Textbook of Interventional Cardiovascular Pharmacology phần 3 potx

of 25 ␮g/kg/min, adjusted to achieve an ACT of 300 to 450 seconds. Argatroban was found to be a safe and effective anticoagulant in HIT patients undergoing PCI without a significant increase in bleeding. On this basis, argatroban was approved by the FDA as an anticoagulant for patients with or at risk for HIT undergoing PCI. When used in combination with GPIIb/IIIa inhibitors, the dose of argatroban was reduced to a bolus of 250 or 300 ␮g/kg followed by a 15 ␮g/kg/min infusion to target lower ACT of about 300 seconds in non-HIT patients (34). Strict monitoring by ACT is required to avoid unexpected overdose of argatroban in intensive-care patients with hepatorenal failure, especially after cardiac surgery. Hirudin has been used for anticoagulation in non-HIT patients undergoing PCI treatment (50). The molecular structure of drug is completely different from UFH, and the drug does not stimulate generation of HIT antibodies. Although theoretically hirudin might be employed as an alternative to UFH, it has not been studied in HIT patients undergoing PCI, because of its higher incidence of bleeding. In a trial with 25 HIT patients who underwent PCI and were enrolled after platelet recovery to greater than 50,000/␮L, the drug was clinically and angiographically efficacious (78). However, generation of antibodies against hirudin was detected in about half of the hirudin-treated patients after five days of treatment. The antibodies could interfere with anticoagulant activity of the drug. Again, strict monitoring is necessary to avoid unexpected bleeding complications. Bivalirudin is indicated as an anticoagulant for HIT patients undergoing PCI (79). In the Anticoagulant Therapy with Bivalirudin to Assist in the Performance of Percutaneous Coronary Intervention in Patients with Heparin-Induced Thrombocytopenia (ATBAT) trial, 52 patients undergoing PCI with current or previous HIT were enrolled. These included high-risk patients such as those with an increased risk of ischemic and bleeding complications, a higher population of women, a majority of patients with prior MI, and 21% reported a history of HITTS. The bivalirudin treatment appeared safe, and 98% of patients undergoing PCI had a successful procedure. One patient had major bleeding. Two dose regimens, high and low dosages, were used. Despite the relatively small number of patients, this trial suggests that bivalirudin in high-risk patients with HIT undergoing PCI may be used safely and with a good effect. The lowdose, a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr during a procedure, is the one recommended for this indication. Conclusion UFH has been a valuable therapeutic option for ACS. UFH remains unsurpassed by any drugs discovered within the last century, and the prevention and treatment of ACS are still achieved by routine use of heparin. For heparin anticoagulation, careful monitoring is required due to the individual variation in efficacy and the risk of bleeding. To achieve improved efficacy and safety of heparin, new drugs such as low-molecular weight heparins and DTIs have been intro- duced, and new drugs are continuously studied. It has been delineated that platelet activation and subsequent thrombin generation are pathogenic for thrombus formation in ACS, and the neutralization of thrombin is crucial not only for the treatment of ACS but also for a successful PCI procedure. Three DTIs, argatroban, hirudin, and bivalirudin, have been studied to explore if these are better treatments than UFH in ACS and PCI. In the trials of DTIs as adjunctive therapy to thrombolytics in AMI, it is suggested that hemorrhagic complications of DTIs would be less or at least have the same 104 Clinical application of direct antithrombin inhibitors Drug Dose regimen Monitoring Characteristics Approved countries Trial (reference) Argatroban 350 ␮g/kg bolus ϩ Target ACT Low bleeding risk US ARG 25 ␮g/kg/min 300–450 sec No antigenicity 216/310/311, during procedure n ϭ 91 (76) Hirudin 0.4 mg/kg bolus ϩ Target aPTT High bleeding risk — n ϭ 25 (77) 0.10–0.24 mg/kg/hr 60–100 sec Antibody formation for 24 hr or/ ϩ (Ϸ40%) 0.04 mg/kg/hr for 24 hr Bivalirudin 0.75 mg/kg bolus ϩ Target ACT Low bleeding risk US ATBAT, 1.75 mg/kg/hr for 350 sec Antibody formation n ϭ 52 (78) 4 hr during procedure (Ͻ1.0%) Abbreviations : ACT, activated clotting time; aPTT, activated partial thromboplastin time. Table 6 Alternative anticoagulants in percutaneous coronary intervention in heparin-induced thrombocytopenia 1180 Chap08 3/14/07 11:24 AM Page 104 frequency as those of UFH. Now the DTIs are anticipated to be alternatives to UFH, but they are still unrecognized and not used as frequently as UFH in ACS. HIT is the most avoidable adverse reaction in heparin anticoagulation, but it is not uncommon in clinical settings and is often unrecognized. Platelet activation induced by heparin/PF4 complex antibodies and subsequent thrombin generation play a central role in the pathophysiology of HIT, which result in thrombocytopenia and the thrombotic complications of HIT. Patients with HIT should be treated with an alternative anticoagulant to avoid potentially fatal thrombotic complications. DTIs have been used for the treatment of HIT. In particular, argatroban has been also recommended to substitute for heparin in HIT patients undergoing PCI. One of the advantages of argatroban is that it does not generate anti-bodies. The other two DTIs generate more or less antibodies, leading to intricate anticoagulant action, especially antibodies for lepirudin are considered to be relevant to anaphylactic shock. As the number of aged patients with ACS and/or undergoing PCI is increased, heparin exposure is repeated and it promotes the generation of HIT antibodies and subsequently develops to HIT. Risk for HIT by re-exposure to heparin should be given careful atten- tion to in the current clinical settings. References 1 Smith SC, Feldman TE, Hirshfeld JW, et al. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. Circulation 2006; 113:166–286. 2 Silber S, Albertsson P, Aviles FF, et al. Guidelines for percutaneous coronary interventions. Eur Heart J 2005; 26:804–847. 3 Matsuo T, Tomaru T, Kario K, et al. 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A multicenter, randomized study of argatroban versus heparin as adjunc to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with Novastan and TPA (MINT) study. J Am Coll Cardiol 1999; 33:1879–1885. 36 Vermeer F, Vahanian A, Fels PW, et al. Argatroban and alteplase in patients with acute myocardial infarction: the ARGAMI study. J Thromb Thrombolysis 2000; 10:233–240. 37 Behar S, Hod H, Kaplinsky E, et al. Argatroban versus heparin as adjuvant therapy to thrombolysis for acute myocardial infarction: safety considerations-ARGAMI-2 study. Circulation 1998; 98:I-453–I-454. 38 Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 2001; 103:1838–1843. 39 Lewis BE, Wallis DE, Leya F, et al. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 2003; 163:1849–1856. 40 Reichert MG, MacGregor DA, Kincaid EH, et al. Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 2003; 37:652–654. 41 Kubiak DW, Szumita PM, Fanikos JR. Extensive prolongation of aPTT with argatroban in an elderly patient with improving renal function, normal hepatic enzymes, and metastatic lung cancer. Ann Pharmacother 2005; 39:1119–1123. 42 Miyata S. Editorial comment to “Heparin-induced thrombocytopenia and treatment with thrombin inhibitors”. Jpn J Thromb Hemost 2005; 16:621–622. 43 Harder S, Graff J, Klinkhardt U, et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and ecarin clotting time. Thromb Haemost 2004; 91:1137–1145. 44 Sheth SB, DiCicco RA, Hursting MJ, et al. Interpreting the International Normalized Ratio (INR) in individuals receiving argatroban and warfarin. Thromb Haemost 2001; 85:435–440. 45 Swan SK, St Peter JV, Lambrecht LJ, et al. Comparison of anticoagulant effects and safety of argatroban and heparin in healthy subjects. Pharmacotherapy 2000; 20:756–770. 46 Callas D, Fareed J. Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 1996; 83:463–468. 47 Ahmad S, Ahsan A, Iqbal O, et al. Pharmacokinetics and pharmacodynamics of argatroban as studied by HPLC and functional methods: implications in the monitoring and dosage- optimizations in cardiovascular patients. Clin Appl Thromb Hemost 1998; 4:243–249. 48 Greinacher A, Volpel H, Janssens U, et al. Recombinant hirudin (Lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia. A prospective study. Circulation 1999; 99:73–80. 49 Greinacher A, Lubenow N, Eichler P. Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 2003; 108:2062–2065. 50 Serruys PW, Herrman J-P, Simon R, et al. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333:757–763. 51 Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 5 trial. J Am Coll Cardiol 1994; 23:993–1003. 52 TIMI 6 Investigators. Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 6 trial. Am J Cardiol 1995; 75:7–13. 53 Metz BK, White HD, Granger CB, et al. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: results from the GUSTO-IIb trial. J Am Coll Cardiol 1998; 31:1493–1498. 54 Antman EM for the TIMI 9b Investigators. Hirudin in acute myocardial infarction: thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9b trial. Circulation 1996; 94:911–921. 55 Lubenow N, Eichler P, Lietz T, et al. Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of three prospective studies. Blood 2004; 104:3072–3077. 56 Zeymer U, von Essen R, Tebbe U, et al. Frequency of “optimal anticoagulation” for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023). ALKK Study Group. Am J Cardiol 1995; 76:997–1001. 57 Potzsch B, Hund S, Madlener K, et al. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86:373–383. 58 Bates SM, Weitz JI. Direct thrombin inhibitors for treatment of arterial thrombosis: potential difference between bivalirudin and hirudin. Am J Cardiol 1998; 82:P12–P18. 106 Clinical application of direct antithrombin inhibitors 1180 Chap08 3/14/07 11:24 AM Page 106 59 Shah PB, Popma JJ, Piana RN. Bivalirudin in percutaneous coro- nay interventions and acute coronary syndromes: new concepts, new directions. Curr Interv Cardiol Rep 1999; 1:346–358. 60 Eichler P, Lubenow N, Strobel U, et al. Antibodies against lepirudin are polyspecific and recognize epitopes on bivalirudin. Blood 2004; 103:613–616. 61 Topol EJ, Bonan R, Jewitt D, et al. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation 1993; 87:1622–1629. 62 Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable angina or postinfarction angina. N Engl J Med 1995; 333:764–769. 63 Bittl JA, Chaitman BR, Feit f, et al. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142:952–959. 64 Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289:853–863. 65 Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004; 292:696–703. 66 White HD, Aylward PE, Frey MJ, et al. Randomized, double- blind comparison of Hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96:2155–2161. 67 The Hirulog and Early Reperfusion or Occlusion (HERO) -2 Trial Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial. Lancet 2001; 358:1855–1863. 68 Angiox: EMEA Summary of Product Characteristics. 2006 September. 69 Sciulli TM, Mauro VF. Pharmacology and clinical use of bivalirudin. Ann Pharmacother 2002; 36:1028–1041. 70 Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy 2002; 22(part2):105S–111S. 71 Lui HK. Dosage, pharmacological effects and clinical outcomes for bivalirudin in percutaneous coronary intervention. J Invasive Cardiol 2000; 12(suppl F):41F–52F. 72 The Medicines Company. Angiomax US label. 2005 December. 73 The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO IIa) Investigators. Randomized trial of intra- venous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90:1631–1637. 74 Antman E for the TIMI 9A Investigators. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994; 90:1624–1630. 75 Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-hirudin for improve- ment of thrombolysis (HIT-III) study. Circulation 1994; 90:1638–1642. 76 GUSTO II b Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335:775–782. 77 Suzuki S, Sakamoto S, Koide M, et al. Effective anticoagulation by argatroban during coronary stent implantation in a patient with heparin-induced thrombocytopenia. Thromb Res 1997; 88:499–502. 78 Cochran K, DeMartini TJ, Lewis BE, et al. Use of lepirudin during percutaneous vascular interventions in patients with heparin-induced thrombocytopenia. J Invas Cardiol 2003; 15: 617–621. 79 Mahaffey KW, Lewis BE, Wildermann NM, et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin- induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol 2003; 15:611–616. 80 Pifarre R, Scanlon PJ. Evidence-Based Management of the Acute Coronary Syndrome. Philadelphia: Hanley & Belfus, 2001:132. References 107 1180 Chap08 3/14/07 11:24 AM Page 107 1180 Chap08 3/14/07 11:24 AM Page 108 Introduction Improved understanding of the molecular mechanisms of blood coagulation has led to the development of new anticoagulants for the prevention and treatment of thromboembolic disorders in order to overcome the limitations of existing anticoagulants. These limitations include the need for coagulation monitoring and subsequent dose adjustment for vitamin K antagonists (Table 1), the difficulty of continuing prophylaxis out of hospital due to require parenteral administration for heparins, and the risk of heparin-induced thrombocytopenia (1). Various new anticoagulants target specific coagulation enzymes or different steps in the coagulation cascade, that is, the initiation of coagulation by factor VIIa/tissue factor (FVIIa/TF), its propagation by factors IXa, Xa and their cofactors, and the thrombin-mediated fibrin formation (2). The serine proteinase thrombin is the central enzyme in the coagulation pathway. It catalyzes the conver- sion of fibrinogen to fibrin by cleaving the peptide bond between arginine and glycine in the fibrinogen sequence Gly- Val-Arg-Gly-Pro-Arg, activates the factors V, VIII, and XIII, and strongly stimulates platelet aggregation. Besides its procoagu- lant activities, thrombin also exhibits anticoagulant properties via the activation of the protein C pathway. Because of its pivotal role in the coagulation process, thrombin has been a target for the development of specific and selective inhibitors for many years (3). Intensive structure-based design over the last 20 years resulted in the development of numerous direct thrombin inhibitors (TIs), most of which have been peptidomimetic compounds that mimic the fibrinogen sequence interacting with the active site of thrombin (4). The new TIs bind directly to thrombin and block its interaction with different thrombin substrates. At present, the most important TIs that have been extensively evaluated for clinical use are the bivalent inhibitors, hirudin and bivalirudin, which interact with both the active site and the exosite-1 of thrombin in an irreversible and reversible manner, respectively, as well as argatroban, which reversibly binds to the active site. Unfortunately because of their chemical structures, these new agents are not sufficiently absorbed after oral administration and have to be administered parenterally. Thus, they are less suitable for long-term anticoagulation. The development of orally effective, direct TIs seems to be a promising alternative to the existing direct or indirect anticoagulants for long-term use in patients with thromboembolic disorders. However, the design of those new drugs is difficult because different physicochemical properties are required for either the binding of a compound to the active site of thrombin or its absorption from the gastrointestinal tract (5). At present, various oral direct TIs are reported to be under development, of which ximelagatran and dabigatran etexilate are in a more advanced stage of clinical development (6,7). Ximelagatran Chemistry Ximelagatran (Exanta ® ) was the first oral TI and the first new oral anticoagulant to become available since the development of warfarin more than 50 years ago. Ximelagatran is a prodrug of the small-molecule noncovalent tripeptidomimetic direct TI melagatran, which mimics the D-Phe-Pro-Arg sequence. Melagatran has a strong basic amidine structure, a free carboxylic acid, and, in addition, a less basic amine function, implying that it will be positively charged under physiological conditions, and thus it exhibits poor bioavailability and absorption upon oral dosing. Chemical modification of the melagatran molecule by N-hydroxylation at the amidine function and inclusion of an ethyl group at the carboxylic acid structure leads to the development of the double prodrug ximelagatran (Fig. 1). Ximelagatran is 170 times more 9 Oral antithrombin drugs Brigitte Kaiser 1180 Chap09 3/24/07 12:46 PM Page 109 lipophilic than melagatran and uncharged at intestinal pH, resulting in a much better penetration of the gastrointestinal barrier, and thus an increased bioavailability (8–10). Melagatran binds rapidly, reversibly, and competitively to the active site of thrombin with a K i value of 0.002 ␮mol/L. It has a high selectivity for ␣ -thrombin; except for trypsin, the K i value for thrombin is at least 300-fold lower than for other serine proteases involved in blood coagulation and fibrinolysis (11). Pharmacodynamics Melagatran inhibits both thrombin activity and its generation and it effectively inactivates free and clot-bound thrombin with similar high potency (8,12–16). Using routine coagulation assays, clotting times in human plasma are prolonged to twice the control value at low concentrations of melagatran, that is, at 0.010, 0.59, and 2.2 ␮mol/L for thrombin time, activated partial thromboplastin time, and prothrombin time, respectively. The IC 50 value for thrombin-induced platelet aggregation is 0.002 ␮mol/L. Inhibition of fibrinolysis is not observed at concentrations below the upper limit of the proposed therapeutic concentration interval (Ͻ0.5 ␮mol/L) (11). The antithrombotic effectiveness of ximelagatran was demonstrated in different species using experimental models of venous (9,17,18) and arterial (16,19–22) thromboembolism, as an adjunct in coronary artery thrombolysis (23), and in animal models of disseminated intravascular coagulation (24). In healthy volunteers, melagatran was effective in inhibiting thrombus formation at low and high shear rates in an ex vivo model of human arterial thrombosis (25). In experimental models, ximelagatran was at least as effective as warfarin in the prevention of thrombus formation, but with a wider separation between antithrombotic effects and bleeding (7,21). Pharmacokinetics Studies on the pharmacokinetic behavior of ximelagatran and melagatran have been carried out in animal species (26), as well as in healthy volunteers (26,27), orthopedic surgery patients (28,29), patients with deep venous thrombosis (DVT) (30), and volunteers with severe renal impairment (31) and mild-to-moderate hepatic impairment (32). After oral administration, ximelagatran is rapidly absorbed from the small intestine and undergoes rapid biotransformation to the active agent melagatran. The absorption of ximelagatran is at least 40% to 70% in rats, dogs, and humans, whereas the bioavailability of melagatran following oral administration of ximelagatran is 5% to 10% in rats, 10% to 50% in dogs, and about 20% in humans. The reason for the lower bioavailability of melagatran is a first-pass metabolism of ximelagatran with subsequent biliary excretion of the formed metabolites (26). After absorption, ximelagatran is rapidly bioconverted to its active form melagatran via two minor intermediates, that is, ethyl-melagatran, which is formed by reduction of the hydroxyamidine, and N-hydroxy-melagatran, which is formed by hydrolysis of the ethyl ester. Both intermediates 110 Oral antithrombin drugs Warfarin sodium Melagatran/Ximelagatran Reduces synthesis of clotting factors Targeted specificity for thrombin; direct competitive and (II, VII, IX, and X, protein C and S) reversible inhibition of both free and clot-bound thrombin Slow onset and offset of action Rapid onset of action, rapid reversal of thrombin inhibition after cessation of therapy (dependent on plasma concentration and elimination half-life) Large interindividual dosing differences Predictable and reproducible pharmacokinetic and pharmacodynamic profile Multiple drug and food interactions No interactions with food and alcohol, only low potential for drug interactions Individual dose adjustment required Use of fixed-dose regimens, no dose adjustment Need for frequent and careful monitoring No routine monitoring of the anticoagulant effect; control of liver enzymes at long-term therapy Reversal of anticoagulation with vitamin K No antidote available or with plasma or clotting factors replacement Once daily oral administration Twice daily oral administration Table 1 Comparison of vitamin K antagonists (warfarin sodium) with oral direct thrombin inhibitors (melagatran/ximelagatran) 1180 Chap09 3/24/07 12:46 PM Page 110 Introduction 111 are subsequently metabolized to melagatran. Ethyl-melagatran is an active metabolite but due to its low plasma concentration, it unlikely contributes to the anticoagulant action of ximelagatran (9,26,27). Biotransformation of ximelagatran and its intermediates is catalyzed by several enzyme systems located in microsomes and mitochondria of liver, kidney, and other organs (33). Intravenously injected melagatran has a relatively low plasma clearance, a small volume of distribution, and a short elimination half-life. Its oral absorption is low and highly variable. In contrast, ximelagatran is rapidly absorbed after oral administration and then metabolized to melagatran. The plasma concentration of melagatran after oral dosing with ximelagatran declines in a mono-exponential manner with a plasma half-life of four to five hours. Melagatran is primarily excreted unchanged in urine; the renal clearance correlates well with the glomerular filtration rate (Table 2). Only trace amounts of ximelagatran are renally excreted; the major compound in urine and feces is melagatran. In feces of all species, appreciable quantities of ethyl-melagatran are recovered, suggesting a reduction of the hydroxyamidine group of ximelagatran in the gastrointestinal tract (26). In contrast to vitamin K antagonists, the potential of melagatran for drug–drug interactions is very low (34–36). Pharmacokinetic interactions between melagatran and various other drugs mediated via the most common drug-metabolizing enzymes of the CYP 450 system have not been observed (37). Concomitant intake of food or alcohol does not alter the bioavailability of melagatran which also shows only low inter- and intraindividual variability (38–40). The pharmacokinetic/pharmacodynamic profile of ximelagatran and its active form melagatran is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment (39,41–43). In patients with severe renal impairment, excretion of melagatran is delayed, resulting in longer half-life, increased plasma concentrations, and stronger and prolonged anticoagulation (31). Mild-to-moderate hepatic impairment has no influence on the pharmacokinetics and pharmacodynamics of melagatran, thus requiring no dose adjustment in those patients (32). After oral administration, neither ximelagatran nor its two intermediates and only trace amounts of melagatran were detected in milk of breastfeeding women (44). Clinical studies Oral direct TIs have a promising role in the management of venous thromboembolism and other associated medical conditions (3,7,45–48). Ximelagatran has been successfully H 3 C O O O O O O O O HO N N N N N H NH NH 2 O H 3 C N N N N N H N H NH CH 3 O O HO H N H N NH NH 2 N O O O N N Reductioin (→ ethyl-melagatran) Hydrolysis (→ N-melagatran) Ximelagatran Melagatran Dabigatran etexilate Dabigatran H N H N HN 2 OH Figure 1 Chemical structures of the thrombin inhibitors, melagatran and dabigatran, and their orally effective prodrugs, ximelagatran and dabigatran etexilate. Source : From Refs. 4, 26, 33, 68. 1180 Chap09 3/24/07 12:46 PM Page 111 studied in large phase III trials in various clinical settings (49–52). Based on its predictable pharmacokinetic and pharmacodynamic properties without significant time- and dose-dependencies, ximelagatran can usually be administered in fixed doses without the need for individualized dosing or coagulation monitoring. Ximelagatran is effective and well- tolerated for the prevention of venous thromboembolism in high-risk orthopedic patients after hip and knee replacement surgery (EXPRESS ϭ EXpanded PRophylaxis Evaluation Surgery Study; EXULT ϭ EXanta Used to Lessen Thrombosis; METHRO ϭ MElagatran for THRombin inhibition in Orthopedic surgery) (29,53–56). Ximelagatran is also effective in the acute treatment of venous thromboembolism and long-term secondary prevention of recurrent venous thromboembolism (THRIVE ϭ THRombin Inhibitor in Venous thromboEmbolism) (57–59), for the prevention of stroke in patients with nonvalvular atrial fibrillation (SPORTIF ϭ Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation) (60–64), and in the prevention of major cardiovascular events after myocardial infarction (ESTEEM ϭ Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage) (65). A survey of the phase III clinical trials with ximelagatran is given in Table 3. The different clinical trials demonstrated at least comparable efficacy of ximelagatran and warfarin; in terms of prevention of primary events, bleeding, and mortality, the oral TI may offer a promising alternative to the vitamin K antagonist. Together with the convenience of fixed oral dosing and the consistent and predictable anticoagulation, with no need for coagulation monitoring, ximelagatran has a great potential as a new option for long-term prophylaxis and therapy of thromboembolic disorders. Although clinical trials indicated that ximelagatran can potentially be used in clinical indications, the Food and Drug Administration recently refused to approve ximelagatran over concerns about liver toxicity. In clinical trials, in 6% to 10% of patients, raised aminotransferase levels were observed during 112 Oral antithrombin drugs Human Rat Dog Oral dose of ximelagatran a 50 mg (105 ␮mol) 40 ␮mol/kg 40 ␮mol/kg Oral absorption in all species Melagatran Low and highly variable 40–70% Ximelagatran Bioavailability (%) 19 Ϯ 613Ϯ 350Ϯ 13 Maximum melagatran plasma 0.36 Ϯ 0.03 2.16 Ϯ 0.22 15.9 Ϯ 5.0 concentration (C max ) (␮mol/L) Time to reach C max (t max ) (hr) 1.85 Ϯ 0.78 0.80 Ϯ 0.27 1.13 Ϯ 0.6 Elimination half-life (t 1/2 ) (hr) b 3.6 Ϯ 0.7 1.4 Ϯ 0.4 11 Ϯ 3 Elimination half-life (t 1/2 ) (hr) c 1.6 Ϯ 0.2 0.4 Ϯ 0.03 1.2 Ϯ 0.2 Plasma clearance c 145 Ϯ 15 mL/min 15.8 Ϯ 2.1 mL/min/kg 7.0 Ϯ 1.0 mL/min/kg Volume at distribution (V ss ) c 17.3 Ϯ 1.7 L 0.37 Ϯ 0.02L/kg 0.36 Ϯ 0.04 L/kg Renal clearance 120 mL/min 23.1 mL/min/kg 4.37 mL/min/kg Excretion of melagatran (%) c Urine 82.6 Ϯ 3.9 65.9 Ϯ 3.5 42.5 Ϯ 7.8 Feces 5.7 Ϯ 2.2 24.3 Ϯ 4.3 38.9 Ϯ 15.5 Excretion of ximelagatran (%) b Urine 25.2 Ϯ 4.3 21.3 Ϯ 1.9 22.6 Ϯ 2.4 Feces 71.1 Ϯ 4.5 71.3 Ϯ 1.1 66.9 Ϯ 3.1 a n ϭ 5 for humans and rats; n ϭ 4 for dogs. b Measured after oral administration at the aforementioned doses. c Measured after IV administration of melagatran at 2.3 mg (5.3 ␮mol) in humans and 2␮mol/kg in dogs and male rats. Source : From Ref. 26. Table 2 Pharmacokinetic parameters of melagatran after oral administration of ximelagatran in various species 1180 Chap09 3/24/07 12:46 PM Page 112 Introduction 113 Study Indication Study design Interventions Number of patients Reference Ximelagatran Control Ximelagatran Control SPORTIF III Stroke prevention Open-label 36 mg twice daily Warfarin, target 1704 1703 (60,83) in nonvalvular for at least 12 months INR, 2.0–3.0 atrial fibrillation SPORTIF V Stroke prevention Double-blind 36 mg twice daily Warfarin, target 1960 1962 (61,83) in nonvalvular for at least 12months INR, 2.0–3.0 atrial fibrillation THRIVE II and IV Acute therapy for Randomized 36 mg twice daily Enoxaparin (1 mg/kg 1240 1249 (57) proximal DVT double-blind for 6months s.c. twice daily) ϩ warfarin (INR, 2.0–3.0) THRIVE III Extended secondary Randomized 24mg twice daily Placebo for 18months 612 611 (58,59,84) prevention of DVT double-blind for 18months METHRO III Hip and knee Randomized Melagatran 3mg s.c. Enoxaparin 40 mg s.c. 1399 1389 (54) replacement double-blind 4–12hrs after surgery; once daily for 8–11 days then ximelagatran 24 mg starting 12 hrs before twice daily for 8–11days surgery EXPRESS Hip and knee Randomized Melagatran 2mg s.c. Enoxaparin 40 mg s.c. 1410 1425 (53) replacement double-blind immediately before once daily for 8–11 surgery, melagatran days starting 12 hrs 3 mg s.c. 8 hrs after before surgery surgery, then ximelagatran 24 mg twice daily EXULT A Knee replacement Randomized Ximelagatran 24mg Warfarin initiated evening 614 (24 mg), 608 (56) double-blind or 36mg twice daily after surgery and adjusted 629 (36 mg) for 7–12 days, initiated to INR 2.5 12 hr after surgery EXULT B Knee replacement Randomized Ximelagatran 24mg Warfarin initiated evening 1151 1148 (85) double-blind or 36mg twice daily after surgery and adjusted for 7–12 days, initiated to INR 2.5 morning after surgery Note : SPORTIF II and IV, THRIVE I, METHRO I, METHRO II, and ESTEEM were dose-guiding studies. Abbreviations : DVT, deep venous thrombosis; ESTEEM, Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patiEnts with rEcent Myocardial damage; EXPRESS, EXpanded PRophylaxis Evaluation Surgery Study; EXULT, EXanta Used to Lessen Thrombosis; INR, international normalized ratio; s.c., subcutaneous; METHRO, MElagatran for THRombin inhibition in Orthopedic surgery; SPORTIF, Stroke Prevention using an ORal Thrombin Inhibitor in atrial Fibrillation; THRIVE, THRombin Inhibitor in Venous thromboEmbolism. Source : From Refs. 29, 55, 63, 65, 86. Table 3 Clinical phase III trials with ximelagatran 1180 Chap09 3/24/07 12:46 PM Page 113 [...]... infarction during the acute phase of unstable angina Circulation 19 93; 88:2045–2048 Cairns JA, Singer J, Gent M, et al One year mortality outcomes of all coronary and intensive care unit patients with acute myocardial infarction, unstable angina or other chest pain in Hamilton, Ontario, a city of 37 5,000 people Can J Cardiol 1989; 5: 239 –246 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 125 CAPRIE Steering Committee... selective Factor Xa inhibitor ZK-807 834 (CI-1 031 ) Thromb Res 2002; 105 :34 7 35 2 Chu V, Brown K, Colussi D, et al Pharmacological characterization of a novel factor Xa inhibitor, FXV6 73 Thromb Res 2001; 1 03: 309 32 4 Posta JM, Sullivana ME, Abendschein D, et al Human in vitro pharmacodynamic profile of the selective Factor Xa inhibitor ZK-807 834 (CI-1 031 ) Thromb Res 2002; 105 :34 7 35 2 Morishima Y, Tanabe K, Terada... in a dog model of coronary artery thrombosis can be inhibited with a direct, small molecule thrombin inhibitor (melagatran) Thromb Haemost 2002; 87:557–562 Elg M, Gustafsson D A combination of a thrombin inhibitor and dexamethasone prevents the development of experimental disseminated intravascular coagulation in rats Thromb Res 2006; 117:429– 437 25 26 27 28 29 30 31 32 33 34 35 36 37 38 Sarich TC,... focus on recombinant hirudin J Thromb Thrombolysis 2000; 10:S47–S57 Iqbal O, Ahmad S, Lewis BE, et al Monitoring of argatroban in ARG310 study: potential recommendations for its use in 25 26 27 28 29 30 31 32 33 34 35 36 37 interventional cardiology Clin Appl Thrombosis/Hemostasis 2002; 8 (3) :217–224 Becker RC Hirudin-based anticoagulant strategies for patients with suspected heparin-induced thrombocytopenia... 20 03; 42:765–777 Sarich TC, Johansson S, Schutzer KM, et al The pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct 1180 Chap09 3/ 24/07 12:46 PM Page 117 References 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 thrombin inhibitor, are unaffected by a single dose of alcohol J Clin Pharmacol 2004; 44 :38 8 39 3 Wolzt M, Sarich TS, Eriksson UG Pharmacokinetics and pharmacodynamics of. .. by the combination of aspirin and heparin.) In 1981, a study showed the incidence of myocardial infarction to be only 3% in aspirin-treated patients as compared with 15% in the control group (33 ) These findings were confirmed in studies by Lewis et al and Cairns et al (32 ,33 ), showing a very clear benefit of aspirin without heparin In these studies, the dose of aspirin varied from 32 5 mg twice daily... anticoagulants Blood 2005; 105:4 53 4 63 Gurm HS, Bhatt DL Thrombin, an ideal target for pharmacological inhibition: a review of direct thrombin inhibitors Am Heart J 2005; 149:S 43 S 53 Kikelj D Peptidomimetic thrombin inhibitors Pathophysiol Haemost Thromb 20 03; 33 :487–491 Hauptmann J, Sturzebecher J Synthetic inhibitors of thrombin and factor Xa: from bench to bedside Thromb Res 1999; 93: 2 03 241 Nutescu EA, Shapiro... study N Engl J Med 19 83; 30 9: 39 6–4 03 Cairns JA, Gent M, Singer J, et al Aspirin, sulfinpyrazone or both in unstable angina: results of a Canadian multicenter trial N Engl J Med 1985; 31 3: 136 9– 137 5 Theroux P Ouimet H, Mc Cans J, et al Aspirin, heparin or , both to treat unstable angina N Engl J Med 1988; 31 9: 1105–1111 Raschke R, Hirsh J, Guildry JR Suboptimal monitoring and dosing of unfractionated heparin... Williams and Wilkins, 2006: 138 7–1404 Davies MJ The composition of coronary-artery plaques N Engl J Med 1997; 33 6: 131 2– 131 4 Harrington RA, Califf RM, Holmes DR Jr, et al Is all unstable angina the same? Insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) Am Heart J 1999; 137 :227– 233 Silva JA, White CJ, Collins TJ, et al Morphologic comparison of atherosclerotic lesions... Chap09 3/ 24/07 114 12:46 PM Page 114 Oral antithrombin drugs long-term use ( 35 days) of ximelagatran The increase in levels of alanine aminotransferase (more than three-fold over the upper level of normal) occurred one to six months after initiation of therapy, but in 96% of patients, recovery was confirmed regardless of continuation of therapy or not (66) Although the true clinical significance of these . (V ss ) c 17 .3 Ϯ 1.7 L 0 .37 Ϯ 0.02L/kg 0 .36 Ϯ 0.04 L/kg Renal clearance 120 mL/min 23. 1 mL/min/kg 4 .37 mL/min/kg Excretion of melagatran (%) c Urine 82.6 Ϯ 3. 9 65.9 Ϯ 3. 5 42.5 Ϯ 7.8 Feces 5.7 Ϯ 2.2 24 .3. comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 33 3:757–7 63. 51 Cannon CP, McCabe CH, Henry TD, et al. A pilot trial of recombinant. 2002; 35 9:294 30 2. 20 Yeh RW, Jang IK. Argatroban: Update. Am Heart J 2006; 151:1 131 –1 138 . 21 Weitz JI, Bates ER. Direct thrombin inhibitors in cardiac disease. Cardiovasc Toxicol 20 03; 3: 13 25. 22

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