Significant advances have been made during

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1 ANTICOAGULATION MANAGEMENT STRATEGIES: GUIDE FOR THE COMMUNITY PHARMACIST James Groce, PharmD, CACP * ABSTRACT In recent years, significant progress has been made in the treatment and prophylaxis of thromboembolic disorders. Low molecular weight heparins have gradually replaced unfractionated heparin and are now considered the standard of care for venous thromboembolism (VTE) prophylaxis in high-risk patients, as well as offering the option of outpatient treatment of VTE. These agents are also indicated for use in the management of acute coronary syndrome. The addition of new anticoagulant agents, such as direct thrombin inhibitors and synthetic factor Xa inhibitors, may offer additional clinical and financial benefits over current therapies. (Adv Stud Pharm. 2007;4(9): ) Significant advances have been made during the past decade in the prevention and treatment of venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), and the treatment of acute coronary syndrome (ACS), a term that encompasses unstable angina (UA), ST-elevation myocardial infarction (STEMI), and non-stemi (NSTEMI). VTE is estimated to affect approximately *Professor of Pharmacy, Campbell University School of Pharmacy, Buies Creek, North Carolina; Clinical Assistant Professor of Medicine, University of North Carolina School of Medicine, Clinical Pharmacy Specialist-Anticoagulation, Moses Cone Health System, Greensboro, North Carolina. Address correspondence to: James Groce, PharmD, CACP, Department of Pharmacy, The Moses H. Cone Memorial Hospital, 1200 North Elm Street, Greensboro, NC couminator@mindspring.com. 1 to 2 per 1000 people each year, increases exponentially with age, 1 and has an estimated prevalence of more than cases per year. 2 More than 33% of these cases are thought to represent recurrent disease, 3 despite initial management of a first DVT or PE. Patients remain at high risk for recurrence, with 7% to 14% of patients experiencing a subsequent DVT or PE. The majority of recurrence is typically noted within 3 months following the index or initial DVT or PE event. 4 It is important to note that although DVT and PE most commonly complicate the course of medically ill or surgical hospitalized patients, they also may affect ambulatory and otherwise healthy patients. 5 As previously discussed in this monograph, ACS also represents a significant public health burden. Heparin and heparin-derived drugs play a major therapeutic role in thrombotic and cardiovascular disorders. Infusion of unfractionated heparin (UFH) followed by the oral agent vitamin K antagonist (ie, warfarin) has been a mainstay of anticoagulant therapy for VTE for nearly 60 years. UFH also plays an important role in the management of ACS. However, these anticoagulants have several limitations, such as the need for frequent monitoring, variable dosage requirements, 6 and the risk of hemorrhage and other associated interventions. 7 Warfarin interferes with the metabolism of vitamin K and inhibits the synthesis of biologically active coagulation factors II, VII, IX, and X (Figure). 8,9 It has a slow onset of action and is influenced by dietary fluctuations in vitamin K and drug interactions. UFH exerts its anticoagulant effect through antithrombin, a plasma cofactor. UFH binds to antithrombin, which in turn inhibits thrombin (factor IIA) and factor Xa. Over the past decade, low molecular weight heparins (LMWH; eg, enoxaparin, dalteparin, and tinzaparin) have been a welcome addition to antithrombotic therapy because they have several University of Tennessee Advanced Studies in Pharmacy 247

2 advantages over UFH. They have a longer half-life, which permits once- or twice-daily dosing, allowing the possibility for patients to continue their antithrombotic treatment as outpatients following hospital discharge. 10 In addition, LMWH has a more predictable dose response than UFH, which lessens the need for anticoagulation monitoring and dose adjustments. These advantages may provide a cost benefit as well. In an evaluation of 8 outpatient studies comparing the efficacy, safety, and cost of outpatient use of LMWH versus inpatient UFH, Segal et al 8 found similar rates of recurrent DVT and major bleeding between the 2 groups, but the LMWH outpatients had shorter hospital stays (2.7 days vs 6.5 days) and incurred fewer costs (median cost savings of $1600). It is important to note that not all patients are appropriate for outpatient treatment with LMWH; contraindications include active bleeding, cardiopulmonary instability, hereditary bleeding disorders, history of heparin-induced thrombocytopenia (HIT; a rare side effect of heparin therapy), and allergy to heparin or LMWH. It is imperative that patients be individually assessed for clinical contraindications as well as their ability to maintain follow-up care. 11 Guidelines published by the American College of Chest Physicians for VTE prevention support the use of either LMWH or UFH for most medical or surgical patients (Level 1A evidence) and recommends LMWH over UFH for inpatient treatment (Level 1A evidence). In the outpatient setting, LMWH is recommended for appropriate patients (Level 1C evidence). 12 Revised UA/NSTEMI Guidelines (2007) from the American College of Cardiology (ACC) and the AHA emphasize selection of an initial invasive versus conservative strategy for treating such patients. For patients treated with an invasive strategy, anticoagulant therapy should be initiated as soon as possible after presentation to the hospital with LMWH (enoxaparin) or UFH (Level 1A evidence) or bivalrudin or fondaparinux (1B evidence) in addition to antiplatelet therapy (ie, aspirin and clopidogrel) or intravenous glycoprotein IIb/IIIa inhibitor therapy (Level 1A evidence) or both (Level IIa, B evidence). For the conservative strategy, the guidelines recommend addition of anticoagulant therapy as soon as possible after presentation with LMWH (enoxaparin) or UFH (Level 1A evidence) or fondaparinux (Level 1B evidence), citing enoxaparin or fondaparinux as preferable (Level IIa, B evidence) as well as antiplatelet therapy (Level 1A evidence) with consideration given to intravenous glycoprotein IIb/IIIa inhibitor therapy (eg, eptifibatide or tirofiban [Level IIb, B evidence]). 13 In a recent review of 6 major trials that compared enoxaparin with UFH for the treatment of NSTEMI, results from approximately patients showed that enoxaparin was associated with modest reductions in the incidence of death and myocardial infarction (MI) at 30 days. 14 Several studies have compared the use of LMWH for preventing thrombosis after major surgical interventions. Koch et al 15 compared the effectiveness of LMWHs versus UFH by reviewing 23 randomized, double-blind trials of patients who underwent general surgery. LMWHs and UFH were equally efficacious in preventing DVT, but low doses of LMWH reduced the risk of wound hematoma. Patients who underwent orthopedic surgery and received LMWH experienced lower rates of DVT than patients who received UFH. Other meta-analyses have assessed the safety and efficacy of LMWH compared with UFH in the treatment of DVT and VTE (Table). 14,16-18 These analyses show that LMWH is at least as effective or superior to UFH for the prevention of recurrent VTE and reduction of mortality and major bleeding. Figure. Coagulation Cascade Intrinsic pathway UFH XII AT XI LMWH IX AT VIII X V II Fibrinogen Fibrin clot VII Extrinsic pathway AT Warfarin Tissue factor Pentasaccharide Xa inhibitors Direct thrombin inhibitors Common pathway Roman numerals represent clotting factors. AT = antithrombin; LMWH = low molecular weight heparin; UFH = unfractionated heparin. Reprinted with permission from Nutescu et al. Cleve Clin J Med. 2005;72:S2-S Vol. 4, No. 9 October 2007

3 In a recent review of 6 major trials that compared enoxaparin with UFH for the treatment of NSTEMI, results from approximately patients showed that enoxaparin was associated with modest reductions in the incidence of death and MI at 30 days. 19 Based on recently published and ongoing clinical trials, LMWHs have found their way into therapeutic armamentariums for prevention and treatment of venous embolic disease, as well as ACS management. 14,16-19 Several new classes of antithrombotics have emerged, including direct thrombin inhibitors (DTI) and direct and indirect inhibitors of factor Xa. DTIs bind with thrombin to prevent an interaction between the enzyme and the substrate. Several parenteral DTIs are approved for use in the United States, including lepirudin, bivalirudin, argatroban, and desirudin. 9 The advantages of DTIs include a targeted specificity for thrombin, the ability to inactivate clot-bound thrombin, and an absence of plasma protein and platelet interactions that can lead to complications, such as HIT. Unlike heparins, DTIs do not require antithrombin as a cofactor and do not bind to plasma proteins. Therefore, they produce a more predictable anticoagulant effect, and variability of patient response is low relative to other drug classes. LEPIRUDIN Lepirudin has a short half-life approximately 80 minutes following intravenous administration. Its elimination is primarily renal, thus dosing must be adjusted according to the patient s renal function. The dose should be monitored and adjusted to an activated partial thromboplastin time (aptt) ratio of 1.5 to 2.5 because bleeding risk increases above this range without an Table. Summary of Meta-analyses Comparing Safety and Efficacy of LMWH with UFH for Prevention and Treatment of VTE and DVT Author Studies, n LMWH Used Main Efficacy Result Main Safety Results TREATMENT of VTE Siragusa et al Nadroparin Significant reduction in relative risk of Significant reduction in relative risk of CY 222 recurrent VTE in blinded studies during major bleeding in blinded studies Fraxaparin first 15 d and over entire period Significant reduction in relative risk of Logiparin overall mortality Gould et al Nadroparin No difference in prevention of Significant reduction in odds ratio for Tinzaparin thromboembolic recurrences major bleeding, but reduction in absolute risk not significant Dalteparin Significant reduction in mortality rates Reviparin over 3 6 months Rocha et al Dalteparin Significant reduction in clot reduction Significant reduction in incidence of CY 222 No difference in thromboembolic hemorrhage OP 2123 recurrences Significant decrease in total mortality Certoparin Nadroparin Logiparin Reviparin Dolovich et al Dalteparin No difference in risk for recurrent VTE No difference in risk for major or Nadroparin or PE minor bleeding or thrombocytopenia Tinzaparin Significant reduction in risk of total mortality Reviparin DVT = deep venous thrombosis; LMWH = low molecular weight heparin; PE = pulmonary embolism; UFH = unfractionated heparin; VTE = venous thromboembolism. Data from Dolovich et al 14 ; Siragusa et al 16 ; Gould et al 17 ; and Rocha et al. 18 University of Tennessee Advanced Studies in Pharmacy 249

4 increase in efficacy. Lepirudin is approved for use in patients with HIT and related thrombosis. 20,21 BIVALIRUDIN Bivalirudin, a DTI with a smaller molecular weight, is also given intravenously. It has a shorter elimination half-life than lepirudin ( 25 min) and is eliminated only partly through the kidney. Patients with moderate or severe renal impairment (creatinine clearance <60 ml/minute) may require dose adjustment and monitoring of anticoagulation status because clearance of bivalirudin is reduced by approximately 20% in these patients. The activated clotting time can be used to monitor bivalirudin s anticoagulant effect during percutaneous coronary intervention (PCI). Bivalirudin is approved for use in patients undergoing percutaneous transluminal coronary angioplasty. 20,21 ARGATROBAN Argatroban, a small-molecule DTI, is also given intravenously. It has an elimination half-life of 40 to 50 minutes. Monitoring of the aptt is required to assess its anticoagulant activity. Argatroban is hepatically metabolized, thus dose reductions and careful monitoring are recommended in patients with hepatic dysfunction. Renal impairment has no influence on its elimination half-life and therefore, does not require dose adjustment. Like the other DTIs, argatroban has no known antidote. Argatroban is approved for the prevention and treatment of thrombosis in patients with HIT and in patients with HIT undergoing PCI. 20,21 DESIRUDIN Desirudin is the first subcutaneously administered DTI and also the first DTI approved by the US Food and Drug Administration (FDA) for prevention of VTE after hip replacement surgery. Desirudin has an elimination half-life of 2 to 3 hours and is typically dosed every 12 hours. It is primarily eliminated and metabolized by the kidney, thus dose reduction is needed in patients with renal impairment. The aptt is the test used to measure desirudin s anticoagulant activity. ORAL DTIS Direct thrombin inhibitors also can be structurally modified for oral administration. The most extensively studied agent is ximelagatran. Ximelagatran had been noted to have several advantages compared with warfarin, which include the following: A predictable dose response, requiring no dose adjustment or coagulation monitoring A wider therapeutic index A rapid onset and offset of effect An apparent lack of clinically significant interactions with drugs and foods metabolized via the CYP450 isoenzyme Stable, fixed doses of ximelagatran without monitoring of coagulation parameters have been successfully studied in large phase III trials in various clinical settings, including stroke prevention in patients with atrial fibrillation, VTE prevention after major joint replacement, acute VTE treatment and secondary prevention of VTE after idiopathic VTE, and secondary prevention of MI Although these studies indicate that the drug can potentially be used in these clinical settings, the US FDA refused to approve ximelagatran over concerns about liver toxicity. Specifically, ximelagatran is associated with a 6% to 10% increase in hepatic transaminase levels in the first 2 to 6 months of long-term therapy, which is likely to require intensive liver function monitoring. Several other drawbacks also exist. Because the kidney eliminates melagatran, dose adjustment is required in patients with renal impairment. There is no known antidote for reversal of ximelagatran s effect, though it is much shorter-acting than warfarin. 24 Even with these hurdles, ximelagatran s advantages would have likely made its use attractive in clinical practice, as it would have been more convenient and less complicated to administer on a chronic basis than warfarin. However, in February 2006, the manufacturer announced it would withdraw ximelegatran from all markets worldwide because of concerns about patient safety, specifically, hepatotoxicity. Other oral DTIs are in development, such as BIBR 1048, and may prove useful in the future. FONDAPARINUX Fondaparinux is a newer agent that indirectly inhibits factor Xa. Because of its very small molecular size, fondaparinux exerts its inhibitory activity specifically on activated factor X and, unlike heparins, has no direct effect on factor IIa. 25,26 Because it does not inactivate thrombin itself, fondaparinux is not likely to interfere with thrombin s wound-healing properties. 27 And unlike UFH, fondaparinux does not require rou- 250 Vol. 4, No. 9 October 2007

5 tine monitoring of its anticoagulant effect. However, fondaparinux is eliminated through the kidneys, thus it is contraindicated in patients with severe renal dysfunction and should be used cautiously in patients with moderate renal dysfunction. DIRECT FACTOR XA INHIBITORS Direct factor Xa inhibitors currently in development include tick anticoagulant peptide, YM , and DX-9065a. The indirect inhibitors bind to antithrombin with high affinity, causing a permanent conformational change in antithrombin and increasing its rate of factor Xa inhibition. Because they are selective for factor Xa, they reduce thrombin generation without affecting circulating thrombin. Fondaparinux is the only member of the class that is commercially available in the United States. Additional agents, such as idraparinux and razaxaban (formerly DPC-906), are undergoing clinical trials. Fondaparinux and idraparinux are given subcutaneously, whereas razaxaban is an oral formulation. 14,16-18 DX-9065a is the first direct synthetic inhibitor to be studied in patients with coronary disease. Razaxaban, BAY , ZK , and JTV-803 are orally active direct factor Xa inhibitors currently in phase II trials. Several other synthetic direct inhibitors of factor Xa (such as FXV673, YM60828, and KFA-1411) are in a preclinical stage of research. As synthetic compounds, factor Xa inhibitors offer several advantages, including no risk of animal pathogen-transmission, batch-to-batch consistency, and unlimited sourcing. Other favorable attributes include a predictable and linear dose-response relationship, a quick time to maximum concentration, and a long half-life. Similar to the LMWHs, which have a predictable anticoagulant effect, factor Xa inhibitors do not require routine anticoagulation monitoring or dose adjustment. Unlike the heparins, factor Xa inhibitors do not affect platelet function and do not react with heparin-platelet factor 4 antibodies, thus reducing the risk of HIT. Fondaparinux is indicated for prophylaxis of venous thrombosis in patients undergoing hip replacement surgery, knee replacement surgery, and hip fracture surgery (including extended prophylaxis after hip fracture surgery). It is also US FDA approved for acute treatment of acute DVT and PE. Idraparinux is being investigated for the treatment of VTE and for stroke prevention in patients with atrial fibrillation. Although a once-weekly agent, such as idraparinux, would improve convenience and perhaps patient compliance, a theoretical drawback of these longacting anticoagulants is that there is no antidote if the patient bleeds or requires an invasive procedure. To overcome this theoretical concern, researchers are investigating a biotinylated form of idraparinux that will provide a means of rapid reversal. Because of their convenience of use, factor Xa inhibitors are a welcome addition to the more traditional anticoagulants for the treatment and prevention of VTE. CONCLUSIONS Significant progress has been made in the treatment and prophylaxis of thromboembolic disorders. LMWHs have gradually replaced UFH and are now considered an important strategy for the treatment of VTE in high-risk inpatients. These agents also provide the option of outpatient management for patients with VTE and inpatient management of ACS by ACC/AHA guidelines. In addition, newer anticoagulants, such as DTIs and factor Xa inhibitors, enhance the safety and efficacy of the traditional mainstays of anticoagulation management, permitting not only outpatient management in some instances, but the use of oral agents and parenteral administration with less reliance on traditional laboratory monitoring to assure efficacy and safety. REFERENCES 1. White RH. The epidemiology of venous thromboembolism. Circulation. 2003;107: Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost. 2002;28: Prandoni P, Villalta S, Bagatella P, et al. The clinical course of deep-vein thrombosis. Prospective long-term followup of 528 acute symptomatic patients. Haematologica. 1997;82: Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004;117: Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet. 1999;353: Nutescu EA. Emerging options in the treatment of venous thromboembolism. Am J Health Syst Pharm. 2004;61:S12-S Berqvist D. : a pharmacoeconomic review of its use in the prevention and treatment of venous thromboembolism and in acute coronary syndromes. Pharmacoeconomics. 2002;20: University of Tennessee Advanced Studies in Pharmacy 251

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