Contemporary Clinical Practice: State of the Art in VTE Management

According to estimates, 2 million Americans have some form of venous thromboembolism (VTE). Pulmonary embolism (PE) affects about 600,000 people, and is fatal in 10% of cases. Approximately 800,000 individuals have received a diagnosis of post-thrombotic syndrome. And, silent PE threatens the health and lives of about 1 million Americans, according to experts. Clinical pharmacists and other clinicians agree that an aggressive approach to therapy is called for in these patients. Evidence suggests that adequate anticoagulation early in the disease process reduces the incidence of later and secondary recurrence. This symposium, presented in conjunction with the 2003 Annual Meeting of the American College of Clinical Pharmacy, featured five nationally recognized experts who outlined newer approaches to VTE management, including the value of prophylaxis, and the emerging role of specific Xa inhibitors.

This program was supported by an educational grant from Sanofi-Synthelabo, LLC.

Introduction

Post-thrombotic syndrome provides a vivid example of the costs of VTE—both health-wise and economic. According to program chair, Henry I. Bussey, PharmD, Professor in the College of Pharmacy at the University of Texas at Austin, and Clinical Professor at University of Texas Health Science Center at San Antonio, when valves are damaged during a thrombotic event, they are either unable to prevent the backflow of blood, or thrombi cause persistent outflow obstruction. Permanent disability can result, as is evident from the fact that 4% of the US population with post-thrombotic syndrome has or will develop a venous leg ulcer. (Nicolaides et al. (Int Angiol 1997;16(1):3-38). And if a patient who has experienced one event goes on to have a second in the same leg, the risk of developing severe post-thrombotic syndrome increases by 6-fold (Prandoni et al. Ann Intern Med 1996).

Recent findings in VTE management include recommendations for early and adequate anti-coagulation and longer treatment for secondary prophylaxis. Fortunately, treatment options are expanding. Low molecular weight heparin (LMWH) offers a predictable and early response, and the convenience of outpatient treatment. Emerging agents include fondaparinux and ximelgatran.

The questions in VTE management are evolving along with the advances in recent years, Dr. Bussey said. Today, important questions include:
• Can we do more to prevent VTE?
• How long should we treat the initial event?
• Is post-treatment monitoring warranted?
• Can we identify sub-groups who should be treated for a longer period?
• What INR should we use?
• Can the specific agent used for treatment influence recurrence?
• Is there a difference in bleeding risk with the newer agents?
• How do we reverse newer anticoagulants?

The Rationale for Selectively Inhibiting Factor Xa

More can indeed be done to prevent VTE, according to David Hawkins, PharmD, Professor and Senior Associate Dean at Mercer University School of Pharmacy in Atlanta. Although LMWH is a safe and effective agent, it is still associated with a 4% to 5% symptomatic recurrence rate at 3 months of follow-up. The rate of VTE remains unacceptably high in patients undergoing major joint surgery and surgery for cancer. With prophylaxis, the risk of fatal pulmonary embolism in hip fracture repair patients is 1 to 2%. Without antithrombotic prophylaxis, the rate of deaths from PE is anywhere from 4% to 13%. While low molecular weight heparins have been a “welcome addition” to options for managing patients with pulmonary embolism and deep vein thrombosis, Dr. Hawkins pointed out that a 4% to 5% rate of recurrence of symptomatic VTE is still too high.

What is fondaparinux?
Fondaparinux is the first in a new therapeutic class of Factor Xa inhibitors. A chemical compound of low molecular weight that binds specifically to anti-
thrombin, “... fondaparinux is then released so it can bind to the antithrombin molecule. Dr. Hawkins explained. “The binding of antithrombin Xa is irreversible; the binding of fondaparinux to the antithrombin is reversible.” When it is administered subcutaneously, this agent is 100% bioavailable. Its half-life is around 17 hours.

Differentiating Factor Xa inhibitors from heparins and warfarin is a single site of action. Both extrinsic and intrinsic systems converge at Xa, located at the intersection of the final common pathway leading to the production of thrombin. In other words, Dr. Hawkins said: “The rate-limiting step to the formation of thrombin is Factor Xa,” and this explains its value as a therapeutic target. One molecule of Xa generates 100 molecules of thrombin per second.

The pharmacokinetics of fondaparinux 2.5 mg sc are linear: tmax is reached at 1.7 hours, and Cmax/2 occurs at 25 minutes. A very rapid onset of
action results in almost immediate anti-coagulation. A highly predictable anti-thrombotic effect is one of the major advantages fondaparinux has over heparin and warfarin. Another advantage of fondaparinux is that it is a product of chemical synthesis, versus being a derivative of an animal source, like heparin and LMWHs. Fondaparinux is a single, pure chemical entity, Dr. Hawkins added, whereas heparins are complex heterogeneous molecules. Fondaparinux does not interact with platelets, monocytes, and osteoblasts whereas the contrary is true of heparin and LMWH. Importantly, fondaparinux inhibits the generation of thrombin, and not thrombin itself. An inhibition of 65% of thrombin generation achieves virtually 100% inhibition of clot thrombosis. Long-term use of LMWH agents can lead to osteoporosis, but because there is no interaction with osteoblasts, there is no such risk with fondaparinux.

Antithrombotic Therapy in Orthopedic Surgery
Results from three large, randomized, controlled trials in hip fracture, hip replacement, and knee replacement demonstrated a greater than 50% relative risk reduction in VTE—either DVT or PE, or both—in all three categories.

Post-surgery, and after discharge, orthopedic surgery patients remain at increased risk for VTE. Despite this risk, most do not receive an antithrombotic agent as a form of preventive therapy. The “Potential for Clot” study not only revealed this risk, but dramatically demonstrated the benefit of post-surgery prophylactic antithrombotic treatment to reduce this risk (Eriksson BI, Lassen MR. Arch Intern Med 2003;183(11):1337-1342). In this study, post-hip-fracture patients were randomized to receive either fondaparinux therapy or placebo for 7 to 10 days, and then followed for one month. The results showed a 96% relative risk reduction in all VTE events in the fondaparinux-treated group of patients, and an 89% reduction in symptomatic events. The incidence of PE mortality was also very low with antithrombotic treatment versus placebo: no PEs, either fatal or nonfatal, occurred in the fondaparinux group. Two nonfatal and one fatal PE took place in the placebo-treated patient group.

Fondaparinux is presently the only antithrombotic agent with an FDA-approved indication for three orthopedic surgery procedures: total hip, total knee, and hip fracture, and for extended prophylaxis after hip fracture surgery. It has been shown to have a very favorable safety profile.

Evolving Data in VTE Prophylaxis

New data in the prevention of VTE have provided valuable insights in the medically ill patient, a heterogeneous population that suffers about 70% of all VTE events. Paul P. Dobesh, PharmD, BCPS, from St. Louis College of Pharmacy, reviewed findings from several important trials that have shown that VTE can be reduced in medically ill patients withthe help of effective newer agents.

The MEDENOX study evaluated patients with NYHA Class III or IV heart failure, acute respiratory failure not requiring ventilation, and/or systemic infection (Samama M et al. N Engl J Med 1999; 341:793-800). On day one of the study that had a follow-up extending to 110 days, hospitalized patients were randomized to two doses (20 mg and 40 mg) of enoxaparin. By day 14, each patient was evaluated via bilateral venography for VTE risk. Results indicated that the 40 mg dose of enoxaparin significantly reduced total thromboembolic events and proximal thromboembolic events by over 60% in this patient group.

More recently, the ARTEMIS trial evaluated the efficacy and safety of fondaparinux 2.5 mg once daily, compared to placebo, in preventing VTE at 15 days. Like MEDENOX, ARTEMIS included patients with heart failure, respiratory disease, and acute infection, but did not require additional VTE risk factors.

The primary composite of VTE endpoints were asymptomatic DVT as assessed by bilateral venograph; symptomatic DVT; and fatal and non-fatal pulmonary embolism.

Safety outcomes included major bleeding (defined as fatal bleeding, bleeding into a critical organ, bleeding leading to intervention, and a bleeding index of 2 or greater); minor bleeding; and death.

Patients receiving fondaparinux demonstrated a significant 50% relative risk reduction in the incidence of total VTE at day 15 (Figure 1). There was also a significant reduction in the incidence of PE, which has not been demonstrated in other medically ill prophylaxis trials. There was no difference in safety outcomes between the fondaparinux arm and placebo-treated groups.

What can be concluded from this trial? According to Dr. Dobesh, “...the time for placebo-controlled trials is over...” and the current question to be addressed is how to choose among available agents, and what is the role for extended prophylaxis? “A few studies now show that, as you follow these patients out longer and longer, their risk doesn’t go away.” In fact, the risk of mortality grows with time, and evidence suggests that antithrombotic prophylaxis can have a positive impact on this long term risk.

Another group of patients at high risk for VTE are those undergoing abdominal surgery. Without prophylaxis, up to 25% of abdominal surgery patients develop DVT, with a 1% risk of PE (Geers et al. Chest 2001; 119(1):32S-75S). In cancer surgery, the risk of VTE and fatal PE is 2 to 4-fold higher (Kakkar AK, et al. Thromb Haemost 2001;86:OC1732). Despite this, as Dr. Dobesh reported, thromboprophylaxis is underused—anywhere from 25 to 62% of patients are managed without any form of prophylaxis (Bratzler DW, et al. Arch Intern Med 1998;158:1909-12. Stratton MA, et al. Arch Intern Med 2000;160:334-40). In patients who are treated with heparins after abdominal surgery, there is a residual VTE incidence of 5-15%, suggesting that there is much room for improvement (Geerts WH, et al. Chest 2001;119(1):32S-75S; Mismetti P, et al. Br J Surg 2001;88:
913-30).

Accordingly, the PEGASUS study was designed to evaluate post-operative fondaparinux versus dalteparin, given before and after surgery, in the prevention of VTE after abdominal surgery. The primary outcomes were a composite of VTE events that included asymptomatic DVT as assessed by bilateral venography; symptomatic DVT; and fatal and non-fatal PE, up to day 10 post-surgery. Safety outcomes were similar to those in other fondaparinux trials.

Enrolled patients underwent abdominal surgery of 45 minutes or more in duration. The majority received general anesthesia. Inclusion criteria required that patients have some risk for developing VTE. Risk factors included a BMI greater than 30 for men and 28.6 for women; a history of DVT or PE; heart failure (NYHA classification III or IV); COPD, and IBD.

Study patients received either dalteparin 2500 units 2 hours before surgery, a first post-operative dose of 2500 units about 10 hours after surgery; and 5000 units thereafter (FDA-labeling for high-risk abdominal surgery); or fondaparinux 2.5 mg daily beginning 6 hours after surgery. Patients in both groups received therapy for 7 days, and then were evaluated by venography.

At 10 days, dalteparin-treated patients had an event rate of 6.1%, versus a rate of 4.6% with fondaparinux—a non-significant difference that established the comparable efficacy of both agents in preventing VTE after abdominal surgery. However, in high-risk cancer surgery patients, which constituted about 60% of the patients in PEGASUS, fondaparinux was statistically more effective than dalteparin (odds reduction = 40.5%, p = 0.02). The safety of both agents was comparable.

Preliminary data are also available for the use of fondaparinux in cardiology patients. The PENTALYSE trial evaluated the efficacy of unfractionated heparin
versus fondaparinux in preventing re-occlusion 6 ± 1 days after reperfusion therapy (t-PA). For these patients (~300) the risk of re-occlusion is high: “We know that 20 to 30% of patients can re-occlude an open artery,” Dr. Dobesh said, adding that “If you have an open artery at 90 minutes after receiving the lytic agent...7% of UFH patients had reoccluded, versus less than 1% with fondaparinux.”

Large studies are underway to further evaluate the role of fondaparinux in the treatment of patients with acute coronary syndromes. The large, 10,000 patient MICHELANGELO, or OASIS-6 trial is a worldwide study in STEMI patients. The United States protocol for this trial compares fondaparinux or heparin, placebo, versus IV heparin and a fondaparinux placebo, for 9 days after pharmacologic reperfusion.

PENTUA, a Phase II dose-finding study in patients with unstable angina, and non-ST segment elevation MI patients, found that fondaparinux at 2.5 mg
provided significantly better reduction in death, MI, and recurrent ischemia at 9 days than the 4- or 8-milligram dose, or enoxaparin. The large OASIS-5 trial is currently enrolling 16,000 patients, to compare the efficacy and safety of fondaparinux compared to enoxaparin in patients with UA/NSTEMI. These are but a few of many world-wide initiatives that, according to Dr. Dobesh, will pave the way for reducing thromboembolic risk in several types of patients.

Contemporary Venous Thromboembolism Treatment: Update for 2004

Since the mid-1990s, as many as eight new anticoagulant agents have received FDA approval, including three low-molecular weight heparins, one heparinoid, one pentasaccharide, and three injectable thrombin inhibitors for HIT (heparin-induced thrombocytopenia) and coronary intervention. Along with these newer agents come new considerations in the treatment of DVT, especially in light of an aging population, and longer duration of treatment. Bruce Davidson, MD, MPH, Clinical Associate Professor of Medicine at the University of Wisconsin School of Medicine addressed four of these concerns.

1. Awareness of renal insufficiency, resulting in dosage adjustments, especially during prolonged treatment
“Physicians should pay more attention to the calculated creatinine clearances,” said Dr. Davidson. This is becoming the standard of care, and there are new recommendations regarding duration and intensity. Dr. Davidson described two patient cases that make the point about adjusting DVT prophylaxis dosing. Both are elderly women—87 and 82 years old respectively. One, who is recovering well from a first stroke, weighs 85 pounds and has a serum creatinine of 0.9. The second has osteoarthritis, is 3-months post total hip replacement, and is experiencing nausea and vomiting. This patient weights 103 pounds and has a creatinine clearance of 1.0. Using the Cockroft-Gaullt estimator for determining the usual prophylaxis dose: (140 - age) x (weight in kg) x (0.85 for women)/72 x (serum creatinine), the 87-year old has a creatinine clearance of 27, and the 82-year old women a creatinine clearance of 32. Based on a request from the manufacturers of enoxaparin to the FDA and European authorities, Dr. Davidson explained, patients with a creatinine clearance of less than 30 should receive a prophylaxis dose of 30 (not 40) mg once daily, or a treatment dose of 1 mg/kg once daily rather than twice a day. “Keep in mind that this is a 50% reduction,” Dr. Davidson added to emphasize that drug levels in high-risk patients receiving treatment for long periods of time will accumulate, and that a calculated creatinine clearance of 30 is not rare in the elderly.

To maintain a safe dosing level of drug in fragile elderly patients who are receiving antithrombotic prophylaxis, Dr. Davidson recommends modifying the dose to target a target anti-Xa level, reasoning that the anti-Xa level is the most sensitive marker of heparin in plasma. A simple assay is available and in use in many hospitals and may be used once per day to manage patient risk. Use caution with published “target” anti-Xa levels, Dr. Davidson said. His own recommended target anti-Xa levels for prophylaxis are 0.2-0.4 peak (4 h), and >0.06 (trough). For treatment, he recommends anti-Xa levels ranging from 0.5 to 1.0 (peak) and 0.35 (trough).

2. New recommendations for duration of treatment
For acute DVT, to reduce risk in post-operative patients stopping birth control pills, treatment is recommended for a minimum of 3 months. To control a persistent risk factor such as recurrent DVT or cancer, a minimum treatment duration of 6 months is recommended. And for high risk patients such as those with an anti-phospholipid antibody (APLA), treatment should continue until the condition resolves. For patients with a significant antithrombin (AT) deficiency, treatment should continue indefinitely. Unresolved and under study at the present time is how to manage patients with unprovoked DVT, and the development scheme for patient-specific assessment of risk and treatment feasibility.

3. Superiority of prolonged LMWHrather than warfarin for cancer patients
At least five pro- and retrospective studies demonstrate that cancer patients are at a high risk for bleeding, and that injected anticoagulants have superior efficacy to VKA (Prandoni P et al. Blood 2002;100(10): 3484-8. Lee A et al. N Engl J Med 2003; 349(2):146-53. Matisse Investigators. N Engl J Med 2003;Oct 20:1695-1702. Meyer G et al. Arch Intern Med 2002; 162(15):1729-35. A fondaparinux DVT treatment study is not yet published).

4. Clinical trials of fondaparinux for PE and DVT treatment
Fondaparinux is a synthetic Xa inhibitor devoid of anti-IIa activity, with proven efficacy in the prevention of DVT or PE. The current standard initial therapy in DVT and PE are body-weight-adjusted LMWH bid or od, sc, and continuous, dose-adjusted unfractionated heparin iv. The objective of the MATISSE studies was to evaluate whether a fixed dose of fondaparinux is at least as effective and safe as the current initial therapy. As principal investigator, Dr. Davidson adopted a protocol that was acceptable worldwide (LMWH is not approved in the US). “At three months, there was a roughly 5% failure rate for unfractionated heparin” Dr. Davidson commented, for a relatively good result of non-recurrence in 95% of patients at the 3-month mark (Figure 2). Overall, the Matisse studies added to evidence that factor Xa inhibition by fonadparinux is at least as effective as a PTT-adjusted UFH for the initial treatment of DVT. As a once-daily subcutaneous injection, without body weight adaptation other than for extremes of weight, the fondaparinux regimen offers a uniform approach for both DVT and PE patients. The investigators further concluded that fondaparinux is a potential therapy for HIT. The incidence of major bleeds and recurrent VTE is higher in cancer patients, regardless of their treatment.

Fondaparinux will allow for simplified treatment at home, Dr. Davidson speculated, but suggested that clinicians who are familiar with the risks and uncertainties of LMWHs educate their colleagues as to its proper and safe use. Based on his extensive research and the available literature, Dr. Davidson urged that clinicians “...strongly consider once-daily, prolonged therapy of DVT/PE in cancer patients” after an initial period of 2 weeks of q 12 hours treatment, if LMWH is used for initial treatment. Finally, he recommended that physicians who treat HIT patients undertake a critical review of the fondaparinux NEJM article, and consider it as an alternative to hirudin and argatroban infusion for treatment of HIT (Warkentin TE et al. Blood 2003;102:suppl #1145. Savi P et al. Blood 2003;102:suppl #1145. Kuo KHM et al. Blood 2003;102:suppl #1147. Rubin N et al. Blood 2003;102: suppl #4190. Lian EC et al. Blood. 2003; 102: suppl #4206).