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Issue #2, 2002


NEW ANTICOAGULANTS IN CLINICAL PRACTICE

Joseph E. Kiss, M.D., Medical Director, Hemapheresis & Blood Services
Senior Staff Physician, Coagulation Laboratory

                                                                                                                                                                           


INTRODUCTION

Oral coumadin and parenterally-administered unfraction-ated heparin have been the mainstays of anticoagulant therapy since the 1940ís.  Along with the acknowledged clinical utility of these drugs are several undesirable characteristics, such as unpredictability in dosage required for therapeutic effect, the need for careful laboratory monitoring, and the potential for life-threatening toxicity.  Low molecular weight heparins (LMWHs) have gained wider acceptance due to equivalent efficacy to unfractionated heparin for treatment and prophylaxis of thrombosis, reduced risk of heparin-associated thrombocytopenia, and ease of administration and monitoring.  To the extent that LMWHs allow outpatient management, they also appear to be cost-effective.Several new anticoagulants Ė some with unique mechanisms of action Ė were recently approved for clinical use.  These drugs fall into two main categories in terms of their therapeutic target: Thrombin (Factor IIa) inhibitors and specific Factor Xa inhibitors.  The general characteristics, indications, and metabolic clearance for these agents will be summarized.  Readers are referred to the package insert for specific information regarding dosage.

 

THROMBIN (Factor IIa) INHIBITORS

Indirect thrombin inhibitors such as unfractionated heparin, LMWHs, and heparinoids (danaparoid, or Orgaran“), exert anticoagulant effects by binding to antithrombin, initiating complex formation and  inactivation of thrombin, Factor Xa, and Factor IXa.  Direct thrombin inhibitors offer several advantages over heparins/heparinoid drugs.  Because they do not rely on ATIII levels and do not bind to plasma proteins, the anticoagulant response is more predictable.  These agents are not neutralized by Platelet Factor 4, which may be increased in the vicinity of platelet-rich thrombi.  This may lead to greater anticoagulant activity.  A further significant advantage is the ability of these compounds to inhibit fibrin-bound thrombin, as well as fluid-phase thrombin, leading to greater antithrombotic activity.  A disadvantage with specific thrombin inhibitors is that none has a specific antidote.  Therefore, safe use of these drugs requires knowledge of their pharmacokinetics and metabolic clearance. 

 

Lepirudin (Refludan“) is a recombinant polypeptide consisting of 66 amino acids, which is structurally similar to hirudin isolated from the medicinal leech.  It is administered by bolus followed by continuous infusion, with a half-life of 40-60 minutes. It is cleared by the kidneys, with dose reduction required for renal impairment.  The drug is monitored using the APTT with a target range of 1.5 to 2.5 baseline median value. Anti-Xa levels cannot be used to monitor therapeutic drug levels.  Lepirudin was approved in February of 1998 for management of heparin induced thrombocytopenia (HIT) type 2.  Approval was based on results of two prospective trials in which lepirudin reduced the combined endpoint of death, thromboembolism, and limb amputation from 6.1% per day before treatment (using historical controls) to 1.3% during treatment.  Although lepirudin has shown antithrombotic efficacy in other clinical situations, e. g., in conjunction with thrombolytic therapy in patients with acute myocardial infarction, excessive bleeding has been observed in comparison with standard heparin in several large multicenter clinical trials.  

 

Argatroban (ACOVA“-Formerly Novastan“) was approved for prophylaxis or treatment of thrombosis in patients with HIT type 2 in June of 2000.  Argatroban, a synthetic small molecule derived from arginine, is a competitive inhibitor of thrombin.  The half-life in normal individuals is approximately 45 minutes. It is hepatically cleared, requiring major dose adjustment in patients with hepatic dysfunction.  It too is monitored by use of the APTT with the goal of 1.5 to 3 times baseline value.  Again, anti-Xa levels cannot be done.  Approval was based on results of two studies in patients with HIT and heparin induced thrombocytopenia with thrombosis (HITT), showing statistically significant increase in proportion of patients free of a composite endpoint defined as death, amputation, or new thrombosis.  Normalization of platelet count was noted within three days in 53 to 58% of the patients. A disadvantage with all direct thrombin inhibitors is prolongation of the prothrombin time (PT) in addition to the APTT.  This may pose difficulty in regulating coumadin administration (for argatroban, temporary discontinuation of the drip for 4 hours is recommended prior to determining the PT/INR).  The differences in metabolism and excretion of these two drugs complement each other, providing therapeutic alternatives in patients with significant renal dysfunction (argatroban preferred) or hepatic failure (lepirudin preferred).

 

Bivalirudin (Angiomax“) is also a direct thrombin inhibitor that was approved in December of 2000 for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (with aspirin).  It is given intravenously with a half-life of 25 minutes and is excreted by a combination of renal (minor) and other proteolytic pathways (major).  Bivalirudin is also monitored by using the APTT. It has been compared to heparin in over 4,000 patients undergoing coronary angioplasty for unstable or post-infarction angina, using a combined endpoint of in-hospital death, myocardial infarction, abrupt vessel closure, or acute coronary intervention.  In the initial interpretation of this study, bilvalirudin was of clear-cut benefit only in the high-risk group, i.e. those with post-infarction angina.  Subsequent reanalysis shows benefit in the entire cohort of patients with a statistically significant overall risk reduction of 78% at 7 days and 82% at 90 days relative to heparin.2  Interestingly, this study demonstrated a lower major bleeding risk associated with bilvalirudin in comparison to heparin (3.5% versus 9.3% respectively, p < 0.001).  The reduced bleeding risk seen with bivalirudin offers a potential benefit in the cardiac intervention setting, where powerful antiplatelet agents such as IIbIIIa inhibitors are often used and bleeding complications are  frequent.  Limited data suggests that bivalirudin may be especially useful in patients with HIT or a history of HIT who need percutaneous coronary angioplasty. 3

 

FACTOR Xa INHIBITORS

Selective Xa inhibitors have been synthesized based on the key pentasaccharide antithrombin-binding site of the heparin molecule.  The resulting conformational change in ATIII allows specific binding and inactivation of factor Xa, with release of the pentasaccharide to catalyze multiple rounds of Xa/ ATIII complex formation.

 

Fondaparinux (Arixtra“), the first in this new class of anticoagulants, was approved in December of 2001 for prophylaxis of deep venous thrombosis in orthopedic surgery patients with hip fracture, hip replacement, and knee replacement surgery.  The drug has a 15 hour half-life and is given once a day by subcutaneous injection. It is renally excreted. Patients with creatinine values ≥ 2.0 were excluded in the clinical study; the manufacturer recommends that it not be used in patients whose creatinine clearance is < 30 mls/min.  Although anti-Xa assay can be used to measure activity, the therapeutic range has not been established.  Approval of fondaparinux for DVT prophylaxis was based on prospective, controlled multi-center clinical trials which used a LMWH, enoxaparin, in control patients4-6.  Efficacy was based on mandatory venography between days 5 and 11 post-operatively, or symptomatic documented DVT or PE.  Safety was based on the incidence of major and minor bleeding episodes.  Enoxaparin was begun 12 to 24 hours post-op; fondaparinux was begun 6 +/- 2 hours post-op.  The incidence of VTE in total hip replacement surgery patients was reduced by 56% from 9.2% in control to 4.1% in the treatment group.  Similar findings were demonstrated in hip fracture and major knee surgery patients.  Overall, there was a reduction in proximal DVTs from 2.9% to 1.3% when results were combined for all studies.  Bleeding risk was generally comparable with no significant differences in fatal bleeding and non-fatal bleeding in a critical site or of re-operation due to bleeding.  These results indicate superiority of fondaparinux over enoxaparin in DVT prophylaxis for orthopedic surgery.  It should be noted, however, that because a very sensitive screening measure (bilateral venography) was utilized, most of the observed benefit was in reduction of distal DVT. Pulmonary embolism and death were not significantly different in the two groups. The demonstrated anticoagulant efficacy of Xa inhibition using fondaparinux is now being evaluated for the treatment of acute DVT/PE and other indications.

 

CONCLUSIONS

Several new anticoagulant drugs have been approved, while others are in late stage clinical trials. For example, ximelagatran, an oral direct thrombin inhibitor, has shown promising efficacy and safety in comparison to coumadin in preliminary studies of patients with chronic atrial fibrillation. The list of new anticoagulant drugs and indications for their use will continue to grow into the future, providing more therapeutic choices as well as challenges in selecting the right drug for a specific clinical indication. 

 

REFERENCES

  1. Gould MK,et al. Ann Int Med  1999;130(10):789-99.
     

  2. Bittl JA, et al.  Am Heart J. 2001; 142:952-59.
     

  3. Campbell KR,et al.  J Inv Cardiol.  2000; 12S:14F-19F
     

  4. Turpie AG,et al. NEJM  2001;344(9):619-25.
     

  5. Bauer KA,et al. NEJM  2001; 345(18): 1305-10.
     

  6. Eriksson BI,et al.  NEJM 2001; 345(18): 1298-1304.

 

 

 Copyright © 2002, Institute For Transfusion Medicine


For questions or further information regarding New Anticoagulants in Clinical Practice, please contact
Joseph E. Kiss, M.D., at The Institute For Transfusion Medicine: (412) 209-7349

Copies of previous Transfusion Medicine Update issues can be obtained from our web page: www.itxm.org.  To be placed on our mailing list for a hard copy, please contact Deborah Small by e-mail: dsmall@itxm.org or by phone: (412) 209-7320.