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The new oral anticoagulants

L. BERNARDO MENAJOVSKY, MD, MS, Assistant Professor of Medicine, Thomas Jefferson University, Jefferson Medical College; Codirector, Jefferson Antithrombotic Therapy Service, Philadelphia, Pa.

DEBORAH DeEUGENIO, PharmD, CACP, Assistant Professor of Pharmacy, Temple University, Philadelphia, Pa; Clinical Pharmacist, Jefferson Antithrombotic Therapy Service, Philadelphia, Pa.

Novel oral anticoagulant agents that do not require laboratory monitoring, have a rapid onset of therapeutic effect, and have minimal drug-drug and drug-diet interactions should soon be available for clinical use.

Anticoagulation therapy is considered one of the most challenging interventions in medicine. The challenge stems from the risk of bleeding associated with treatment that is both patient- and agent-dependent. From the practitioner's standpoint, bleeding is the most significant barrier to prescribing anticoagulants to eligible patients; from the patient's perspective, bleeding and compliance are the main barriers to therapy. The problem is the lack of an "ideal anticoagulant"—one that fulfills certain characteristics set forth in formal and informal expert opinion and consensus (see Table 1).

 

TABLE 1 Characteristics of the ideal anticoagulant

Rapidly inhibits thrombus formation Oral absorption No therapeutic monitoring No bleeding Minimal/no side effects Minimal/no drug interactions

Warfarin is the most commonly used oral anticoagulant in the United States. Despite its proven efficacy, it is considered the least ideal anticoagulant agent. Patients on warfarin therapy require frequent laboratory monitoring due to the drug's narrow therapeutic index and multiple drug-drug and drug-diet interactions. Other safety precautions include strict diet and lifestyle restrictions. Warfarin also takes several days to exert its full antithrombotic effect and initially, to provide full benefit, it must be coadministered with an injectable agent.

New oral anticoagulants such as direct thrombin inhibitors (DTIs) and direct factor Xa inhibitors have the potential to offer viable alternatives to warfarin therapy. The new agents have wider therapeutic indexes and more predictable dose-response relationships and routine therapeutic coagulation monitoring will not be necessary. The drugs exert rapid antithrombotic effects when given orally and appear to have minimal drug-drug and drug-diet interactions. All of these agents remain in various stages of clinical trials and none have yet been approved by the FDA. However, it is expected that patients will soon have effective, safe, and convenient alternatives to warfarin therapy. This article describes the most recent evidence for the new anticoagulants.

DIRECT THROMBIN INHIBITORS

DTIs exert their anticoagulant effects by directly inhibiting thrombin without requiring an intermediate such as antithrombin as in the case of heparin and low molecular weight heparins (LMWHs). The importance of directly inhibiting thrombin lies in the pivotal function of this molecule in the coagulation process (see "Coagulation cascade"). The first known DTI was hirudin, which was isolated from leech protein in the 1800s but not used clinically until recently. Two injectable agents that are structurally similar to hirudin—bivalirudin (Angiomax) and lepirudin (Refludan)—are currently on the market. Synthetic smaller molecules with favorable pharmacologic properties have been developed also. These include argatroban (Acova), an injectable DTI currently in use and ximelagatran (Exanta), the first oral DTI, which is being reviewed for approval by the FDA (see Table 2).¹

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TABLE 2 Direct thrombin inhibitors
Drug	Action	Half-life	Excretion	Monitoring	Administration	Neutralization
Hirudin	DTI	120 min	Renal	aPTT	IV or SC	None
Lepirudin	DTI	1.5 h	Renal	aPTT or ECT	IV or SC	None
Argatroban	DTI	40 min	Hepatic, renal	aPTT	IV	None
Melagatran*	DTI	3 h	Renal, GI	None	SC, po	None
*Metabolite of ximelagatran. Key: aPTT, activated partial thromboplastin time; DTI, direct thrombin inhibition; ECT, ecarin clotting time.

Ximelagatran

Ximelagatran has several characteristics that make it a desirable agent. Its peak concentration is achieved in 2 hours. The drug can be taken orally, is well-tolerated, and food does not appear to affect absorption. It readily converts to its active form, melagatran which has a half-life of 2.5 to 3.5 hours, allowing for fixed dosing every 12 hours.² Melagatran is not metabolized and therefore appears to have a low incidence of drug-drug interactions with drugs metabolized by the hepatic cytochrome P-450 system.³

Melagatran is predominantly excreted unchanged via the kidneys (approximately 80%) and the total body clearance linearly correlates to the creatinine clearance. Accumulation of ximelagatran in patients who have severe renal insufficiency is possible because this drug is predominantly excreted unchanged by the kidneys; its safe use in patients who have renal insufficiency has not been established.⁴ However, obesity and mild to moderate liver dysfunction do not appear to significantly affect ximelagatran pharmacokinetics when the medication is given as a fixed dose.

Ximelagatran use elevates the activated partial thromboplastin time (aPTT) in a nonlinear manner, but a therapeutic range has not been established. Therapeutic coagulation monitoring was not utilized in clinical trials with fixed dosing of ximelagatran (see "Recent anticoagulation drug clinical trials").⁴

 

Recent anticoagulation drug clinical trials Direct thrombin inhibitors EXPRESS (EXpanded PRophylaxis Evaluation Surgery Study), a randomized, double-blind, parallel group, placebo-controlled trial, examined the safety and efficacy of ximelagatran compared to enoxaparin to prevent venous thromboembolism (VTE) in 2800 patients undergoing total knee or hip replacement surgery.1 Patients received melagatran, 2 mg SC, immediately prior to surgery and then 3 mg SC the night after surgery. These patients then received oral ximelagatran, 24 mg bid. Patients in the second group received enoxaparin, 40 mg SC once daily, starting the night before surgery. The occurrence of deep vein thrombosis (DVT) with pulmonary embolism (PE) was 2.3% and 6.3% in the ximelagatran and enoxaparin groups. The overall rate of VTE was significantly lower in the ximelagatran group than in the enoxaparin group. There was no difference in clinically significant bleeding; however, there was a trend toward increased bleeding in the ximelagatran group. The investigators concluded that SC melagatran with subsequent oral ximelagatran is more effective than enoxaparin in preventing VTE and PE after total hip and knee replacement. It should be noted that enoxaparin is recommended to be given 30 mg SC bid in patients following total hip and knee replacements.2 Therefore, enoxaparin efficacy may be underestimated in this study due to suboptimal dosing. EXULT (EXanta Used to Lessen Thrombosis), a multicenter, randomized, double-blind study, compared the safety and efficacy of ximelagatran and warfarin for VTE prophylaxis in 2301 patients undergoing total knee replacement.3 Patients received ximelagatran, 24 mg or 36 mg bid, initiated the morning after surgery, or warfarin titrated to an internationalized ratio (INR) of 2.5 initiated in the evening on the day of surgery. The combined end point of PE, DVT, and all-cause mortality showed significantly increased efficacy with ximelagatran 36 mg compared with that of warfarin. The incidence of any bleeding was 4.8% for ximelagatran, 24 mg; 5.3% for ximelagatran, 36 mg; and 4.5% for warfarin. The authors concluded that ximelagatran was superior to warfarin in preventing VTE after total knee replacement in patients receiving ximelagatran, 36 mg bid. THRIVE III (THRombin Inhibitor in Venous thromboEmbolism), a multicenter, double-blind, placebo-controlled trial of 1233 patients, evaluated the safety and efficacy of ximelagatran in secondary prevention of VTE.4 All patients had confirmed DVT or PE and received standard anticoagulation for 6 months. Patients were then randomized to receive ximelagatran, 24 mg bid, or placebo for an additional 18 months. Compared with placebo, ximelagatran significantly reduced the risk of recurrent VTE without a significant increase in the risk of bleeding. Increases in liver aminotransferases were generally transient and asymptomatic. The investigators concluded that ximelagatran was safe and effective when used for secondary prevention of VTE. SPORTIF III (Stroke Prevention by ORal Thrombin Inhibitor atrial Fibrillation), a multicenter, randomized, open-label, noninferiority trial, evaluated warfarin and ximelagatran for stroke prevention in 3407 patients with atrial fibrillation and 1 additional risk factor for stroke.5 Patients received ximelagatran, 36 mg bid, or warfarin adjusted to an INR of 2.5 for a mean of 17 months. Primary occurrence of stroke in the intention-to-treat analysis in the ximelagatran and warfarin groups was 2.3% and 1.6%, respectively. There was no difference in major bleeding and an increase of minor bleeding in the warfarin group. There was a higher incidence of liver enzyme elevations in the ximelagatran group compared with the warfarin group. Increased liver enzyme levels tended to be elevations at 2 to 6 months duration of therapy and returned to normal spontaneously or with cessation of therapy. The researchers concluded that ximelagatran is at least equivalent to warfarin therapy for prevention of stroke in patients with nonvalvular atrial fibrillation. THRIVE (THRombin Inhibitor in Venous thromboEmbolism), a randomized, double-blind study evaluated 2491 patients with acute DVT.6 PE was present in 37% of patients. Patients received either ximelagatran 36 mg twice a day or enoxaparin, 1 mg/kg SQ every 12 hours for 5 days, followed by warfarin (INR 2-3) for a total of 6 months. Occurrence of VTE in the intention-to-treat analysis was 2.1% and 2% in the ximelagatran and enoxaparin/warfarin groups, respectively. All-cause mortality was 2.3% and 3.4% in the ximelagatran and enoxaparin/warfarin groups, respectively. Major bleeding in the on protocol analysis occurred in 1.3% and 2.2% in the ximelagatran and enoxaparin/warfarin groups, respectively. The authors concluded that ximelagatran was not inferior, in safety or efficacy analysis, to enoxaparin/warfarin therapy for treatment of acute DVT with or without PE. ESTEEM (Efficacy and Safety of the oral Thrombin inhibitor ximelagatran in combination with aspirin, in patients with recent Myocardial damage), is a phase II randomized, multicenter, placebo-controlled, double-blind, dose-finding study of ximelagatran and aspirin versus aspirin alone in 1883 recent MI patients who received aspirin, 160 mg/d, alone or in combination with ximelagatran, 24, 36, 48 or 60 mg bid, for a period of 6 months.7 All dose groups of ximelagatran collectively had reduced risk of death, recurrent MI or unstable angina from 16.3% to 12.7%, compared to aspirin therapy alone. Rates of major bleeding in the ximelagatran/placebo versus aspirin/placebo groups were 1.8% versus 0.9%. Total cumulative major and minor bleeding was increased in the ximelagatran groups. Elevated liver enzymes occurred in 6.5% of patients receiving the 24-mg dose of ximelagatran and in 12.2 to 13% of patients receiving higher doses. The authors concluded that ximelagatran provides significant additional benefit, in combination with aspirin therapy, to post-MI patients. Phase III trials need to be completed to validate this conclusion. Oral heparins PROTECT (PRophylaxis with Oral SNAC/ heparin against ThromboEmbolic Complications following Total hip replacement), a randomized, double-blind, multicenter study, compared the safety and efficacy of 2 oral dosing regimens of liquid oral/SNAC heparin with SC enoxaparin for the prevention of VTE following total hip replacement or revision.8 Patients received high-dose SNAC/heparin, low-dose SNAC/UFH, or enoxaparin, 30 mg SC every 12 hours. Patients received therapy for 30 days and were assessed by venography. Documented DVT occurred in 31.8% of the low-dose SNAC/UFH group, 30% of the high-dose SNAC/UFH group, and 26.1% of the enoxaparin group. Proximal DVT/PE occurred at a rate of 18.6%, 13.9%, and 12.7% for the 3 groups previously mentioned. There was a very low incidence of major bleeding which was reported to be comparable among groups. The study demonstrated safety and efficacy of SNAC/UFH in VTE prophylaxis for patients undergoing total hip replacement or revision. 1. Eriksson H, Wahlander K, Lundstrom T, et al. The oral direct thrombin inhibitor ximelagatran, and its subcutaneous form melagatran, compared with enoxaparin for prophylaxis of venous thromboembolism in total hip and total knee replacement: the EXPRESS Study-Preliminary Results. Int J Clin Pract. 2003;57:57-59. 2. Geerts WH, Heit JA, Clagett P, et al. Prevention of venous thromboembolism. Chest. 2001;119 (suppl 1):132s-175s. 3. Francis CW, Berkowitz SD, Comp PC, et al. Randomized, double-blind, comparisons of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism after total knee replacement [abstract]. Presented at the American College of Hematology 44th Annual Meeting; December 2002; Philadelphia, Pa. 4. Eriksson H, Wahlander K, Lundstrom T, et al. Extended secondary prophylaxis with the oral direct thrombin inhibitor ximelagatran for 18 months after 6 months of anticoagulation in patients with venous thromboembolism: a randomized, placebo-controlled trial. J Thromb Haemost. 2003;1 (suppl )July:0C005. 5. Halperin JL, et al. A long-term randomized trial comparing ximelagatran with warfarin for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation [abstract]. Presented at the 52nd Annual Scientific Session of the American College of Cardiology; March-April 2003; Chicago, Ill. 6. Huisman MV, et al. Efficacy and safety of the direct thrombin inhibitor ximelagatran compared with current standard therapy for acute, symptomatic deep vein thrombosis, with or without pulmonary embolism: A randomized, double-blind, multinational study. J Thromb Haemost. 2003;suppl 1: abstract 0C003. 7. Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomized controlled trial. Lancet. 2003;362:789-797. 8. Hull RD, Kakkar AT, Marder VJ, et al. Oral SNAC-heparin versus enoxaparin for preventing venous thromboembolism [abstract]. J Thromb Haemost. 2003;suppl:P1889.

Clinical considerations

Ximelagatran may soon offer an alternative oral anticoagulant option for patients that would allow fixed dosing without the need for continuous therapeutic coagulation monitoring. In addition to its rapid onset of antithrombotic effect with a low incidence of drug-drug and drug-diet interactions, ximelagatran has demonstrated efficacy in venous thromboembolism (VTE) prophylaxis in patients undergoing total hip and knee replacements, stroke prevention in patients with nonvalvular atrial fibrillation, primary treatment and extended secondary prevention of deep vein thrombosis/pulmonary embolism (DVT/PE), and reduction of cardiovascular events post-MI in combination with aspirin therapy. Ximelagatran has not been examined in published clinical trials for use in patients with prosthetic heart valves or patients with other known hypercoagulable conditions.

Because ximelagatran has been shown to induce a chemical hepatitis, it is expected that the FDA will require routine hepatic monitoring, at least during initial therapy. There is also currently no antidote available to rapidly reverse the drug's effects.

ORAL HEPARINS

Heparin is a naturally occurring glycosaminoglycan that exists as a heterogeneous mixture of oligosaccharides. The average molecular weight of unfractionated heparin (UFH) is approximately 20,000 d, with ranges from 5000 to 30,000 d. Heparin is a highly acidic, negatively charged molecule that exerts its anticoagulant effect via antithrombin, thereby inhibiting thrombin and factor Xa (see "Multimechanistic role of thrombin"). Heparin is not absorbed efficiently across the GI mucosa because of its large molecular weight.

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SNAC and SNAD

To overcome the problem of heparin's molecular size, numerous carrier molecules have been developed such as sodium N-[10-(2-hydroxybenzoyl) amino] decanoate (SNAD) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC). SNAD and SNAC are small compounds that bind noncovalently with heparin. They neutralize heparin's negative ionic charge and make it more lipophilic. Therefore, the heparin and carrier molecule are more easily and regularly absorbed across the GI mucosa and into the circulation. Once in the circulation, the carrier molecules dissociate from the heparin allowing it to produce its anticoagulant effects. The agents have been demonstrated to provide reproducible and adequate anticoagulation when administered orally. In basic animal studies, the combination of SNAC/oral heparin or SNAD/LMWH successfully prevented and treated venous thromboembolic disease (VTED).

The combination of SNAC/heparin, when taken as an oral liquid, increased aPTT and induced the release of tissue factor pathway inhibition (TFPI) like intravenously administered heparin. The anti-Xa/anti-IIa ratios were also similar to IV UFH.⁵ In healthy volunteers, peak anti-Xa, anti-Xa, and TFPI levels were reached 1 hour after dosing with SNAC/heparin.⁶

Clinical considerations

The SNAC/UFH molecule may offer a way to administer UFH effectively via the oral route. Early studies report an increased incidence of nausea and emesis with high doses of SNAC/UFH; however, a solid formulation with improved patient tolerability is under development.^6,7 Noncompliance is also an issue, probably related to multiple daily dosing with SNAC/UFH, an issue which must be considered. Heparin induced-thrombocytopenia is a concern, although it has not been documented as a problem in clinical trials to date.

DIRECT FACTOR XA INHIBITORS

Factor Xa, like thrombin, binds to the clot and contributes to the propensity of thrombi to activate the coagulation system.⁸ Favorable results with LMWHs, which have a greater propensity for factor Xa than UFH, suggest that factor Xa may be a more biologically appealing therapeutic target.⁹ Several orally active compounds that are direct factor Xa inhibitors—including DX-9065a, YM60828, and DPC-423—have successfully completed early studies in animal models and in healthy volunteers.^10-12 These early studies show promise for use of these compounds as oral anticoagulants.

PRODUCED BY DEBORAH KAPLAN

REFERENCES

1. Hyers TM. Management of venous thromboembolism: past, present and future. Arch Int Med. 2003;163:759-768.

2. Wahlander K, Lapidus L, Olssen C-G, et al. Pharmacokinetics, pharmacodynamics and clinical effects of the oral direct thrombin inhibitor ximelagatran in acute treatment of patients with pulmonary embolism and deep vein thrombosis. Thromb Res. 2002;107:93-99.

3. Johansson S, Eriksson LM, Thuresson A, et al. Ximelagatran, an oral direct thrombin inhibitor, has no effect on the pharmacokinetics of P450 metabolized drugs. Clin Pharm Ther. 2002;71:65.

4. Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. Eur J Clin Pharm. 2001;57:751-758.

5. Berkowitz SD, Marder VJ, Kosutic G, et al. Oral heparin administration with a novel drug delivery agent (SNAC) in healthy volunteers and patients undergoing elective total hip arthroplasty. J Thromb Haemost. 2003;1:1914-1919.

6. Baughman RA, Kapoor SC, Agarwal RK, et al. Oral delivery of anticoagulant doses of heparin: a randomized, double-blind, controlled study in humans. Circulation. 1998;98:1610-1615.

7. Hull RD, Kakkar AT, Marder VJ, et al. Oral SNAC-heparin versus enoxaparin for preventing venous thromboembolism [abstract]. J Thromb Haemost. 2003;suppl:P1889.

8. Herault JP, Bernat A, Pflieger AM, et al. Comparative effects of two direct and indirect factor Xa inhibitors on free and clot-bound prothrombinase. J Pharm Ther. 1997;283:16-22.

9. Dyke CK, Becker CR, Kleiman NS, et al. First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation. 2002;105: 2385-2391.

10. Hashimoto M, Onobayashi Y, Oiwa K, et al. Enhanced endogenous thrombolysis induced by a specific Xa inhibitor, DX-9065a, evaluated in a rat arterial thrombolysis model in vivo. Thromb Res. 2002;106:165-168.

11. Hirayama F, Koshio H, Katayama N, et al. The discovery of YM-60828: a potent, selective and orally bioavailable factor Xa inhibitor. Bioorg Med Chem. 2002;10:1509-1523.

12. Taglialatela M. DPC-423 Bristol-Myers Squibb. Curr Opin Invest Drugs. 2002;3:252-254.

 

The new oral anticoagulants. JAAPA January 2004;17:Web.

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