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A Preliminary Assessment of the Critical Differences Between Novel Oral Anticoagulants Currently in Development

From Electrophysiologic and Metabolic Pharmacogenomics, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Address for reprints: Brian F. McBride, PharmD, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 536 Robinson Research Building, Nashville, TN 37232.

	ABSTRACT

TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 
Chronic anticoagulation represents a clinical conundrum for the health care community that balances unquestionable morbidity and mortality benefits against interindividual variability, leading to drug interactions, adverse events, and thromoembolic events related to underdosing. Despite the growing data regarding the appropriate use and dosing of agents used for chronic anticoagulation, use in clinical practice remains low, thus leading to a theoretical reduction in the risk-to-benefit ratio in the clinical setting relative to that reported in the literature. Oral anticoagulants currently in development represent a heterogeneous group of compounds that are specific for the final common pathway in the coagulation cascade and show indications toward a reduced drug interaction profile, reduced interpatient variation in pharmacokinetic parameters, and morbidity and mortality benefits that might be similar to currently available treatment modalities. This review highlights the critical differences among oral anticoagulants in development and places their role in the context of the benefits and limitations of currently available anticoagulants.

Key Words: Anticoagulants • thrombin • factor Xa • razaxaban • ximelagatran

	PHYSIOLOGY

TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 
A review of the activity of the coagulation cascade in the development of thrombosis is essential to appreciate the clinical advantages and disadvantages germane to oral anticoagulation. As depicted in Figure 1, generation of thrombin represents the central process for the progression of thrombosis and is stimulated through the induction of the intrinsic and extrinsic coagulation pathways. The intrinsic cascade becomes activated in response to activation of plasma kallekrein, prekallekrien, and high molecular weight kininogen. Extrinsic pathway activation occurs in response to the release of tissue thromboplastin from the vascular wall, which activates factor VII. The final common pathway begins with simultaneous activation of factor X and culminates with the activation for factor II (ie, thrombin), thus permitting the deposition of thrombin on activated platelets, stabilization of fibrin monomers, continued platelet activation, and thrombin regeneration. Although clot-bound thrombin retains enzymatic activity, conventional anticoagulants (eg, LMWH, heparin, warfarin, etc) are unable to antagonize the effects of clot-bound thrombin. The ensuing thrombin regeneration through feedback stimulation of factors V, VIII, and IX creates the potential for therapeutic failure.^7-10

View larger version (27K): [in this window] [in a new window]   Figure 1. Representation of coagulation cascade illustrating the mechanism of action of warfarin, direct thrombin inhibitors, and factor Xa inhibitors. KO, vitamin K epoxide; KH2, reduced form of vitamin K; NADH, nicotinamide adenine dinucleotide. Roman numerals represent their respective clotting factors.

The hepatic synthesis of clotting factors VII, IX, X, and II and the endogenous anticoagulant proteins C and S requires gamma carboxylation via vitamin K-dependent pathways following translation to enter their inactive clotting factor form. Inhibition of gamma carboxlylation represents the target for warfarin therapy, thus preventing biologic activity of the aforementioned clotting factors. However, because warfarin has no anticoagulant activity on clotting proteins that have already been carboxylated, its anticoagulant effects are contingent on the clearance of circulating clotting factors, which can take up to 10 days, thus calling into question the legitimacy of "warfarin loading," which causes a higher risk of bleeding secondary to overshooting target international normalized ratio (INR) values.^7-10

Taken together, the indirect pharmacodynamic effects of warfarin contribute to the difficulty of achieving and maintaining a therapeutic effect, even within specialized anticoagulation clinics. In a small trial of patients with atrial fibrillation (n = 229 receiving warfarin, 70% followed by standard care and 30% followed by an anticoagulation clinic), only 60% of patients in the clinic population and 36% of patients followed by standard care maintained a therapeutic INR of 2 to 3 (P < .001). This underscores the pharmacologic complexity associated with warfarin therapy and the importance of developing an alternative therapy with predictable pharmacodynamic properties. Such an agent(s) would permit anticoagulation clinics to focus on improving warfarin management for those patients ineligible for conversion to an alternative oral anticoagulant.²¹ Last, the overcorrection of warfarin therapy secondary to excessive administration of exogenous vitamin K also predisposes patients to unnecessary thrombotic risk and should be taken into account when evaluating the risks and benefits of new oral anticoagulants.¹⁰

Conversely, LMWH exerts an indirect anticoagulant effect through enhancement of antithrombin activity via the binding of a pentasaccharide sequence of heparin to antithrombin, which catalyzes the exposure of the arginine reactive site. Clotting factors (II, XII, XI, X, IX) that covalently interact with the arginine reactive site become immune to activation. Thrombin inhibition by LMWH prevents the activation of factors VIII and V, which partially interrupts a positive feedback mechanism that causes enhanced thrombin generation. Like warfarin, LMWH fails to antagonize clot-bound thrombin, creating the potential for thrombus extension and therapeutic failure. Because LMWH is characteristically shorter than unfractionated heparin, its anticoagulant activity is generally limited to reductions in factors X and II.^8-10 Specific pentasaccharide inhibitors of factor Xa (ie, parenteral fondaparinux) ultimately bind to antithrombin, favoring a confirmational shape conducive to the inactivation of factor Xa, with no effects on factor II, and are ineffective against clot-bound thrombin.

	DIRECT FACTOR XA INHIBITORS

TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 
Bay59-7939 and razaxaban represent the 2 known oral direct (ie, not requiring antithrombin) inhibitors of factor Xa. The former selectively inhibits factor Xa (K_i = 0.0002 µmol/L) and requires a 10³ increase in concentration to inhibit thrombin. Animal models indicate that Bay59-7939 at a dose of 0.098 mg/kg significantly inhibited clot formation, reduced activated factor Xa concentrations by 32%, did not prolong PT or aPTT, and required a 2-fold overdose to produce bleeding, indicating that the agent may have promise for a wide therapeutic window in which to provide an antithrombotic effect with a low risk of bleeding.^22-25 In a small human study, 5- and 30-mg doses of Bay59-7939 reduced factor Xa activity by 28% and 56%, respectively, with a peak effect observed at 2 hours with an overall duration of effect lasting longer than 12 hours following administration of the 30-mg dose, which suggests a half-life that may permit once-daily dosing.²⁶

Razaxaban showed similar anti-factor Xa effects relative to Bay59-7939 (K_i = 0.0004 µmol/L) but required an increase in concentration 10-fold greater than Bay59-7939 (10⁴ vs 10³) to inhibit thrombin generation.²⁷ In phase I trials, razaxaban was effective over a wide range of doses (ie, 25, 50, 75, 100, or 225 mg q12h, and 300 mg qd), and 25 mg q12 provided qualitatively larger reductions in the incidence of venous thromboembolism (VTE) relative to enoxaparin (30 mg sc q12) when both were administered following total hip replacement (THR) (8.6% vs 15.9%; no intergroup comparisons reported).²⁸ Although pharmacokinetic data have not been reported to date, the potential for once-daily dosing shows promise. Adverse events and postadministration hepatic transaminase levels were not reported for either agent relative to active control.

	DIRECT THROMBIN INHIBITORS

TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 
Dabigatran etexilate and ximelagatran represent orally available prodrugs of the small-molecule direct thrombin inhibitors dabigatran and melagatran, respectively. A third compound TGN167 is an intrinsically available direct thrombin inhibitor. Like the aforementioned direct factor Xa inhibitors, dabigatran and TGN167, the limited preclinical and phase I data carry increasing relevance secondary to the FDA rejection of ximelagatran. Direct thrombin inhibitors are characterized by their reversible or irreversible binding to the active site on thrombin, interaction with exosite-2, and ability to antagonize the effects of clot-bound thrombin. Reversible binding to the active site on thrombin permits a linear dose-effect relationship for the onset and offset of anticoagulant effect, whereas exosite-2 ensures fibrin deposition. Once fibrin binds to this site, the anticoagulant effect of the heparin/antithrombin complex is blocked, thus explaining the inability of LMWH to antagonize clot-bound thrombin. Large-molecule direct thrombin inhibitors that allosterically bind to exosite-2 (ie, bivalirudin, hirudin) prolong the duration of interaction between the active site and direct thrombin inhibitor, which can lead to prolonged anticoagulant effects as serum concentrations fall.¹⁰ However, the clinical relevance of this effect may be limited as phase II/III clinical data indicate that direct thrombin inhibitors are as effective as LMWH, which do not antagonize clot-bound thrombin.

Dabigatran demonstrates high affinity for thrombin (K_i = 0.005 µmol/L) without exerting an impact on anticoagulant proteins C and S. Although it exhibits a higher affinity for trypsin relative to either TGN167 or ximelagatran, clinical relevance has not been demonstrated in clinical trials to date. Interestingly, animal models suggest a wide safety margin.^29-31 With respect to its pharmacokinetic profile, dabigatran exhibits a peak pharmacodynamic effect 1.5 to 2 hours following administration and a half-life of 8 hours. Dabigatran also demonstrated dramatic increases in plasma concentrations among those with moderate renal impairment (ie, creatinine clearance 50 mL/min).^32,33 No drug interaction or ethnicity studies have been reported to date. In a phase II clinical trial, postoperative dabigatran (150 mg q12) was compared to preoperative enoxaparin (40 mg sc qd) following total hip replacement in the BISTRO II study. Dabigatran provided significantly larger reductions in the incidence of venous thromboembolism relative to 40 mg sc qd enoxaparin (17.4% vs 24%; P = .04) and a comparable rate of bleeding.³⁴ Although adverse events, including elevations in liver transaminase activity, were similar between the 2 groups, BISTRO II did not evaluate the effects of chronic dabigatran therapy on this critical safety endpoint. It should be noted that TGN167 is just entering the clinical arena, and studies similar to those available with dabigatran are currently enrolling patients (Trigen Co. Ltd, London, 2005, personal communication).

Ximelagatran
Pharmacodynamic/Pharmacokinetic Effects
Following bioconversion of ximelagatran, melagatran exerts a similar antithrombotic effect to dabigatran (K_i = 0.0020 µmol/L), and in a rabbit bleeding model, melagatran produced a comparable antithrombotic effect relative to the polypeptide direct thrombin inhibitor, hirudin, with significantly less bleeding at the highest doses evaluated (344 ± 94.3 µL vs 714.7 ± 212.1 µL; P < .001).^35-38 With respect to the pharmacokinetic profile of ximelagatran, conversion to melagatran takes place through hydrolysis of an ethyl ester protecting group and reduction of a hydroxyamidine protecting group via pathways independent of the hepatic cytochrome P (CYP) 450 enzyme system. A linear dose-response relationship is evident, and a C_max occurs at approximately 1.5 to 2 hours following oral administration. In healthy subjects, the half-life of melagatran is about 3 hours, thus requiring twice-daily dosing.^39-41 Declining renal function, as measured by creatinine clearance, is inversely proportional to the plasma level of melagatran. When patients with severe renal impairment (n = 12; mean CL_CR = 29 mL/min) were compared to healthy controls (n = 12; mean CL_CR = 104 mL/min) using a single 24-mg oral dose of ximelagatran (the dose most commonly used in clinical trials, discussed below), the area under the curve (AUC) increased 5-fold (95% confidence interval [CI] = 3.76-7.56), C_max nearly doubled (relative risk [RR] = 1.89; 95% CI = 1.42-2.37), and half-life increased more than 2.5-fold (95% CI = 2.07-3.26).⁴² Based on this information, it is likely that ximelagatran will be contraindicated among patients with a CL_CR < 30 mL/min until further pharmacokinetic studies are performed. In addition, ximelagatran demonstrated no significant differences in its pharmacokinetic profile among those based on ethnicity, a diagnosis of obesity, or mild to moderate or hepatic impairment when adjusted for creatinine clearance.^43-45 Finally, studies indicate that both agents can be delivered as oral solutions, thus permitting administration via a nasogastric tube.^32,46

Clinical Trials
Currently, ximelagatran represents the only agent with available phase II/III data, whereas the other aforementioned compounds show promise at various stages of early clinical development. Although ximelagatran was recently rejected by the US Food and Drug Administration (FDA) secondary to a high rate of adverse events, an anticipatory overview of the clinical trials (see Table I) can provide insight into possible mechanisms for the adverse events and direct the design of future trials of other developmental oral anticoagulants.^47-60 The inherent limitations of currently available anticoagulants would permit an agent with equal efficacy (ie, noninferiority) to be chosen on the basis of ease of use, the absence of adverse reactions or interactions, and the need for therapeutic monitoring.⁶¹ However, the design of noninferiority trials is based on the minimum acceptable difference in clinical endpoints between the treatment arms. If the minimum difference selected is too wide, the 2 agents may be falsely characterized as equivalent. The potential for such an error could be reduced by choosing the lowest event rate for the active control drug (ie, warfarin or LMWH) from prior placebo-controlled trials.

Atrial Fibrillation
The population of patients with atrial fibrillation continues to explode at an alarming rate and may approach 5 million patients by 2050.¹⁵ Clearly, the need for alternative oral anticoagulants will be dominated by this population. In the Stroke Prevention by Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials, 24 mg ximelagatran provides an equivalent level of protection from cerebrovascular events relative to warfarin. Furthermore, the rate of major bleeding was qualitatively lower and minor bleeding significantly lower than warfarin. The long-term nature of the SPORTIF trials relative to those for venous thromboembolism presented below provides more insight into chronic adverse events—most notably, hepatic enzyme (ie, aspartate aminotransferase/alanine aminotransferase [AST/ALT]) elevations. In SPORTIF III, hepatic enzyme levels were measured at monthly intervals and then measured at weekly intervals when levels exceeded 3 times the upper limit of normal, which was considerably higher in patients (n = 107) receiving ximelagatran (6% vs 1%; P < .0001). Forty-eight of these patients continued therapy and experienced normalization of these levels by the 6-month time point.^48,49

Venous Thromboembolism Treatment and Prevention of Recurrence
Examination of the impact of ximelagatran relative to a combination of LMWH/warfarin for the treatment of an active venous thromboembolism event represented the focus of the Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial series. THRIVE II/V (also known as the THRIVE Treatment Trial) was designed to examine the impact of 6 months of treatment with ximelagatran 36 mg twice daily versus standard of care. Investigators designed the trial as a noninferiority trial and determined that ximelagatran was as effective as the LMWH/warfarin regimen.⁵⁰ THRIVE III was designed to gain insight into whether extended anticoagulant treatment (ie, beyond 6 months) for secondary venous thromboembolism prevention is warranted. Patients in this trial completed 6 months of standard anticoagulant therapy and were then randomized to receive ximelagatran 24 mg twice daily or placebo.⁵¹ At the end of 18 months (total treatment of 2 years), patients in the active groups experienced significantly less recurrence relative to placebo. In both trials, bleeding was not significantly different from the control. As in the SPORTIF trials, hepatic transaminases were significantly elevated among patients receiving ximelagatran (9.6% vs 2%, P < .01 and 6.4% vs 1.2%, P < .001 for THRIVE II/V and III, respectively). In THRIVE III, this effect led to discontinuation of the study drug in 13 of 37 patients. Among the 24 who remained on the study drug, the median time for return of these levels of baseline was approximately 3 months.^52,53

Prophylaxis of Venous Thromboembolism
Comparison of ximelagatran to warfarin following total knee replacement was the focus of the EXULT series of trials in which a 36-mg dose of ximelagatran conferred a superior prophylactic benefit over warfarin. Interestingly, the rate of bleeding associated with the 36-mg dose was not only not different from that of warfarin but was similar to the bleeding rates observed with the 24-mg ximelagatran group in EXULT and other comparative trials in which ximelagatran was compared with LMWH following surgery. Thus, differences observed between trials among similar patient populations may be related to differences in study design (ie, use of a subcutaneous melagatran bolus in the perioperative period) or the adequacy of preventive measures and underscore the need for adequate assessment, monitoring, and notification of patients to reduce this adverse effect.^57-59

Administration of melagatran/ximelagatran provides at least equivalent if not superior efficacy relative to LMWH, with a comparable rate of bleeding among patients receiving total knee replacement that is dependent on the timing of the initiation of therapy. However, the efficacy of ximelagatran for thromboprophylaxis following total hip replacement is under debate in light of conflicting safety and efficacy results from several trials. Trials evaluating postoperative ximelagatran (or a melgatran/ximelagatran hybrid) showed that it was not as effective as LMWH in this population. However, pre/perioperative initiation of melagatran and postoperative oral ximelagatran is at least as effective or superior to LMWH (either enoxaparin or dalteparin) among patients receiving total hip replacement, with the pre/perioperative administration demonstrating higher rates of bleeding complications. This might indicate that the coagulation cascade is more thrombin dependent in the early stages of surgical insult (eg, vascular injury), with extrinsic and intrinsic pathways (eg, vessel injury and venous stasis) contributing to vascular insult following surgery. Taken together, the use of ximelagatran over LMWH in the population of patients undergoing hip replacement requires consideration of the surgeon's preferred timing of anticoagulant administration (ie, pre- or postsurgery), the LMWH used, and an assessment of the risk-to-benefit ratio on a case-by-case basis and careful assimilation of the actual patient with those represented by the study populations. It should be noted that trials evaluating a hybrid regimen with subcutaneous melagatran currently have low external validity because the subcutaneous product is unlikely to reach therapeutic development with its oral counterpart. Thus, given the results of the available clinical trials, LMWH would represent the preferred prophylactic modality for venous thromboembolism prophylaxis following hip replacement, whereas ximelagatran would represent an acceptable prophylactic measure following knee replacement.^51-58

Adverse Events and Drug Interactions
Because warfarin therapy is plagued by a myriad of drug interactions, data indicating lack of such interactions or other adverse events would obviously be advantageous. However, of all the agents discussed, the majority of available data examined ximelagatran in this regard. Ximelagatran was probed for and failed to demonstrate drug interactions with agents, including diclofenac (2C9 substrate), diazepam (2C19 substrate), nifedipine (3A4 substrate), amiodarone (a 1A2, 2C19, 2D6, 3A4, and P-glycoprotein [PGP] inhibitor), atorvastatin (3A4 and PGP inhibitor), and digoxin (a PGP substrate). Interestingly, erythromycin (a PGP inhibitor) increases the AUC and C_max of melagatran by 82% and 74%, respectively, by pathways reported to be unrelated to CYP 450 activity or interactions with PGP.^62-64 PGP is encoded by the gene MDR1, a member of the superfamily of adenosine triphosphate (ATP) binding cassette proteins known as the multidrug resistance protein (MRP) family, and the interaction with erythromycin could suggest that ximelagatran acts as a substrate for a related MRP transporter(s). If this supposition is accurate, inhibition of a drug efflux transporter by erythromycin could potentially explain the interaction with ximelagatran, whereas loss of function polymorphisms in the aformentioned transporters may prompt sequestration of ximelagatran inside the hepatocyte to cause cellular injury or death.^65,66 Clearly, this area requires further study to help determine if the elevations in liver transaminase activity could be isolated to a specific subpopulation or if ximelagatran is hepatotoxic.

Unfortunately, administration of ximelagatran is not without serious risk of hepatotoxicity and thus has indefinitely delayed US FDA approval of this agent pending further study.⁶⁷ Although short-term administration of ximelagatran (ie, less than 30 days) did not demonstrate a significant elevation in hepatic transaminase activity (0.57%, 0.83%, and 1.70% for ximelagatran 24 mg, 36 mg, and warfarin, respectively), the lack of a monitoring plan to prevent extended exposure to this population concerned FDA panelists.^68,69 Conversely, long-term exposure to ximelagatran was much more insidious with respect to hepatic transaminase activity (7.9% vs 1.2% and 4.7% vs 0.5% for 3 and 5 times above the upper limit of normal, respectively; P values not reported). Furthermore, the relative risk of serious hepatic injury (AST/ALT >3x above the upper limit of normal and total bilirubin >2x above the upper limit of normal) was nearly 7-fold greater for the ximelagatran group relative to comparative agents, which translates into 1 occurrence per 200 patients and 1 death per 2000 patients treated with ximelagatran. These results are disturbingly similar to the new drug application for troglitazone, which showed that 48 of 2510 (ie, 1.9%) of studied patients experienced elevations in AST/ALT greater than 3x the upper limit of normal, preceding its subsequent removal from the market.^68,70 Based on the available data, this adverse effect appears to be unique to the ximelagatran molecule because preclinical and clinical data of melagatran, dabigatran, and TRI50c demonstrated similar or reduced effects on AST/ALT relative to either warfarin or LMWH. Although the risk of drug-induced hepatoxicity is of concern, the risk should be considered in the context of the number of patients who suffer adverse events related to overdosing and overcorrection of the pharmacodynamic effects of warfarin when administered by inexperienced providers. Thus, restricted launch of ximelagratran to certified inpatient and outpatient anticoagulation services and mandatory postmarketing reporting and surveillance (not a component of the initial new drug application to the FDA) could foster approval of ximelagatran.

As with all antithrombotic agents, oral direct thrombin and factor Xa inhibitors could carry an increased risk of bleeding, with the ideal agent demonstrating a shallower dose-response curve and thus reduced rates of bleeding relative to warfarin. In a model of rat bleeding, the therapeutic dose of melagatran (ie, 0.01 µmol/kg) produced a 25% reduction in thrombus size, whereas a 10-fold overdose reduced thrombus size by 86%. By comparison, a 2-fold increase in the dose of warfarin conferred a similar 86% reduction in thrombus size but may increase bleeding disproportionately.⁷¹ Similarly, a dose-ranging study in healthy volunteers indicated that a 98-mg dose of ximelagatran produced a 5-fold increase in area under the curve but did not significantly increase capillary bleeding time.³⁰ However, clinical studies in patients with or at risk for thromboembolic disease indicated that doses of 24 to 36 mg had statistically similar bleeding rates relative to warfarin with an INR of 2 to 3.^44-57

	CONCLUSIONS

TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 
Limitations conferred by both warfarin and LMWH underscore the need for an agent with a predictable dosing interval, manageable drug interactions, and similar clinical efficacy. The developmental oral anticoagulants show promise to become acceptable therapeutic alternatives to warfarin and LMWH as additional efficacy data become available. Approval of the first of these agents, ximelagatran, might be reconsidered by the FDA, provided that the manufacturer can design an improved patient safety and monitoring program and is able to elucidate the mechanism by which the agent increases hepatic transaminase levels. Preliminary data with the remaining direct thrombin inhibitors, such as dabigatran and TGN167, and direct factor Xa inhibitors, such as razaxaban or Bay59-7039, suggest that their compounds may not share the same effect on hepatic transaminase activity as ximelagatran; however, data on bleeding as an adverse event with these agents are not available. Although these direct thrombin and factor Xa inhibitors remain in early clinical development, they could surpass warfarin, LMWH, and even ximelagatran should their clinical equivalence and the lack of similar adverse hepatic effects persist throughout clinical development.

DOI: 10.1177/0091270005278084

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TOP ABSTRACT PHYSIOLOGY DIRECT FACTOR Xa INHIBITORS DIRECT THROMBIN INHIBITORS CONCLUSIONS REFERENCES

 

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