Update on Anticoagulants: New Mechanisms and New Options

Joseph A. Caprini, MD
Northwestern University Medical School

Although unfractionated heparin was discovered by McLean in 1916, it wasn't until the sixties that Barritt and Jordan established this anticoagulant as the standard of care to successfully treat pulmonary emboli.1 For many years this drug has been the mainstay of the acute treatment of venous thromboembolic (VTE) problems, as well as many thrombosis prophylaxis applications.  Although this drug has an immediate onset of action, short half-life, and can easily be measured and reversed, there are a number of problems associated with its use.  The effects of this anticoagulant on the clotting system are often unpredictable.  Due to significant protein binding to proteins not involved in clotting, there are difficulties in establishing a therapeutic level within 12 to 24 hours in most patients with acute thrombosis.  Finally, the incidence of heparin-induced thrombocytopenia may be as high as 1-3% in patients receiving the drug. 

The emergence of the low molecular weight heparins (LMWH) in the 1970s and eighties represented a major breakthrough in the approach to thrombosis prophylaxis and treatment.  These drugs have a greater bioavailability, longer half-life, more predictable dose response, and are associated with a lower incidence of heparin-induced thrombocytopenia and heparin-induced osteoporosis.  They also have a survival benefit in the patient with cancer.2

Warfarin, up until very recently, was the only available oral anticoagulant and had been widely used for secondary thrombosis prophylaxis, as well as the treatment of VTE.  This drug is relatively inexpensive, reversible with vitamin K, and requires 36 to 72 hours to achieve an appropriate therapeutic effect.  Problems associated with this drug include a long half-life, frequent food and drug interactions, careful monitoring to adjust the dose, and the suppression of the body's natural anticoagulants before achieving a full circulating anticoagulant effect in the patient.  This latter effect can sometimes produce skin necrosis or paradoxical thrombotic complications if not used with heparin or LMWH.

Over the past decade, a number of new anticoagulant compounds have been created, and some of these have been extensively studied for their ability to prevent and treat VTE. These new drugs selectively inhibit clotting factors within the coagulation cascade.  Some examples include the pentasaccharides, which include fondaparinux with a 17-hour half-life and idraparinux (still investigational), which has a 150-hour half-life.  Both of these pentasaccharides are given by subcutaneous (sc) injection, while razaxaban (still investigational) is a pentasaccharide with a 17-hour half-life that is administered orally.  From a clinical perspective, some of the lowest VTE rates ever seen following total hip or knee replacement or hip fracture involved prophylaxis with fondaparinux.  Unlike warfarin, heparin, or LMWH, the pentasaccharides cause a conformational change in the antithrombin III molecule which results in inhibition of factor Xa.  As a result, fondaparinux does not appear to cause heparin-induced thrombocytopenia or osteopaenia. Surgical wound healing may also be improved in patients receiving fondaparinux due to the fact that fondaparinux use does not completely block thrombin. Fondaparinux 2.5 mg sc once daily administered for up to 11 days, reduced the risk of VTE by more than 50% compared with the LMWH, Enoxaparin. The efficacy benefit was consistent across all patient groups and was independent of age, gender, weight or surgical characteristics. Furthermore, this superior efficacy was achieved without increasing clinically important bleeding.3-6 Another recent trial investigated extended thromboprophylaxis with 2.5 mg sc fondaparinux for 30 days compared to 7 days after hip fracture and a highly significant reduction in the risk of VTE (96%) without an observed increase in clinically relevant bleeding.7  This drug has also been tested as thromboprophylaxis following abdominal surgery where it has been found to be as effective as LMWH and was associated with slightly improved survival in cancer patients. It has been found to provide equivalent efficacy and safety in the treatment of VTE compared to LMWH/warfarin, and equivalent to unfractionated heparin in patients presenting with pulmonary emboli. A fixed once-a-day dose and a 17-hour half –life without the need for monitoring and absence of heparin-induced thrombocytopenia reports are advantages of this drug as a VTE treatment option.

Currently a large treatment trial is underway comparing idraparinux sc once weekly to LMWH/warfarin for acute deep vein thrombosis treatment. Phase II studies suggest this once weekly approach may be equivalent to standard therapy.  This investigational drug has a 150 hour half-life. 

Even more recently, a new class of anticoagulants has been developed that specifically block thrombin, and several of these parenteral thrombin inhibitors play an important role in the treatment of heparin induced thrombocytopenia and in other situations where heparin cannot be given.  Recently an oral thrombin inhibitor has been developed called ximelagatran.  This drug is given in a fixed dose and has a predictable response requiring no coagulation monitoring.  It is not bound to plasma proteins and has a very low potential for food or drug interactions.  The pharmacokinetics are very comparable to the LMWH’s.  Approximately 30,000 patients have now been studied in clinical trials throughout the world comparing ximelagatran to either warfarin or LMWH.  The results of these trials indicate that ximelagatran is as effective as or even more effective than standard anticoagulants depending on the clinical scenario.

The efficacy and safety of ximelagatran were tested in patients with acute symptomatic deep vein thrombosis with or without pulmonary embolism.  Patients received 36 mg of ximelagatran twice daily or enoxaparin, 1 mg per kilogram sc twice daily, followed by standard warfarin therapy to achieve an INR of 2 to 3 for six months.  The ximelagatran group consisted of 1,240 patients, while 1,249 patients received standard therapy.  In the intention-to-treat group, recurrent VTE occurred in 2% of the standard therapy group and 2.1% of the ximelagatran group.  In those patients completing therapy for six months, 1.5% of the standard therapy group and 2% of the ximelagatran group suffered recurrent VTE with all-cause mortality of 0.6 % in both groups.  Elevated liver enzymes were seen in 2% of the standard therapy group and 9.6% of the ximelagatran group.  There were no clinical adverse events related to elevated liver enzymes in any of the patients in either study group. There were three deaths in each group not related to the drug.8  A second trial involving ximelagatran in a fixed dose of 24 mg twice daily was conducted in patients with VTE, who had completed a six-month period of treatment with LMWH and warfarin.  1,223 patients were randomized to receive either 24 mg of ximelagatran twice daily or placebo for 18 months.  Recurrent VTE events were seen in 2.8% of the ximelagatran group and 12.6% of the control group (P. < 0.0001).  There was no difference in bleeding events or mortality between the two groups after 18 months.  Liver enzymes were elevated in 6.4% of the ximelagatran group and 1.2% of the placebo group.  There were no clinical adverse effects associated with the elevation of liver enzymes in any patients in this study.9

Ximelagatran in a fixed dose of 36 mg twice daily was tested in patients with atrial fibrillation compared to standard warfarin anticoagulation in two large studies involving 7320 patients.  Patients underwent at least one year of treatment in either group, and this represented an overall exposure of over 4,000 patient years in aggregate.  The quality of warfarin control was excellent, with 81% of patients having an INR between 1.8 and 3.2 for the entire duration of treatment.  The on-treatment analysis revealed 52 events (2.2%) in the warfarin group compared to 29 events (1.3%) in the ximelagatran group.  There was no statistically significant difference in hemorrhage between the two groups.  Elevated liver enzymes occurred in 6.5% of the ximelagatran group and 0.7% of the warfarin group without any clinical adverse effects.10 These results represent the open label portion of the study, which involved half of the 7,000 patients from 23 countries.  A closed label portion of the study was done in North America in the other half of the patients and achieved similar results.  This large multinational effort demonstrated that in high-risk patients with atrial fibrillation, Ximelagatran was as effective as well-controlled warfarin in preventing stroke and systemic embolic events.

Despite all of these data, more questions need to be addressed through head-to-head comparisons of six months of enoxaparin, fondaparinux, idraparinux, and ximelagatran for the acute treatment of VTE. What will the VTE recurrence rate in cancer patients be using the new drugs compared to LMWH in VTE patients with cancer? Which drug will be best for the long-term secondary prophylaxis after acute VTE treatment? Will the incidence of the post-thrombotic syndrome be different when using any of these new drugs? Finally, more studies are necessary to elucidate the nature of the liver function test abnormalities seen following the use of ximelagatran.

References

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2. Warkentin TE, Bernstein RA. Delayed-onset heparin-induced       thrombocytopenia  and cerebral thrombosis after a single administration of unfractionated heparin. N    Engl J Med 2003;348:1067-9.
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7. Eriksson BI, Lassen MR. Duration of prophylaxis against venous  thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med  2003;163:1337-42.
8. Huisman M. Efficacy and safety of the oral 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 (THRIVE II&V). Supplement to the Journal of Thrombosis  and Haemostasis 2003;XIX International Congress.
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10. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF   III): randomised controlled trial. Lancet 2003;362:1691-8.