The Future of Medical Therapy for Venous Thromboemboli

Transcription

1 Supplement issue Joseph A. Caprini, MD, MS, RVT Department of Surgery, Evanston Northwestern Healthcare, Evanston, Illinois, USA; Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA; and Robert R. McCormick School of Engineering and Applied Sciences, Evanston, Illinois, USA ABSTRACT The field of medicine has a 30-year experience of prophylactic anticoagulation treatment in surgical patients, especially those with joint replacement and hip fracture. Extensive research to find anticoagulation alternatives beyond the use of unfractionated heparin has resulted in the development of low-molecular-weight heparin and vitamin K antagonist for prophylaxis of venous thromboembolism (VTE). In this article, drug administration regimens, pharmacologic activity, major adverse events, and costs for anticoagulation treatment are reported through a literature review. Clinical trial results are reported to provide the relative risk reduction and clinical benefit considerations in the administration of these drugs. The results show that in the absence of prophylactic treatment, hospitalacquired VTE occurs in approximately 10% to 40% of medical or general surgical patients and 40% to 60% of major orthopedic surgical patients. Patients treated in a major clinical study with the pentasaccharide fondaparinux demonstrated a 12.5% incidence of VTE compared with 27.8% of patients treated with enoxaparin (P 0.001). Major bleeding occurred in 3.1% of fondaparinux patients versus 0.3% 2 groups in the incidence of bleeding leading to death, reoperation or occurrence in a critical organ. The most recent anticoagulant class of drugs, oral direct thrombin inhibitors dabigatran and rivaroxaban, demonstrate great promise owing to fixed dosages, rapid onset and offset of action, and a predictable anticoagulation effect without coagulation monitoring. Multiple clinical trials are demonstrating efficacy and safety in VTE prevention and treatment. VTE is the leading cause of death in hospitalized patients. Successful prevention of VTE and fatal pulmonary embolism remain a challenge in patients undergoing surgery for hip fracture or joint replacement. The value of appropriate prophylaxis must be emphasized in these patients. Effective anticoagulation with intermittent pneumatic compression remains an underutilized regimen despite studies showing a significant reduction in mortality and morbidity. The newer oral direct thrombin inhibitors show significant promise Elsevier Inc. All rights reserved. The American Journal of Medicine (2008) 121, S10 S19 KEYWORDS: Anticoagulants; Pulmonary embolus; Thrombosis prophylaxis; Thrombosis treatment; Venous thromboembolism; Venous thrombosis Thromboembolic disorders are a major cause of significant morbidity and mortality. Patients with a history of orthopedic trauma and surgery, major trauma, and spinal cord injury present a high risk for thromboembolic events, such as deep vein thrombosis (DVT) and pulmonary embolism (PE). For example, 50% to 80% of patients undergoing major orthopedic joint replacement are at risk for the development of venous thromboembolism (VTE), with a risk of PE as high as 10%. 1,2 Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Joseph A. Caprini, MD, MS, RVT, 28 Coventry Road, Northfield, Illinois address: j-caprini@northwestern.edu or jcaprini2@aol.com. Prophylactic anticoagulation treatment can reduce these risks. Anticoagulation therapy works by targeting many of the serine proteases within the coagulation cascade. The American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy guidelines recommend the routine use of antithrombotic therapies, including unfractionated heparin (UFH), low-molecularweight heparin (LMWH), and vitamin K antagonist for prophylaxis against thromboembolic events. 3 Despite significant advances over the past decades, antithrombotic therapy remains an important clinical challenge. UFH has a short half-life and must be given by injection 3 times daily, which is impractical for use after hospital discharge. Although inexpensive, serious problems are associated with /$ -see front matter 2008 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 Caprini S11 UFH, including heparin-induced thrombocytopenia (HIT) and heparin-induced osteoporosis. LMWH is an excellent drug and may be given once daily; it has a much lower incidence of HIT or osteoporosis. This drug is more costly and still requires a subcutaneous injection. The vitamin K antagonist warfarin can be orally administered, but it includes major drawbacks such as the need for monitoring due to a narrow therapeutic window and a wide range of variability in dose response. Warfarin is also limited by a slow onset and offset of action, and extensive food and drug interactions. Consequently, the need still remains for safe anticoagulants for both short-term and long-term use. 4 PREVIOUS MEDICAL TREATMENTS FOR THROMBOEMBOLISM A revolutionary advance in the treatment of VTE occurred in the 1930s with the development of anticoagulation therapy with UFH. The active heparin molecules bind tightly to antithrombin. Thrombin reactions are accelerated several hundred-fold in the presence of a commercial preparation UFH-antithrombin complex. 5 The LMWHs were introduced in the 1980s, and remain the established standard of care for the prevention of VTE after orthopedic surgery. 6 These drugs inhibit factor Xa more strongly than thrombin, through a ratio of 1.5:1 to 4:1. Potential treatment complications include the fact that these drugs must be administered through the parenteral route, as well as potentially dangerous side effects, such as bleeding, anaphylaxis, HIT, and osteoporosis. 7 Both heparins bind to platelet factor-4 (PF4), which may promote the autoimmune reaction of HIT. Vitamin K antagonist anticoagulants were developed in the 1940s, with warfarin being the most widely used drug. Vitamin K antagonists can be administered orally and are more convenient in long-term use than parenteral heparin. A popular approach to anticoagulation treatment is to follow an initial course of heparin with a 3-month course of warfarin. 8 Associated complications include the fact that highdose warfarin has been associated with an increased risk for bleeding. 9 Drugs developed in the 1990s include indirect factor Xa inhibitors and direct thrombin inhibitors, both administered parenterally. Fondaparinux is the commercially available synthetic indirect factor Xa inhibitor, which exerts its effect by binding to antithrombin. Dabigatran etexilate represents the relatively new class of direct thrombin inhibitors. These drugs exert their anticoagulant effect through binding directly to the active site of thrombin without additional proteins, thus reducing the potential for negative side effects. The 21st century has seen the development of an important class of drugs that directly inhibits factor Xa and includes an ideal profile of once-daily oral dosing without the need for coagulation monitoring. Rivaroxaban and apixaban are currently undergoing phase 3 clinical trials, and may be a revolutionary advance in anticoagulation therapy. PROPHYLACTIC TREATMENT REGIMENS FOR PATIENTS UNDERGOING MAJOR ORTHOPEDIC SURGERY A standard medication regimen for patients at risk for the development of DVT involves prophylactic treatment with UFH, LMWH, or warfarin. However, despite treatment advances, specific populations still remain at risk for the development of thromboembolism. Patients with joint replacement or hip fracture represent an important subgroup of individuals who may require a different treatment regimen. VTE is among the most common serious complications following major orthopedic surgery of the lower extremities, and it is associated with significant morbidity and mortality in addition to increased healthcare costs. 10 Primary sequelae can be acute, subacute, or chronic, and may include fatal PE, recurrent nonfatal VTE, chronic thromboembolic pulmonary hypertension, paradoxical stroke, and postthrombotic syndrome (chronic venous insufficiency) Patients undergoing surgery for hip fracture and elective hip and knee replacement are at the highest risk for the development of postoperative VTE, 14,15 and the routine use of VTE prophylaxis is recommended for all patients after major orthopedic surgery of the lower extremities. 10 Despite current treatments, the incidence of venographically confirmed DVT within these populations occurs in the range of 24% to 34% 14 in conjunction with increased mortality within the first 60 to 90 days after surgery. 16,17 Patients with hip fracture have demonstrated a 3.6% to 12.9% incidence of fatal PE, whereas patients undergoing elective hip replacement surgery exhibit fatal PE rates between 0.l% and 0.4%. 14,18 Furthermore, DVT frequently results in longterm sequelae such as chronic venous insufficiency and chronic leg ulcers. 14,15 VTE has also proved to be a frequent life-threatening postoperative complication of total knee-replacement surgery. Without thromboprophylaxis, the incidence of venographically verified postoperative DVT ranges between 40% and 84%, with PE rates in the range of 2% to 7%. 14 Anticoagulant regimens effective in hip-replacement surgery, such as low-dose UFH, LMWH, and warfarin are less successful in knee replacement surgery, and only reduce the DVT incidence to between 31% to 47%, 14 presenting a significant risk for potentially fatal PE. Consequently, more effective antithrombotic prophylaxis is needed through the improvement of treatment in hip fracture, and hip- and knee-replacement surgery. 19 FONDAPARINUX IN PATIENTS UNDERGOING JOINT ARTHROPLASTY AND HIP FRACTURE SURGERY The pentasaccharide fondaparinux is the first synthetic selective indirect factor Xa inhibitor. The pentasaccharide structure selectively binds to antithrombin, enabling it to rapidly inhibit factor Xa through a conformational change

3 S12 The American Journal of Medicine, Vol 121, No 11A, November 2008 and increased specificity. Fondaparinux is a synthetic, nonbiologic compound, eliminating the risks for blood-borne virus transmission. Its pharmacokinetic properties, including high bioavailability and a half-life of 15 to 17 hours, facilitate simple, fixed-dose, once-daily subcutaneous injection without the need for monitoring. As an indirect factor Xa inhibitor, fondaparinux demonstrates increased safety over UFH because it does not bind to platelets or PF4, and has only rarely reported association with HIT or osteoporosis. Fondaparinux has demonstrated effectiveness in decreasing the risk VTE in patients undergoing hip-fracture surgery compared with alternative regimens of LMWH. 20 The Pentasaccharide in Hip-Fracture Surgery (PENTHIFRA) multicenter randomized trial demonstrated an 8.3% incidence of VTE in 626 patients treated with fondaparinux, compared with a 19.1% incidence in 624 patients treated with enoxaparin, yielding a 56.4% risk reduction (P 0.001). There were no differences between the 2 groups in the incidence of death or clinically relevant bleeding. 21 Of importance is that proximal DVT, which has proved to be more prone than Calf DVT to embolization and treatment resistant, occurred in 1% of patients treated with fondaparinux compared with 4.4% of patients treated with enoxaparin (P 0.001), yielding a 78.7% risk reduction. These results suggest that prophylactic fondaparinux is more effective than enoxaparin in preventing VTE up to day 11 in patients undergoing hipfracture surgery, without increasing the risk for clinically relevant bleeding. 22 The success of fondaparinux may be attributed to its ability to inhibit factor Xa rapidly and selectively, its predictable linear pharmokinetics, and a long half-life that yields an antithrombotic effect for 24 hours. 21 Treatment success was influenced by the duration of drug administration: the incidence VTE was higher in patients treated for 5 days (11.3%) compared with patients treated for 5 days (7.9%). 22 Benefits of an increased treatment duration were confirmed in the PENITHFRA- Plus trial, which demonstrated that the risk of VTE associated with hip fracture surgery is higher and persists beyond standard treatment periods of 11 days compared to when treatment is given short-term and the patient is studied at 30 days. A 4-week dosing schedule of fondaparinux reduced the incidence of venographically confirmed VTE from 35% at 1 week to 1.4% at 4 weeks, yielding an RRR of 95.9% (P 0.001). A 4-week dosing schedule of fondaparinux also significantly reduced the incidence of symptomatic VTE from 2.7% in the 1-week fondaparinux group to 0.3%, yielding a relative risk reduction (RRR) of 88.8% (P 0.021) 22 and increased clinical benefit. Fondaparinux has also demonstrated effectiveness in patients undergoing elective hip-replacement surgery. One randomized trial revealed a 4% incidence of VTE in 908 patients treated with fondaparinux, compared with 9% of 919 patients treated with enoxaparin (P ), yielding a 55.9% RRR with no increased risk for bleeding. Although enoxaparin was started 12 hours before surgery, the drug was proved to be less effective than a 2.5-mg regimen of once-daily fondaparinux begun 6 hours after surgery. Preoperative drug administration is not necessary to achieve efficacy with fondaparinux: a second study confirmed that a 2.5-mg medication regimen of fondaparinux started 6 hours after hip replacement surgery reduced the risk for VTE by 26% compared with a 30-mg twice-daily enoxaparin regimen. Although statistical significance was not achieved, the authors concluded that the 26% reduction in risk recorded for fondaparinux was clinically important, with no increase in relevant bleeding. 23 Knee arthroplasty is characterized by a substantial bleeding risk, a relative resistance to the effects of most prophylactic treatments, and a lack of consensus on the safest and most effective prophylaxis method. Patients undergoing prophylactic treatment with warfarin after knee arthroplasty have demonstrated rates of DVT in the range of 37.4% 24 to 51.7%, 25 compared with 31.4% 24 to 36.9% 25 of patients treated with LMWH, which is recognized as the most effective thromboprophylactic drug class to date. 14 In contrast, an important study revealed that patients treated with fondaparinux demonstrated a 12.5% incidence of VTE compared with 27.8% of patients of patients treated with enoxaparin (P 0.001). 26 A 12.5% incidence reflects the lowest rate ever achieved for the reduction of VTE after knee surgery. Although major bleeding occurred more frequently in patients receiving treatment with fondaparinux (3.1%) compared with enoxaparin (0.3%), (P 0.006), there were no significant differences between the 2 groups in the incidence of bleeding leading to death, reoperation, or occurrence in a critical organ. 26 MAJOR BLEEDING IN JOINT-REPLACEMENT SURGERY Patients undergoing joint replacement are at significantly increased risk for bleeding. For example, knee surgery is associated with hemorrhage and hemoarthrosis, which may require surgical drainage or compromise reconstruction. 27 As such, physicians have been uncertain about the safety of prophylactic treatment after hip-fracture 14,15 and knee surgery. 27 The involvement of anticoagulant therapy in orthopedic surgery carries an increased risk for bleeding, and the timing of administration has been shown to influence both safety and efficacy Ideally, anticoagulant treatment can be delayed to increase safety and minimize the risk for bleeding without compromising treatment efficacy. 10 Fondaparinux presents an important treatment advantage in that dosing can be delayed until the morning after jointreplacement surgery, consequently decreasing bleeding risk without compromising effectiveness. The flexible thrombosis prophylaxis using Arixtra (FLEXTRA) randomized trial demonstrated that delaying the administration of the first dose of fondaparinux until the morning after total hip arthroplasty or total knee arthroplasty did not affect the rate of symptomatic VTE occurring within the first week after surgery, and preserved safety through a decreased bleeding risk. However, the incidence of DVT and its associated

4 Caprini S13 clinical sequelae was measured through the incidence of clinical events, without the objective use of bilateral venography. 10 Further research is needed to examine the effects of delaying treatment on venographic outcome. TREATMENT WITH FONDAPARINUX IN NONSURGICAL POPULATIONS While fondaparinux has demonstrated effectiveness in the surgical patient population, its generalizability to the entire population of patients with DVT remains a relatively new area of exploration. The Mondial Assessment of Thromboembolism Treatment Initiated by Synthetic Pentasaccharide with Symptomatic Endpoints (MATISSE) multicenter double-blind trial was designed to measure the effectiveness of fondaparinux compared with LMWH in preventing recurrent DVT, and compared with UFH in preventing the incidence of symptomatic PE. 32,33 Results confirmed that a once-daily subcutaneous medication regimen of fondaparinux demonstrated a safety and efficacy profile comparable to subcutaneous twice-daily enoxaparin as initial therapy for symptomatic DVT. Both groups of patients demonstrated similar rates of symptomatic recurrent DVT (3.9% of patients receiving treatment with fondaparinux compared with 4.1% of patients treated with enoxaparin), fatal P/unexplained death (0.5% for both groups), and nonfatal PE/DVT (3.5% for patients receiving treatment with fondaparinux, compared with 3.6% receiving treatment with enoxaparin). Both medications demonstrated a similar profile of safety, with a comparable incidence of overall bleeding (3.7% for patients receiving treatment with fondaparinux, compared with 4.2% receiving treatment with enoxaparin), major bleeding (1.1% for patients receiving treatment with fondaparinux, compared with 1.2% receiving treatment with enoxaparin), and clinically-relevant nonmajor bleeding (2.6% for patients receiving treatment with fondaparinux, compared to 3.0% receiving treatment with enoxaparin). 32 Similarly, fondaparinux demonstrated equivalency to UFH in the incidence of symptomatic recurrent DVT (3.8% with fondaparinux compared with 5.0% with UFH), nonfatal PE or DVT (2.4% with fondaparinux compared with 3.6% with UFH), and fatal PE or unexplained death (1.5% with fondaparinux compared with 1.4% with UFH). Both drugs demonstrated a comparable profile of safety, with similar rates of overall bleeding, (4.5% in patients receiving treatment with fondaparinux, compared with 6.3% in patients receiving treatment with UFH), major bleeding (1.3% in patients receiving treatment with fondaparinux, compared with 1.1% in patients receiving treatment with UFH), and clinically relevant nonmajor bleeding (3.2% in patients receiving treatment with fondaparinux, compared with 5.2% in patients receiving treatment with UFH). 33 The Arixtra for thrombosis prophylaxis in the medically Ill (ARTEMIS) study 34 was a multinational, randomized, double-blind trial examining the effects of prophylactic treatment with fondaparinux compared with placebo in medical patients 60 years old, hospitalized for acute cardiac, respiratory, infectious or inflammatory disease; and expected to remain bedridden for 4 days. Results indicate that prophylactic treatment with fondaparinux significantly decreased the rate of VTE without an increase in major bleeding. Prophylaxis reduced the composite end point of venographically proven DVT, symptomatic DVT, and/or PE from 10.5% to 5.6%, yielding an RRR of 49.5% (P 0.029). A 0% incidence of symptomatic thromboembolic events occurred up to day 15 in the patients receiving fondaparinux, compared with a 1.2% incidence of fatal PE in the placebo arm (P 0.029), with a 0.2% rate of major bleeding events in both groups. 34 The Prophylaxis in General Surgery (PEGASUS) trial 35 examined the safety and efficacy of fondaparinux compared with the LMWH dalteparin in patients undergoing high-risk general surgery, yielding a 24.6% RRR in the incidence of VTE. Although results were not statistically significant (P 0.14), trends were consistent with previously reported results in major orthopedic surgery. 35 As confirmed in previous studies, the initial administration of fondaparinux 6 hours following incision closure demonstrated a low rate of major bleeding without loss of antithrombotic efficacy. Of importance is that the PEGASUS trial highlighted significant risk factors for the development of VTE despite effective prophylaxis, including advanced age, obesity, duration of surgery, and cancer. A subgroup analysis suggested that fondaparinux may be more effective in patients at significantly high risk for VTE, including a 38.6% risk reduction in patients undergoing cancer surgery (4.7% with fondaparinux vs. 7.7% with dalteparin), a 39.4% risk reduction in individuals undergoing prolonged surgery (5.5% with fondaparinux vs. 9.1% with dalteparin) and a 45.2% risk reduction in patients 75 years of age (6.2% with fondaparinux vs. 11.2% with dalteparin). 35 IMPORTANCE OF PROPHYLACTIC TREATMENT In the absence of prophylactic treatment, the incidence of objectively confirmed hospital-acquired DVT occurs in approximately 10% to 40% of medically-ill or general surgical patients, and in between 40% to 60% of patients following major orthopedic surgery. 14,36 Patients presenting with DVT also have a recurrence rate of 30% and a 1-year mortality rate from PE that is 20%. 37,38 Although VTE is the number 1 cause of death in hospitalized patients, fatal PE may be the most common preventable cause of inpatient death in the United States. 36,39 The importance of appropriate prophylaxis against VTE must be reemphasized, because it remains the most appropriate strategy to prevent PE and any associated clinical sequelae. In 2001 the Agency for Healthcare Research and Quality (AHRQ) published a systematic review of 79 patient safety interventions based on the strength of supporting evidence. The highest ranked safety practice was the appropriate use of prophylaxis to prevent venous thromboembolism in patients at risk. 40 This recommendation was based on overwhelming evidence that thromboprophylaxis reduces ad-

5 S14 The American Journal of Medicine, Vol 121, No 11A, November 2008 Table 1 Levels of thromboembolism in surgical patients without prophylaxis Level of Risk Successful Prevention Strategies Low risk Minor surgery in patients aged 40 yr with no additional risk No specific prophylaxis; early and aggressive mobilization factors Moderate risk Minor surgery in patients with additional risk factors Low-dose UFH, (q 12 hr) LMWH ( 3,400 U/day), GCS, or IPC Surgery in patients aged yr with no additional risk factors High risk Surgery in patients aged 60 yr or yr with additional risk Low-dose UFH (q 8 hr), LMWH ( 3,400 U/day), or IPC factors (e.g., prior VTE, cancer, molecular hypercoagulability) Highest risk Surgery in patients with multiple risk factors (e.g., aged 40 yr, cancer, prior VTE) Hip or knee arthroplasty, hip-fracture surgery Major trauma; spinal cord injury LMWH ( 3,400 U/day), fondaparinux, oral vitamin K antagonist (INR, ) or IPC/GCS low-dose UFH/LMWH GCS graduated compression stockings; INR international normalized ratio; IPC intermittent pneumatic compression; LMWH low-molecularweight heparin; UFH unfractionated heparin; VTE venous thromboembolism. verse patient outcomes while concomitantly decreasing overall hospitalization costs For example, a doubleblind trial of 23,078 patients demonstrated that appropriate prophylactic treatment decreased the rate of death from PE to approximately to 0.15%. 18 These results are comparable to those reported in the large Pulmonary Embolism Prevention (PEP) trial. 46 Across both studies a similar number of patients (0.2%) experienced major perioperative and postoperative blood loss, with low rates of clinically obvious bleeding and wound hematoma. The authors concluded that given the large patient population and the wide range of surgical procedures, these reassuring data should help to allay concerns of surgeons who cite the possibility of bleeding as a reason for withholding thromboprophylaxis. 3 The ACCP conference specified that abundant meta-analyses and placebo-controlled, blinded, randomized clinical trials have demonstrated little or no increase in the rates of clinically important bleeding with prophylactic doses of low-dose UFH, LMWH, or a vitamin K antagonist Appropriately used thromboprophylaxis has a desirable risk-benefit ratio, is cost-effective, 41-45,55,56 and provides an opportunity to improve patient outcome while reducing hospitalization costs. Most hospitalized patients demonstrate 1risk factor for VTE, 57 with many features exhibiting a cumulative effect. For example, surgical patients often have a history of advanced age and obesity, in conjunction with previous cancer and hormone treatment. These individuals possess 5 risk factors, approaching 100% risk for the development of DVT. 58 AACP guidelines recommend prophylactic treatment for patients considered to be at moderate or greater risk for DVT 3 (see Table 1). Patients undergoing hip-fracture surgery and patients who have cancer requiring surgery represent 2 groups that continue to remain at high risk despite current prophylactic treatment, and may require a higher level of intervention compared with the general patient population. A doubleblind study of 23,078 patients treated with a medication regimen of either LMWH or fondaparinux revealed that the highest rates of fatal PE (0.66%) and death (6.10%) occurred after hip fracture surgery, leading the authors to conclude that the absolute risk for fatal PE after hip fracture is significantly higher relative to other surgical groups. Although heparin prophylaxis has demonstrated effectiveness in many patient populations, patients with hip fracture did not benefit from an overall reduction in mortality compared with other groups treated with heparin. Surgical patients with a history of cancer represent another high-risk group: this population accounted for 57% of cases of fatal PE, yielding a fatal PE rate of 0.33%. Despite prophylactic treatment with heparin, the risk for PE in this group was almost 4 times higher relative to surgical patients without cancer. 18 At present, ACCP guidelines recommend treatment with fondaparinux for individuals at the highest risk for the development of thromboembolism. Fondaparinux has proven increased effectiveness in patients undergoing hip-fracture surgery, and elective hip and knee replacement. Additional research demonstrates success in patients with a history of symptomatic DVT, medical illness, and cancer. Despite current recommendations, treatment with fondaparinux remains underutilized in daily clinical practice. One concern may involve a risk of increased bleeding. Because of its long half-life (approximately 18 hours), patients whose creatinine clearance is 0.5 ml/sec may experience an accumulation of fondaparinux, leading to a greater bleeding risk. 3 However, a slight increase in surgical site bleeding and wound hematoma is more than offset by a decrease in the risk for fatal PE. Due to its flexibility in administration, patients at risk for bleeding can have fondaparinux treatment delayed until the next day with no change in effectiveness, 10 allowing physicians the opportunity to delay anticoagulation until the patient s stability can be achieved. Research demonstrates that despite prophylac-

6 Caprini S15 tic treatment with LMWH, approximately 1 of 5 patients undergoing total hip-replacement surgery and one of 21 patients undergoing elective knee-replacement surgery who initially demonstrate asymptomatic DVT will experience symptomatic thromboembolism. 59 Fondaparinux has demonstrated increased effectiveness in preventing the incidence of thromboembolism as evidenced on bilateral venography, in conjunction with significant clinical success. Therefore, the adoption of fondaparinux into routine clinical practice is recommended. APOLLO TRIAL AND TREATMENT WITH INTERMITTENT PNEUMATIC COMPRESSION Treatment with mechanical thromboprophylaxis through the use of intermittent pneumatic compression represents an important strategy to provide prophylactic treatment while reducing bleeding risks associated with anticoagulant therapy. Success of the combination of anticoagulation and mechanical therapy was first demonstrated in A total of 328 surgical patients who received treatment with anticoagulation therapy and pneumatic compression revealed a DVT rate of 1.5%, as detected by 125 I fibrinogen scanning, as compared with a 26.8% incidence within a control group. 60 Despite successes, the use of intermittent pneumatic compression (IPC) devices has been poorly studied compared with anticoagulant-based therapy. 3 The Arixtra prophylaxis in surgery (APOLLO) trial 61 was a randomized, double-blind study designed to measure the safety and effectiveness of fondaparinux combined with the use of IPC. This study was conducted at 40 US centers and is the largest trial in the modern era of patients treated with IPC after general surgery. Of importance is that 94.7% of all VTE was eliminated by treatment with IPC alone. The combination of anticoagulant therapy and IPC reduced the total incidence of VTE to 1.7%, 61 yielding an odds ratio reduction of 69.8%. The combination of fondaparinux and IPC produced the lowest rate of venographic DVT ever achieved in general surgery, despite that fact that 40% of the treatment population consisted of patients with a history of cancer. Furthermore, fondaparinux reduced the rate of proximal DVT by 86%. Although fondaparinux significantly increased the risk for major bleeding compared with IPC alone (1.6% vs. 0.2%), no bleeding episodes were fatal or involved a critical organ, and most incidents occurred at the surgical site. A 1.6% incidence of major bleeding is in the lower range of those reported in meta-analyses of recent trials on anticoagulant agents occurring within the same setting. 35,62-64 Treatment with the combination of anticoagulation and pneumatic compression greatly reduces the incidence of lower extremity thrombus, and provides a viable strategy to prevent the leading cause of death occurring in the hospital setting. Despite the clear benefits associated with combination therapy, this treatment remains underutilized. The AACP recommends that mechanical prophylaxis be used primary in patients who are at high risk for bleeding (grade 1C ) or as an adjunct to anticoagulation-based prophylaxis (grade 2A). 3 Grade 1c is one randomized prospective double blind trial with appropriate endpoint measurements 2-A is not double blinded so not as strong. However, evidence suggests that this highly effective technique may be able to significantly reduce DVT and PE. This possibility of a widespread adoption of combination therapy warrants further scrutiny. FUTURE MEDICAL THERAPY Dabigatran Etexilate New anticoagulant therapies currently in phase 2 and phase 3 clinical trials include the direct thrombin inhibitor dabigatran etexilate, and the direct factor Xa inhibitor rivaroxaban. Following oral administration, the prodrug dabigatran etexilate is rapidly converted to its active form dabigatran, binding to thrombin with high affinity and specificity. The drug can be given in a fixed oral dose, has a rapid onset and offset of action, and provides a predictable and consistent anticoagulation effect without the need for coagulation monitoring. Dabigatran etexilate demonstrates increased safety through a low potential for drug-drug interactions. The pharmokinetic profile is characterized by a time to peak plasma concentration within 2 hours, a terminal half-life of 14 to 17 hours with multiple doses, and once- or twice-daily dosing. 65 The RE-NOVATE phase 3 trial consisted of 3,494 patients undergoing hip-replacement surgery who were randomized to receive either 150 mg or 220 mg oral once-daily dabigatran compared with 40 mg of subcutaneous oncedaily enoxaparin. The primary efficacy end point of total VTE and death from all causes was similar among all 3 groups (8.6% with dabigatran 150 mg, 6.0% with dabigatran 220 mg, 6.7% with enoxaparin 40 mg), as was the safety end point of major bleeding (1.3% with dabigatran 150 mg, 2.0% with dabigatran 220 mg, 1.6% with enoxaparin 40 mg). 66 The RE-MODEL phase 3 European knee-replacement trial of 2,000 patients demonstrated that once-daily doses of both dabigatran etexilate 150 mg and 220 mg are as safe and effective as once-daily enoxaparin 40 mg for preventing VTE and all-cause mortality in patients undergoing elective knee-replacement surgery. 67 The RE-MOBILIZE phase 3 North American knee-replacement trial compared dabigatran with an increased dose of enoxaparin (up to 60 mg daily). Dabigatran failed to show equivalence to the highest dose of enoxaparin for total VTE and all-cause mortality (33.7% with dabigatran 150 mg and 31.1% dabigatran 220 mg vs. 25.3% enoxaparin 60 mg; P 0.02 and P , respectively). These differences were believed to be predominantly caused by asymptomatic distal DVT. Additionally, the higher comparator dose (enoxaparin 60 mg) and a later time to first oral dose may have produced lower effectiveness. 68 Furthermore, the clinical DVT incidence was the same in both the dabigatran and enoxaparin groups. Although bleeding rates were not statistically different between treatment groups, there were twice as many

7 S16 The American Journal of Medicine, Vol 121, No 11A, November 2008 major bleeding events in the enoxaparin group compared with dabigatran (0.6% with dabigatran 150 mg and 220 mg vs. 1.4% with enoxaparin). A pooled analysis of all 3 trials (RE-NOVATE, RE-MODEL and RE-MOBILIZE) concluded that dabigatran etexilate was efficacious and comparable to enoxaparin in the prevention of major VTE and VTE-related mortality after both hip and knee replacement. 69 Further studies of dabigatran etexilate are currently under way, including the RE-VOLUTION trial of 27,000 patients comparing dabigatran with treatment with warfarin or enoxaparin. Additionally, the RE-LY phase 3 study investigated dabigatran etexilate as a potential treatment for stroke prevention in atrial fibrillation. The RE-COVER and RE-MEDY trials are investigating dabigatran etexilate for acute treatment and secondary prevention of VTE. Rivaroxaban Factor Xa has emerged as a promising target for effective anticoagulation because it acts as the convergence point for the internal and external coagulation pathways. This important coagulation factor catalyzes the conversion of prothrombin to thrombin; 1 molecule of factor Xa results in the generation of 1,000 thrombin molecules. The inhibition of factor Xa will prevent this burst of thrombin and consequently diminish thrombin-mediated activation of coagulation and platelets. 4 Rivaroxaban is a direct, specific, competitive factor Xa inhibitor. The drug has a rapid onset of action within 2 to 4 hours, a high oral bioavailability of 80%, and predictable pharmokinetics. It inhibits the active site of factor Xa directly, without the need for antithrombin, thus distinguishing its mechanism of action from indirect Xa inhibitors such as LMWH and fondaparinux. Indirect inhibitors such as fondaparinux, UFH, and LMWH all require antithrombin to be effective. The resulting drug-antithrombin complex is too large to inhibit factor Xa within an existing clot or within the prothrombinase complex, thereby limiting treatment effects to free factor Xa only. In contrast, rivaroxaban inhibits both circulating and fibrin-bound factor Xa within the prothrombinase complex. The drug does not require any dosage adjustment for sex, age, or extreme body weight. It may be safely administered with concomitant agents including aspirin, enoxaparin, digoxin, naproxen, ranitidine, and antacids. Further evidence suggests that rivaroxaban may be suitable for oncedaily administration, because phase 1 studies in healthy subjects have shown that single doses of rivaroxaban have pharmacodynamic effects that persist for 24 hours. 70,71 An oral, direct factor Xa inhibitor that does not require routine coagulation monitoring offers significant advantages over current therapies. 4 Research studies examining the use of rivaroxaban in orthopedic procedures demonstrate promising results. For all trials, the primary efficacy end point was a composite of any DVT, confirmed nonfatal PE, and all-cause mortality during treatment. One randomized, double-blind, doubledummy trial of patients undergoing elective knee-replacement surgery revealed that a wide, 12-fold dose range (2.5 to 30 mg bid) of rivaroxaban started early in the postoperative period was equally efficacious as LMWH for the prevention of VTE, with no apparent dose-response. 72 Patients treated with rivaroxaban exhibited a primary efficacy incidence in the range of 23.3% to 40.4%, compared with 44.3% of patients treated with enoxaparin 30 mg (P 0.29). Lower doses of rivaroxaban (2.5 to 10 mg) demonstrated an incidence of major bleeding in the range of 0% to 1.9%, which was comparable to the 1.9% incidence observed with enoxaparin, and is similar to that reported for patients treated with placebo in a previous total knee-replacement study. 73 The optimal dose range of rivaroxaban was determined to be between 2.5 and 10 mg. Although the frequency of major bleeding increased with higher doses of rivaroxaban (P ), no significant differences were observed between any dose group compared with enoxaparin, highlighting the potential efficacy of postoperative administration of rivaroxaban for the prevention of VTE in total knee replacement. Recently, RECORD-3, 74 a phase 3 double-blind trial, compared patients receiving rivaroxaban 10 mg after total knee replacement with patients receiving enoxaparin 40 mg before surgery. Patients receiving treatment with rivaroxaban demonstrated a 9.6% incidence of VTE at 10 to 14 days follow up, compared with 18.9% of patients receiving treatment with enoxaparin (P 0.001). Bleeding was similarly low in both groups. Of importance is that the RECORD-3 trial is the first demonstration of the safety and effectiveness of a fixed, unmonitored regimen of an oral factor Xa inhibitor in antithrombotic therapy. 74 Rivaroxaban has also demonstrated effectiveness in patients undergoing hip-replacement surgery. A randomized, double-blind, double-dummy trial revealed that treatment with rivaroxaban across a 12-dose range (2.5 to 30 mg bid), demonstrated a primary efficacy incidence in the ranges of 7% to 18%, compared with the 17% rate exhibited for 40 mg enoxaparin. Results confirmed that lower doses of rivaroxaban in the range of 2.5 to 10 mg demonstrated an incidence of major bleeding comparable to enoxaparin (0.8% to 2.3%, compared with 1.5%, respectively). 75 These results were confirmed in the ODIXa-OD-HIP study, 76 which proved that oral rivaroxaban given once daily postoperatively was equally efficacious across an 8-fold range (5 to 40 mg once daily). Use of once-daily rivaroxaban demonstrated a primary end point incidence in the range of 6.4% to 14.9%, compared with a 25.2% incidence when enoxaparin 40 mg was administered once daily. A significant dose-response relation was demonstrated for the incidence of major bleeding, with an incidence in the range of 0.7% to 5.1% (P 0.039), compared with a 1.9% incidence for enoxaparin. However, there were no significant differences in the incidences of major postoperative bleeding between any rivaroxaban dose and enoxaparin. No bleeding into a critical organ was reported, and all major postoperative bleeding events were confined to the surgical site. 76

8 Caprini S17 The results of the RECORD-3 and ODIXa-OD-HIP studies suggest that rivaroxaban 10 mg administered once daily should be further investigated, because this dose demonstrated a low incidence of thromboembolic events in conjunction with a 0.7% incidence of major bleeding. The EINSTEIN-DVT dose-finding study of patients with symptomatic DVT demonstrated that oral rivaroxaban administered once daily at fixed doses between 20 to 40 mg demonstrated a primary efficacy end point in the range of 5.4% to 6.1%, compared with a 9.9% incidence in patients receiving treatment with the combination of a vitamin K antagonist and either LMWH or UFH (LMWH/UFH VKA). 77 Major bleeding occurred in 0% to 1.5% of patients receiving treatment with rivaroxaban, compared with 1.5% of LMWH/UFH VKA, leading to the conclusion that oral rivaroxaban administered once daily at fixed doses of between 20 mg to 40 mg has safety and efficacy similar to that of LMWH/UFH VKA in the treatment of acute symptomatic DVT. A second study of patients with symptomatic DVT revealed a reduced thrombus burden as detected by ultrasound in 43.8% to 59.2% of patients receiving a twice daily dose of rivaroxaban 10 to 30 mg or 40 mg once daily, compared with 45.9% of patients treated with enoxaparin/ vitamin K antagonist. 78 A randomized double-blind study designed to examine the pharmacodynamics and pharmacokinetics of rivaroxaban revealed that a single drug dose resulted in a sustained, dose-dependent inhibition of factor Xa activity and insignificant and nonlinear prolongation of prothrombin time without a significant effect on thrombin or antithrombin activity. 6 All once-daily dosing regimens demonstrated factor Xa inhibition through 24 hours. The improved pharmacologic characteristics of rivaroxaban, such as oral, oncedaily dosing without the need for coagulation monitoring, make it a potentially attractive treatment option for longterm anticoagulation. 77 These impressive results have provided the foundation for once-daily dosing regimens to be evaluated in phase 3 programs. The rivaroxaban clinical development program is very robust, with almost 40,000 subjects to be evaluated in 12 phase 2 and phase 3 trials, spanning multiple venous and arterial indications in both acute and chronic use settings. This scope will make rivaroxaban the most extensively studied oral anticoagulant, with 15,000 patients evaluated thus far in the completed phase 2 and ongoing phase 3 programs. The 4 RECORD phase 3 trials are designed to examine the safety and effectiveness of rivaroxaban compared with enoxaparin in patients receiving total hip and knee replacement. The EINSTEIN phase 3 trials will examine the effectiveness of rivaroxaban compared with the combination of enoxaparin and a vitamin K antagonist in the treatment of DVT and PE. The ROCKET-AF trial will evaluate rivaroxaban compared with warfarin for the prevention of stroke and non-central nervous system systemic embolism in patients with nonvalvular atrial fibrillation, whereas the ATLAS phase 2 trial will evaluate the combination of rivaroxaban plus aspirin, compared with thienopyridine plus aspirin in the treatment of patients with acute coronary syndromes. SUMMARY The past decades have yielded significant treatment advances in anticoagulation therapy. However, the successful prevention of VTE and fatal PE remains a challenge. The achievement of safe and effective anticoagulation continues to require improvement in patients undergoing surgery for hip fracture and elective hip and knee replacement. Additionally, patients with multiple risk factors and a history of cancer constitute important treatment populations that demonstrate a high incidence of VTE despite current therapies. Promising new medical treatments include the indirect factor Xa inhibitor fondaparinux, the direct thrombin inhibitor dabigatran etexilate, and the direct factor Xa inhibitors rivaroxaban and apixaban. Furthermore, the value of appropriate prophylaxis must be reemphasized as the most essential strategy for preventing thromboembolic events and fatal PE. Effective treatment techniques such as combination therapy with anticoagulation and intermittent pneumatic compression remain underutilized despite studies that herald a significantly reduced incidence of mortality and morbidity. Although VTE continues to remain the leading cause of death in hospitalized patients, fatal PE may be the most common preventable cause of inpatient death in the United States. 36,39 It is hoped that the advent of new medical therapies with a high potential for success will highlight the importance of the appropriate prophylactic treatment on a global level and facilitate changes to improve patient safety. AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships: Joseph A. Caprini, MD, MS, RVT, has served as an educational consultant for Boehringer-Ingelheim, ConvaTec, Covidien, Eisai Inc., GlaxoSmithKline, and sanofi-aventis. References 1. Aaron RK, Ciombor D. Venous thromboembolism in the orthopedic patient. Surg Clin North Am. 1983;63: Paiement GD, Mendelsohn C. The risk of venous thromboembolism in the orthopedic patient: epidemiological and physiological data. Orthopedics. 1997;20(suppl): Geerts WH, Pineo GR, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(suppl):338S-400S. 4. Perzborn E, Strassburger J, Wilmein A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY an oral, direct factor Xa inhibitor. J Thromb Haemost. 2005;3: Katzung BG. Basic and Clinical Pharmacology. New York: McGraw Hill, Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78:

9 S18 The American Journal of Medicine, Vol 121, No 11A, November Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106: Hirsh J, Bates SM. Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective. Ann Intern Med. 2001;134: Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348: Colwell CW, Kwong LM, Turpie AG, et al. Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopedic surgery. J Arthroplasty. 2006;21: Edelsberg J, Ollendorf D, Oster G. Venous thromboembolism following major orthopedic surgery: review of epidemiology and economics. Am J Health Syst Pharm. 2001;58(suppl 2):S Hyers TM. Venous thromboembolism. Am J Respir Crit Care Med. 1999;159: Salzman EW, Hirsh J. The epidemiology, pathogenesis, and natural history of venous thrombosis. In: Colman RW, Hirsh J, Marder VJ, et al, eds. Hemostasis and Thrombosis. Philadelphia: JB Lippincott, 1994: Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest. 2001;119(suppl):132S-175S. 15. Nicolaides AN. Prevention of venous thromboembolism: International consensus statement. Guidelines complied in accordance with the scientific evidence. Int Angiol. 2001;20: Murray DW, Carr AJ, Bulstrode CJ. Pharmacological thromboprophylaxis and total hip replacement. J Bone Joint Surg. 1995;77B: Lie SA, Engesaeter LB, Havelin LI, et al. Mortality after total hip replacement: 0-10-year follow-up of 39,543 patients in the Norwegian Arthroplasty Register. Acta Orthop Scand. 2000;71: Haas S, Wolf H, Kakkar AK, et al. Prevention of fatal pulmonary embolism and mortality in surgical patients. Thromb Haemost. 2005; 94: Lassen MR, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomized double-blind comparison. Lancet. 2002;359: Turpie AG, Gallus AS, Hoek JA, for the Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 2001;344: Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med. 2001;345: Eriksson BI. Improvements in the prevention of postoperative venous thromboembolism in hip fracture patients. Orthopedics. 2003;26(suppl): s851-s Turpie AGG, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomized double-blind trial. Lancet. 2002;359: Hull R, Raskob G, Pineo G, et al. A comparison of subcutaneous low-molecular-weight heparin with warfarin sodium for prophylaxis against deep-vein thrombosis after hip or knee implantation. N Engl J Med. 1993;329: Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty a randomized, doubleblind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996;124: Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med. 2001;345: Cushner FD, Friedman RJ. Blood loss in total knee arthroplasty. Clin Orthop. 1991;269: Shaieb MD, Watson BN, Atkinson RE. Bleeding complications with enoxaparin for deep venous thrombosis prophylaxis. J Arthroplasty. 1999;14: Raskob GE, Hirsh J. Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest [suppl]. 2003;124:379S. 30. Hull RD, Pineo GF, Stein PD, et al. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review. Arch Intern Med. 2001;161: Kwong LM, Muntz JE. Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety. Am J Orthop. 2002;31: Büller HR, Davidson BK, Decousus H, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis. Ann Intern Med. 2004;140: The MATISSE Investigators. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349: Cohen AT, Davidson B, Gallus AS, et al. Fondaparinux for the prevention of venous thromboembolism in acutely ill medical patients. Blood. 2003;102:15a. 35. Agnelli G, Bergqvist D, Cohen AT, et al. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005;92: Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. Arch Intern Med. 1991; 151: Morrel MT, Dunhill MS. The postmortem incidence of pulmonary embolism in a hospital population. Br J Surg. 1968;55: Clagett GP, Anderson FA, Heit J, et al. Prevention of venous thromboembolism. Chest. 1995;108:312S-334S. 39. Kniffin WD Jr, Baron JA, Barrett J, et al. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994;154: Shojania KG, Duncan BW, McDonald KM, et al. Making health care safer: a critical analysis of patient safety practices. Evidence Report/ Technology Assessment No. 43 (prepared by the University of California at San Francisco-Stanford Evidence-based Practice Center under Contract no ). Rockville, MD: Agency for Healthcare Research and Quality, July 2001: Sullivan SD, Kahn SR, Davidson BL, et al. Measuring the outcomes and pharmacoeconomic consequences of venous thromboembolism prophylaxis in major orthopaedic surgery. Pharmacoeconomics. 2003; 21: Caprini JA, Botteman MF, Stephens JM, et al. Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States. Value Health. 2003;6: Bergqvist D, Lindgren B, Matzsch T. Cost-effectiveness of preventing postoperative deep vein thrombosis. In: Hull RD, Pineo, GF, eds. Disorders of Thrombosis. Philadelphia: WB Saunders, 1996: Mamdani MM, Weingarten CM, Stevenson JG. Thromboembolic prophylaxis in moderate-risk patients undergoing elective abdominal surgery: decision and cost-effectiveness analyses. Pharmacotherapy. 1996;16: Bick RL. Proficient and cost-effectiveness approaches for the prevention and treatment of venous thrombosis and thromboembolism. Drugs. 2000;60: Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000;355: Collins R, Scromgeour A, Yusuf S, et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin: overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;318: