharmacokinetics when given in s.c. doses ranging from 2 to 8 mg.58,59 It does not bind to other plasma proteins, a finding that explains why it produces a more predictable anticoagulant response than heparin.
Like fondaparinux, idraparinux is a selective indirect FXa inhibitor.61 The idraparinux affinity for AT is more than 10-fold higher than that of fondaparinux. The higher affinity for AT probably explains its long plasma half-life, similar to that of AT, i.e. around 80 h. The anti-FXa activity and inhibition of thrombin generation of idraparinux are dose-dependent.
Dosing
Fondaparinux is given s.c. once daily in fixed doses. A dose of 2.5 mg is used in patients with non-ST-elevation and ST-elevation ACS and for thromboprophylaxis in medical and orthopaedic surgery patients. A dose of 7.5 mg is used for treatment of VTE. Because of the long half-life, idraparinux can be given s.c. once a week.61
Monitoring
Fondaparinux and idraparinux have not been monitored in the clinical studies that evaluated their utility. Both drugs have little or no effect on routine tests of coagulation, such as the aPTT or ACT.62 These tests are therefore unsuitable to monitor the clinical use of these drugs. If monitoring is required, their anticoagulant activity can be measured with anti-Xa assays using fondaparinux or idraparinux as the reference standard.
Side effects
Besides bleeding (see the specific paragraph below), side effects of fondaparinux and idraparinux are largely unknown. In contrast to UFH or LMWHs, fondaparinux does not cause HIT and has actually been used successfully to treat HIT. It also has been used successfully in a patient who had urticarial reactions at the LMWH injection sites. Finally, although patient data are lacking, in vitro and in vivo studies suggest that fondaparinux will have less effect on bone than UFH or LMWHs.63,64
Parenteral direct thrombin inhibitors
In contrast to indirect thrombin inhibitors, such as UFH, LMWHs, and the heparin-derived pentasaccharides, which act by catalysing the naturally occurring thrombin inhibition by AT and/or heparin cofactor II, DTIs bind directly to thrombin and block its interaction with substrates, thus preventing fibrin formation, thrombin-mediated activation of FV, VIII, XI, or XIII, and thrombin-induced platelet aggregation (Figure 4F). By interfering with these feedback mechanisms, DTIs also interfere with thrombin generation.
Hirudins are polypeptides first isolated from the salivary glands of the medicinal leech. Hirudins are bivalent inhibitors that typically bind both to the active site and the fibrin-binding site of thrombin (Figure 4F). Consequently, they form an essentially irreversible 1:1 hirudin/thrombin complex. They are cleared via the kidney with a half-life of 90–120 min when given i.v., and of 120–180 min by s.c. injection. There are two commercially available recombinant hirudin preparations, desirudin and lepirudin. Lepirudin, with a half-life of 90 min, is approved for the i.v. use in HIT. There is no selective antagonist that can reverse over-anticoagulation with hirudins.
Bivalirudin, formerly known as hirulog, is a 20-amino acid, synthetic version of hirudin and is—like original molecules—a bivalent inhibitor of thrombin (Figure 4F). However, bivalirudin is slowly released from thrombin, restoring active site function of the enzyme. Bivalirudin has a half-life of 25 min and is degraded primarily by a combination of hepatic metabolism and proteolytic cleavage. Only a small proportion is eliminated via the kidney. There is no selective antagonist that can reverse the anticoagulant action of bivalirudin.
Argatroban is a small, synthetic, univalent molecule that competitively and reversibly inhibits the active site of free and fibrin-bound thrombin (Figure 4G). It has a half-life of 45 min and is metabolized in the liver via a process that generates three active intermediates. There is no selective antagonist that can reverse the anticoagulant action of argatroban. As a class, DTIs have potential biological and pharmacokinetic advantages over heparins. Unlike UFH and LMWHs, DTIs inactivate fibrin-bound thrombin, in addition to fluid-phase thrombin. Consequently, DTIs may attenuate thrombus accretion more effectively. In addition, DTIs produce a more predictable anticoagulant effect than heparins because they do not bind to plasma proteins and are not neutralized by PF4 (Table 2). Three parenteral DTIs have been licensed in North America and Europe for limited indications. Hirudin and argatroban are approved for the treatment of HIT, whereas bivalirudin is licensed as an alternative to heparin in patients undergoing PCIs.
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Compared pharmacological properties of unfractionated heparin, low-molecular weight heparins, pentasaccharides, and direct thrombin inhibitors
A comparison of the pharmacological properties of the main classes of thrombin inhibitors is shown in Table 2.
The AT action of UFH is limited by variable efficacy and stability, mainly due to a poor bioavailability when given s.c., non-specific protein binding, neutralization by PF4, and a lack of efficacy on fibrin-bound thrombin.49 Moreover, UFH exhibits prothrombotic properties related to platelet activation65 and thrombin generation rebound after discontinuation.33
LMWHs have a more predictable pharmacological profile than UFH, removing the need for therapeutic drug monitoring. This is mainly due to reduced non-specific protein binding and reduced neutralization by PF4. Limiting the amplification of clotting formation by inhibiting thrombin generation is a possible theoretical advantage. Various LMWHs differ according to their anti-Xa:anti-IIa ratio (Table 1) as well as to other biological effects.
Fondaparinux and idraparinux have features that distinguish them from LMWHs. Because they are too short to bridge AT to thrombin, fondaparinux and idraparinux enhance the rate of FXa inactivation by AT, thereby blocking thrombin generation, but have no effect on thrombin activity. Both agents have almost complete bioavailability after s.c. injection. Neither fondaparinux nor idraparinux interact with plasma proteins other than AT. Consequently, these drugs produce a predictable anticoagulant response that eliminates the need for routine coagulation monitoring.66
DTIs (Figure 4 F and G, Table 2) do not bind to plasma proteins, providing a more predictable pharmacological response than UFH. They are not affected by PF4 and are active against fibrin-bound thrombin. However, because they exert a direct action on thrombin, in a 1:1 stoichiometric fashion, the amount of thrombin inhibited is proportional to the concentration of the DTI. This is the main limitation of their action, as increasing their concentration to achieve a greater inhibition of thrombin is associated with prohibitive bleeding rates.49
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Vitamin K antagonists: general pharmacology |
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Mechanism of action
VKAs exert their anticoagulant effect by interfering with the
-carboxylation and thereby activation of the vitamin K-dependent coagulation factors II, VII, IX, and X67 (Figure 5).
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Vitamin K anticoagulant therapy: interference with foods and drugs
Environmental factors such as drugs and diet can importantly alter the pharmacokinetics and pharmacodynamics of VKAs.67 Influence on absorption, clearance, and plasma protein binding of VKAs or their effect on the synthesis of vitamin K-dependent coagulation factors has been documented for numerous drugs and food. Change of dosage of VKAs and a more frequent control of the international normalized ratio (INR) are important in the management of the increased risk of bleeding and thrombo-embolic complications, when interaction may occur. The direction of interaction and the supporting level of evidence have been reviewed recently.67,68
Laboratory control
The prothrombin time (PT) assay is sensitive to the inhibition of factors the carboxylation of which is inhibited by VKAs, and has been used for decades to monitor the intensity of oral anticoagulant therapy. The PT is performed by adding calcium and thromboplastin to citrated plasma. The PT monitoring of VKA treatment is not standardized when simply expressed in seconds or as a simple raw ratio of the value of patient's plasma (in seconds) to that of plasma from healthy control subjects (also in seconds). Dosage of warfarin, the main oral anticoagulant drug, has been shown to differ significantly in different countries,69,70 depending on the thromboplastin used to perform the PT. As a result, there was a great risk of bleeding from overdosage and of ineffective treatment from underdosage. The problem was shown to be due largely to the use of different thromboplastins. Thromboplastins indeed vary in responsiveness to a reduction in the vitamin K-dependent coagulation factors. An unresponsive (‘insensitive’) thromboplastin produces less prolongation of the PT for a given reduction in vitamin K-dependent clotting factors than a responsive (‘sensitive’) one. To meet the challenge of the lack of standardization, the World Health Organization (WHO) in 1983 produced a ‘gold standard’ by the introduction of a PT standardization scheme based on the INR.69,71 The responsiveness of a thromboplastin was measured by assessing its international sensitivity index (ISI). Highly sensitive thromboplastins (ISI, approximately 1.0), which are composed of human or rabbit TF produced by recombinant technology and defined phospholipid composition, are now available. Reporting of PT values is now done by converting the PT ratio measured with the local thromboplastin into an INR, calculated as follows:
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The history of standardization of the PT has been reviewed by Poller,72 and the reader is referred to this review for a detailed discussion of principles and implementation. The INR system of PT standardization was, however, originally based on manual determination of PT and envisaged the assignment of a single ISI value for each batch of thromboplastin reagent.69,70 However, in recent years, the manual PT has been almost universally replaced by coagulometers, and many studies have shown that the ISIs of thromboplastin reagents differ according to the type of instrument used.73–76 Some manufacturers have introduced ‘instrument-specific’ ISIs, but this does not overcome the problem completely because of the many possible instrument/reagent combinations and because ISIs often differ with the same thromboplastin even among instruments of the same type. ISI calibration with local PT system (i.e. thromboplastin/coagulometer combination), therefore appears essential. ISI calibration using the WHO-recommended procedure is not usually possible in routine hospital laboratories for a variety of reasons, including the requirement for manual PT testing with a WHO reference standard thromboplastin. WHO standard thromboplastin is not readily available to routine hospital laboratories. Furthermore, the WHO procedure requires a sample of 60 fresh plasmas from stabilized orally anticoagulated patients, and 20 fresh plasmas from normal subjects (see Table 3 for definitions of terms).
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To avoid the above-mentioned constraints, laboratories may now calibrate their own local system (i.e. instrument/reagent combination) using certified plasmas supplied by manufacturers or reference laboratories. A working group of the International Society of Thrombosis and Haemostasis, Subcommittee on Control of Anticoagulation, has very recently worked out guidelines on preparation, certification, and use of certified plasmas, and these are intended to provide guidance to both manufacturers and users of certified plasmas.77
Currently, there is one procedure for local calibration with certified plasmas, which is a modification of the WHO method of ISI determination. In a European Concerted Action on Anticoagulation (ECAA) study of lyophilized plasmas and of individual VKAs, it has been shown that the number of 60 lyophilized abnormal samples required for a full WHO calibration can be reduced to 20 if combined with results from seven lyophilized normal plasmas.78 Further reductions below this number were associated with decreased precision of the calibration line and hence increased variability of the INR.79 However, the use of pooled VKA plasmas may reduce the scatter of values from individual plasmas,79 and with pooled plasmas and repeat testing it is possible to use an even lower number. For example, acceptable precision has been achieved with six pooled VKA plasmas containing at least 50 patient samples in each pool and two pooled normal plasmas if these were analysed on at least three different days.80
In the other procedure, named ‘direct’ INR determination, certified plasmas are used to calculate a line relating log (PT) to log (INR),77 and the use of orthogonal regression77,81 (Table 3). External quality control for INR performances are available with a number of national and international schemes, including that from the WHO.
Dosing
World-wide increase in the use of VKA treatment in recent years has followed the publication of studies demonstrating its value in a widening spectrum of clinical disorders. Improved benefit/risk ratio has resulted from the increased use of lower-dose VKA administration, pioneered in the UK and the Netherlands, combined with the introduction of the WHO INR system of laboratory control.69,70 With such a great increase in demand, medical, technical, nursing, and administrative staff in hospitals and clinics in many countries are being overwhelmed by the numbers of patients requiring regulation of anticoagulant dosage, with an increasing tendency to devolve management to community-based centres. One possible way of preserving standards achieved in specialized centres is by the computerization of anticoagulant dosages. The ECAA computerized dosage study is the first multicentre randomized evaluation of the safety and effectiveness of computerized treatment with VKAs.82 The results of this study favour computer dosage, with a highly significant overall benefit in achieving the target INR in the clinical groups randomized to this modality at the five centres in that study.82
The usual practice is to start with the expected maintenance dose (stabilization period) and adjust the daily dose according to the INR results from blood samples taken over the following 5–7 days. Because there is a delay before the onset of the clinical effects of warfarin, heparin should be given concomitantly in the initial stages of treatment if patients are thrombosis-prone or carriers of a thrombosis. Once the patient has achieved the target INR, treatment is continued with a maintenance dose (stable period) of warfarin. Time in therapeutic range varies considerably both in the stabilization and in the stable periods. In the ECAA computer study, the time in the therapeutic range varied in the stabilization period between 44 and 69%, and in the stable period between 26 and 70%. In daily clinical practice, the success figures are likely to be considerably lower.82
Thus, there is a clear need for improvement. Patients must undergo periodic blood tests to ensure that their target INR is maintained. With long-term treatment after a stabilization period of 3–4 weeks, the interval between laboratory tests can be increased to 4–6 weeks or even longer. The dose of VKAs required to achieve the desired INR can be estimated using algorithms and treatment tables. Computerized decision support systems (CDSS) have been developed in order to simplify the process of anticoagulation monitoring and to improve the dosing decisions. CDSS systems can also help in identifying patients with inadequate INR control, and in addition suggest intervals for the re-testing.82 The reliability of the CDSS systems is currently being evaluated in the European Action on Anticoagulation (EAA), the successor to the ECAA, under the EC Quality of Life and Management Programme, entitled ‘Cost-Effectiveness of Computer-Assisted Anticoagulant Dosage’, using the clinical endpoints of bleeding and thrombosis, and not only the surrogate endpoints of time in the therapeutic range. This is a randomized clinical endpoint trial of computer-assisted oral anticoagulant dosage. It is a massive study aiming at recruiting 16 000 patient-years at 33 expert centres across the European Union. The EAA has already recruited over 12 000 patient-years, which makes it by far the largest clinical study ever undertaken in the field of oral anticoagulation. Upon completion, this trial should have a major impact on the clinical management of VKA administration.
Point-of-care testing and prothrombin time monitors
The high demand for VKAs have increased the interest for new testing procedures, such as the determination of the INR at the point of care on whole blood samples. There is a general consensus that these procedures do not need the technical expertise of traditional methods. However, both optimal calibration and quality control systems and connection with expert centres are mandatory in order to keep an acceptable quality standard and ensure the transferability to a higher order of calibration (discussed subsequently). Point-of-care test (POCT) monitors must, however, give dependable INR values because the safety and effectiveness of treatment with VKAs depends on keeping patients within the target INR ranges. Thrombotic events increase disproportionately at INR <2.0 and bleeding complications at INR >4.5.
It has been shown that it is possible to calibrate home PT monitors to conform to the WHO standard.83 To find out how accurately two POCT systems, the CoaguChek Mini and the TASPT-NC (RapidPointCoag), measured INRs at 10 ECAA centres, such systems were tested and compared on 600 patients on long-term warfarin therapy.84 The mean INR displayed differed by 21.3% between the two POCT monitoring systems. The INR on one system was 15.2% higher, on the average, than the ‘true’ INR, but on the other system it was 7.1% lower. The percentage difference between the mean displayed INR and the ‘true’ INR at individual centres also varied considerably with both systems. Reliable quality assessment procedures have been developed,85 and their feasibility was recently evaluated in the Netherlands within the framework of the European Concerted Action on Thrombosis.86,87 In Germany, such devices are claimed to be currently in use in 100 000 households for self-testing and self-dosage. It has been estimated that if half of the patients in Europe currently treated with VKAs were to adopt self-monitoring systems, over 1 000 000 devices would be in use within the next 5 years. A comparable expansion may also take place in North America and, in time, in other parts of the developed world. For patients, there is the greater convenience of testing at home or at a local community clinic. In general, such a system would provide savings of time and transportation costs. However, these POCT PT monitors also need appropriate control regarding calibration, quality control, and reference with expert centres. Moreover, the quality control scheme needs to be adequate to ensure accordance with the WHO PT standardization. The same holds true for hospital routine laboratories. Simplified procedures have been developed in order to improve local ISI calibration and also to ensure accordance with the WHO procedure and a coherent reference system in terms of INR.77 These policies should result in a decrease in the bleeding risks, and better prevent or cure thrombosis, in the daily clinical practice.
Self-management of oral anticoagulation
In the self-management of oral anticoagulation, the patients themselves—using a finger stick sample of capillary blood inserted into a point-of-care monitoring device such as the Coagucheck—perform a PT test. They then decide themselves whether a dosing adjustment of the anticoagulant is necessary. Prior to participating in a self-management of oral anticoagulation programme, patients have to follow an intensive training course on how to use the point-of-care device, on the management of their diet (content of vitamin K in various foods), drug interactions of VKAs, effect of excessive alcohol consumption, etc. In Germany, over 100 000 patients on long-term VKAs participate in self-management of oral anticoagulation programmes. In many other European countries, this form of VKA control is catching on. In a recent meta-analysis of 14 randomized trials of self-management of oral anticoagulation, significant reductions were found for thrombo-embolic events (OR 0.27; 95% CI 0.12–0.59) and death (0.37; 0.16–0.85), but not for major bleeding (0.93; 0.42–2.05). In 11 studies INR values were more often in the desired therapeutic range in the self-management of oral anticoagulation arm.88 However, it should be underlined that only highly selected groups of patients were included with a high level of compliance and capability to operate the coagulometer. In addition the studies exhibited various methodological problems and were not weighted in the meta-analysis. A major positive element of self-management of oral anticoagulation is the empowerment of the patient, the better insight of factors that might influence VKA therapy, and a feeling of security89 (reviewed in Ansell et al.67 and Siebenhofer et al.90). All these elements eventually result in a better quality of life.91 Despite these promising aspects, there is a need for high-quality randomized controlled studies involving well-defined clinical and laboratory endpoints.
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Oral direct thrombin inhibitors: general pharmacology |
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The oral DTIs evaluated in phase III so far, ximelagatran and dabigatran etexilate, are synthetic low molecular weight peptidomimetics that bind directly and reversibly to the catalytic site of the thrombin molecule92–96 (Figure 4D). They are administered orally as pro-drugs, which are rapidly metabolized to the active compound; ximelagatran is converted to melagatran in several organs, including the liver, the lungs, the intestine, and the kidneys, whereas dabigatran etexilate is rapidly and completely converted to dabigatran primarily by serum esterase-catalysed hydrolysis. Pharmacokinetic data for dabigatran etexilate in healthy volunteers show peak plasma levels within 2–3 h after oral administration97,98 and a half-life in healthy subjects of 3–4 h for melagatran and around 12–14 h in patients for dabigatran.99 Both are eliminated primarily by the kidney, therefore plasma concentrations are increased for both compounds in patients with impaired renal function (creatinine clearance, CrCl <50 mL/min). The therapeutic window, however, is fairly wide, and they have therefore been tested in fixed doses (ximelagatran 24 or 36 mg bid; dabigatran etexilate 110 and 150 mg bid), in patients with a glomerular filtration rate (GFR) above 30 mL/min.92–95
In long-term use, ximelagatran has been associated with transient elevations of liver function tests [alanine amino transferase (ALAT) three or more times the upper normal limits] in around 8% of patients, in the majority of cases occurring between 1 and 6 months after the start of treatment, which also led to protocol-mandated cessation of treatment in a non-trivial proportion of patients.100 It was therefore decided to withdraw ximelagatran from the market and terminate its development. The withdrawal was triggered by new patient safety data with an adverse event report of serious liver injury in a clinical trial. The long-term treatment with dabigatran etexilate has been evaluated so far only in a limited number of patients. On the basis of current information,