3 : 34. Pankaj Manoria, P C Manoria, Bhopal

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1 3 : 34 Newer Antithrombins and anticoagulants Introduction Thrombosis is a leading cause of morbidity and mortality but for decades, anticoagulant therapy has usually consisted of unfractionate heparin (UFH) or low molecular weight heparin(lmwh) and warfarin, despite their obvious limitations. Thus there is definitely a need for novel anticoagulants in clinical practice. In this article we describe some novel antithrombotics which are under development and some already in clinical use. A lot of research in the development of newer antithrombins is currently underway which might change the antithrombotic management strategies in future. Main limitations of current widely used antithrombotics: Warfarin and heparins lack specificity in terms of their modes of Complicates management of: Bleeding patient Patient with high INR Anticoagulation clinics Long half-life Narrow therapeutic index & drug-diet interactions Slow onset of action Periprocedural anticoagulatin difficult Requires frequent monitoring? Genotype testing Heparin overlap often necessary Fig. 1 : Limitations and challenges associated with vitamin K antagonists Requirement for monitoring Pankaj Manoria, P C Manoria, Bhopal action. Through competition with vitamin K, warfarin interferes with the completed synthesis of four coagulation proteins [prothrombin and factors VII, IX and X] as well as two physiological anticoagulants [protein C and protein S] 1. Heparins act indirectly via the physiological anticoagulant antithrombin III which inhibits at several points in the coagulation mechanism, including thrombin and factor X. LMWH also has mechanism similar to UFH but has much more improved specificity. The efficacy of these conventional anticoagulants has been well proved but despite their proven efficacy, currently used anticoagulants have some limitations which are highlighted in figure1-3. Properties of ideal antithrombotics: Although the development of an antithrombotic which is effective but does not cause increased bleeding is unrealistic, there are certain properties which are desired in newer generation anticoagulants ( see table-1) Understanding the coagulation cascade & incorporating newer anticoagulants in it: Before discussing the novel anticoagulants let us first revise the important aspects of coagulation cascade and role of important coagulation factors. It is recognized now that the tissue factor-dependent pathway of Difficult in reversing action in case of bleeding Wide inter individual dose requirement No antidote available used for long term prophylaxis effect via oral route Antibody formation Short half Need for I/v infusion used for long term Prophylaxis effect via oral route routinely available assay Renal clearance Accumulation in renal impairment Can Lead to HIT Fig. 2: Limitations and challenges associated with unfractionate heparin monitored Fig. 3: Limitations and challenges associated with LMWH

2 blood coagulation [the extrinsic route] is of prime importance in pathophysiology and it is the components of this pathway which are most attractive as targets for development of novel anticoagulants (see figure-4). Factor IIa which is activated prothrombin, better known as thrombin is the pivotal enzyme in blood coagulation. Thrombin cleaves peptides from soluble fibrinogen generating insoluble fibrin. and is also a potent activator of blood platelets. Xa which is activated factor X is a pivotal factor in both the extrinsic [tissue factor-dependent] pathway and the less important intrinsic [contact dependent] pathway. Va, VIIa and tissue factor are other important coagulation proteins in the extrinsic pathways. To make it short and simple the newer anticoagulants are targeting the coagulation cascade mainly at two levels one at the level of factor X a which are called factor Xa inhibitors and other directly at the level of thrombin which are called direct thrombin inhibitors, which block the enzymatic activity of thrombin independently of its physiological inhibitor antithrombin III. Figure-5 gives a non exhaustive list of novel specific anticoagulants. Direct thrombin inhibitors: As the name suggest these agents block the enzymatic activity of thrombin directly independently of its physiological inhibitor antithrombin III. Heparins achieve this indirectly by binding to and enhancing the activity of the natural anticoagulant antithrombin III. The main advantages of these agents Newer Antithrombins and Anticoagulants Table-1: Desired Properties of an ideal anticoagulant: Characteristics Consequences Rapid onset of action No need for overlap with parenteral anticoagulants; simplified management in case of a hemorrhagic event or need for an intervention and minimizes need for an antidote Predictable pharmacokinetics Simplified dosing regimens Predictable anticoagulant response Fixed dose, no need for coagulation monitoring and dose adjustment Oral availability New indications No CYP2C9 or VCOR1 metabolism food interactions, few if any drug interactions Availability of a safe antidote Provide rapid reversal in case of a hemorrhagic event or need for an intervention No off-target effects, such as hepatoxicity No need for monitoring Reasonable cost Improved access, favors use for new indications Tissue factor pathway inhibitor TF Indirect Xa inhibitor: Fondaparinux Parenteral DTIs: Hirudin Argatroban Bivalirudin Tissue factor/viia inhibitor: NAPc2 Xa IIa VIIa Direct Xa inhibitors: DX9065a BAY Active site inhibited factor VIIa Factor Va inhibitors: Va Soluble thrombomodulin apc Oral DTIs: Ximelagatran Dabigatran Fig. 4 : A simplified coagulation cascade which includes the most promising specific targets for new antithrombotics, and some examples 347 Indirect (IV) Fonda parinux Indraparinux Factor Xa inhibitor Oral Direct Rivaroxban Apixaban Newer Anti Thrombins & Anticoagulants IV Otamixaban DX-9865-a Oral Direct Thrombin Inhibitors Ximelagatran Dabigatran Fig. 5 : Gives a non exhaustive list of novel specific anticoagulants. IV Hirudin Bivaluridin Argatroban are that they not only bind to free thrombin but they also bind to the thrombin attached to the clot. The other advantage is that unlike heparin they do not bind to neutralising plasma proteins including some acute phase reactants, thus producing more predictable anticoagulation. Two groups of DTIs have emerged. The first includes three products which have been developed for intravenous use and have found their main roles in the management of HIT 2 and in percutaneous coronary intervention. The second, potentially of broader clinical use, includes oral prodrugs that are rapidly biotransformed into their active forms. They are targeted for use as longer-term antithrombotics, especially in venous thromboembolism and atrial fibrillation. First-Generation Direct Thrombin Inhibitors: The compounds included in this category are lepirudin, bivaluridin, and argatroban. Since among these only bivaluridin is available in India, we will limit our discussion to bivaluridin only. Bivaluridin is synthetic, has a short half life and is cleared through renal route. The Randomised Evaluation in PCI Linking Angiomax to reduced Clinical Events -2 (REPLACE-2) trial 3 demonstrated that bivalirudin with provisional glycoprotein IIb/IIIa inhibition was not inferior to heparin plus GP IIb/IIIa inhibition in patients undergoing PCI. In the large-scale Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) 4 study done in 13,819 patients with acute coronary syndromes, bivalirudin

3 Medicine Update 2010 Vol. 20 alone, as compared with heparin plus a GP IIb/IIIa inhibitor, was associated with a noninferior rate of the composite ischemia endpoint (7.8% and 7.3%, respectively; p¼0.32; relative risk, 1.08; 95% confidence interval [CI], 0.93 to 1.24) and significantly reduced rates of major bleeding (3.0% versus 5.7%; p< Thus in patients with moderate- or high-risk acute coronary syndromes who were undergoing invasive treatment bivalirudin alone was associated with similar rates of ischemia and significantly lower rates of bleeding as compared to heparin plus a GP IIb/IIIa inhibitor. Second-Generation Direct Thrombin Inhibitors: Secondgeneration DTIs can be administered orally. Two compounds have been studied in large-scale clinical development programs: ximelagatran and dabigatran etexilate. Both have been produced with the intention of developing a drug which delivers reliable anticoagulation at fixed doses hence dispensing with the need for monitoring of the anticoagulant effect. Ximelagatran: Ximelagatran fulfilled many of the criteria for an ideal antithrombotic such as oral absorbtion, predictable pharmacokinetic, no monitoring, no drug/food interaction. 5 It has been evaluated extensively, in a variety of clinical scenarios including thromboprophylaxis against venous thromboembolism, stroke prevention in atrial fibrillation, and treatment of venous thromboembolism, and shown to be an effective oral anticoagulant. But unfortunately owing to hepatotoxicity including death from hepatic failure, this drug could not get a FDA approval and was withdrawn from the market by its manufacturer, Astra Zeneca. Dabigatran etexilate: Dabigatran etexilate is converted into its its active form, dabigatran which competitively inhibits thrombin. This conversion is carried out by a serum esterase that is independent of cytochrome P-450. Therefore, dabigatran should be less susceptible to dietary and drug interactions and to genetic polymorphisms that affect warfarin. Furthermore, neither anticoagulation monitoring nor dose adjustments are necessary with dabigatran as compared to warfarin. Dabigatran has been tested in multiple large, phase III trials as a thromboprophylaxis agent following orthopedic surgery and has been found to be efficacious and comparable with enoxaparin in the prevention of mortality related to major venous thromboembolism 6. In the recent Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) 7 Study In patients with atrial fibrillation, dabigatran given at a dose of 110 mg was associated with rates of stroke and systemic embolism that were similar to those associated with warfarin, as well as lower rates of major hemorrhage. However when given in a higher dose (150 mg), Dabigatran was associated with lower rates of stroke and systemic embolism but similar rates of major hemorrhage as compared with warfarin,. Although long-term data are still quite limited, liver function test elevations have not been a concern with the new compound, and there is no indication that the liver toxicity observed with ximelagatran would be a class effect of DTIs, but it is too early to draw firm conclusions on that particular issue. Inhibitors of activated factor X: Activated coagulation factor X (factor Xa) is located at the convergence of the intrinsic and extrinsic coagulation cascade, and activation of one molecule of factor X results in the generation of 1000 molecules of thrombin.1 Therefore, inhibition of factor Xa should theoretically be more effective for reducing fibrin formation than inactivation of thrombin. Although Xa is a target for the UFH and LMWH, the anticoagulant is non-specific since it inhibits several other coagulation enzymes, notably thrombin. However specific inhibition of activated factor X can be achieved with newer agents which have no inhibitory actions against thrombin and other coagulation factors. These are of two types; indirect inhibitors or direct inhibitors. Indirect Inhibitors: The drugs included in this category are Fondaparinux and Idraparinux. Fondaparinux is a synthetic selective indirect inhibitor of activated factor X. Administered subcutaneously, the onset of action of fondaparinux is rapid, half of the maximum plasma level being reached within 30 min after injection. Furthermore, the pharmacokinetic and safety profile of fondaparinux allows once-daily subcutaneous administration without any laboratory monitoring, including platelet count. Fondaparinux exhibits a very positive benefit-risk ratio in the prevention of venous thrombo embolism in both surgical and acutely ill medical patients at risk of thrombosis. Its favourable efficacy and safety have also been demonstrated in the initial treatment of symptomatic deep-vein thrombosis and pulmonary embolism, and in patients with non-st and ST elevation acute coronary syndromes 6. A related compound, idraparinux, is a pentasaccharide with hypermethylation giving it a half-life of in excess of three days. It has a potential role in longer-term prophylaxis against thrombosis when delivered as a subcutaneous injection just once weekly 9. However, unlike UFH, and to a degree LMWH, the synthetic pentasaccharides are not neutralised by protamine sulphate. This renders management of bleeding due to these antithrombotics potentially somewhat more difficult. Direct Xa inhibitors: Unlike the LMWH or pentasaccharides,these molecules inhibit the function of factor Xa directly; that is, they do not require endogenous antithrombin for their anticoagulant effect. (table -2) The two main oral drugs in this group are rivaroxaban and apixaban. Rivaroxaban has been assessed principally as a thromboprophylactic in total hip replacement surgery and total knee arthroplasty In a dose-ranging study, it appeared to be an effective antithrombotic, although dose-related bleeding events were seen. The second oral drug apixaban, has entered phase III clinical trials. in atrial fibrillation, VTE treatment and prevention 12. The intravenous drug in this category is otamixaban has the Table 2 : Showing difference between the direct and indirect factor Xa inhibitor Indirect Direct Inhibitor AT dependent; Non-AT dependent: mechanism catalytic stoichiometric Drug target Free FXa Free and bound FXa Binding Reversible Reversible 348

4 Newer Antithrombins and Anticoagulants Table 3: Polypharmacology of Heparins Compared with Synthetic Organomimetic Anti-Xa and Anti-IIa Agents Attributes LMWHs Anti-IIa Anti-Xa Inhibition of thrombin ± Inhibition of Xa ++ ± +++ Inhibition of thrombin generation Release of TFPI ++ Activation of fibrinolysis + ± Endothelial effects ++ Modulation of platelet function Growth factor modulation ++ advantage of being reversible, with near-immediate onset of action after a bolus and a short half-life, offering rapid on-off anticoagulant activity, which is a desirable feature in the setting of invasive management of ACS. It is also mainly cleared unchanged via the biliary system, suggesting no need for dose modification in case of renal insufficiency. The (SEPIA-PCI) trial showed that intermediate doses of otamixaban (0.12 and 0.16 mg/kg/h) lowered ischemic end points and similar bleeding rates compared with heparin in patients undergoing nonurgent PCI. Comparing the anti-xa and anti-iia agents: These two agents are often compared since these agents represent different targets Remarkably, in the clinical trials, both classes of drugs have performed similarly. Bleeding issues are more with anti- Xa agents where as thrombosis rebound and liver enzyme elevation has been reported with anti-iia agents. The long-term use of thrombin inhibitors may inhibit the regulatory functions of thrombin such as the activation of protein C and thrombin activatable fibrinolytic inhibitor (TAFI). Also, hemostatic effects, including thrombin receptor activation in platelets and activation of factors V and XIII, may be impaired. This may be the reason for enhanced bleeding with antithrombin agents. On the other hand, the Xa inhibitors may exhibit reduced efficacy in patients with preformed thrombin, which can only be inhibited using antithrombin agents. For this reason, newer agents containing both anti-xa and anti-iia activities are being developed. However it is too early to comment on the relative safety and efficacy of these two classes of drugs. Status of heparins LMWH, warfarins in the new era: We know that thrombosis is a polycomponent syndrome, which optimally requires a multiple target therapeutic approach. Recent drugs such as anti-xa and anti-iia agents are only monotherapeutic drugs that have a single target of action where as heparins are polytherapeutic agents which act on multiple levels in the coagulation cascade ( see table-3). Single targeting of thrombotic and cardiovascular diseases may not provide desirable outcomes. Thus, drugs with a polytherapeutic profile such as the LMWHs and combination regimens may be more effective in the management of thrombosis. Despite the reported problem of HIT, heparin has remained the drug of choice for surgical anticoagulation. This is due to the high bleeding risk associated with the new antithrombin agents when used at higher doses coupled with the lack of antagonists. To the contrary, heparin has a well-tolerated Table 4: Limitation of Newer Antithrombotics S.no. Limitation Comment 1 Can not be monitored Required during surgical and percutaneous intervention 2 No antidote available Problem during bleeding 3 Costly May not be useful in long term treatment. 4 Insufficient evidence Needs more randomized trials. 5 Ineffective anticoagulation Due to mono targetic approach. 6 Liver enzyme elevation Seen with ximelagatron antagonist, protamine, and the heparin-protamine combination has been used with much success for many years. Therefore, currently, UFH is the only reliable anticoagulant that can be used in surgical and interventional indications. Table-4 shows some of the limitations of newer antithrombins. Conclusion The data with newer anticoagulants and antithrombins are attractive but they also have their own limitations. If the efficacy and safety benchmarks are met in the ongoing trials and the costs are not prohibitive, these new medications will offer substantial and immediate benefit to individuals with thromboembolic disease. Untill then Heparin, LMWH and warfarin, will continue to play a major role in the management of thrombotic and cardiovascular disorders beyond. References 1. Ansell J, Hirsh J, Poller L, Bussey H, Jacobson A, Hylek E. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126(suppl): 204S-233S Greinacher A. Lepirudin for the treatment of heparin induced thrombocytopenia. Heparin induced thrombocytopenia (ed. By T.E Warkentin and A Greinacher) New York: Marcel Dekker, 2004; Rajagopal V, Lincoff A, Michael MD et al. 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