Anticoagulation in Long-Term Care: The State of the Art

Despite the availability of newer anticoagulant therapies, such as low-molecular-weight heparins, pentasaccharides, and oral direct thrombin inhibitors, the more traditional anticoagulant agents, unfractionated heparin and warfarin, are still used in long-term care. At a session held during the ASCP midyear meeting, a panel of experts discussed clinical, economic, and practical advantages of the contemporary agents.

This program was supported by an unrestricted educational grant from Aventis Pharmaceuticals.

Traditional Anticoagulation Therapy: Any Reason to Abandon a Half-Century of Success?

Edith Nutescu, PharmD, Clinical Assistant Professor, University of Illinois at Chicago College of Pharmacy, reviewed traditional anticoagulation
therapy for treatment of venous thromboembolic disease, including problems with current therapy, and she described some advantages of the newer therapies.

Unfractionated heparin came into clinical use in the late 1930s. In the 1980s, the first studies with low-molecular-weight heparins were reported, and the first drug, enoxaparin, was FDA-approved for treatment of venous thrombosis in 1998. Low-molecular-weight heparins have now become the standard of care for treatment and prophylaxis of venous thrombosis. “As we move beyond 2002, there are some newer therapies on the horizon,” said Dr. Nutescu.

In recent years, several new antithrombotic agents, both oral and parenteral, have been developed or are under development. These include the synthetic pentasaccharides with selective anti-factor Xa activity (fondaparinux), an oral direct thrombin inhibitor (ximelagatran), inhibitors of factor IXa, factor VIIa/
tissue factor complex, oral heparin, and activated protein C.

Looking at the coagulation cascade, warfarin works by inhibiting the four vitamin K-dependent clotting factors (II, VII, IX, and X). Unfractionated heparin and low-molecular-weight heparin act via a cofactor of antithrombin. Heparin then inhibits in a 1:1 ratio both factor Xa and factor IIa. Low-molecular-weight heparins are more specific for factor Xa and affect factor IIa to a limited extent. Direct Xa inhibitors mainly act on factor X. The direct thrombin inhibitors inhibit thrombin directly.

“Traditional heparin can be a fairly effective agent if dosed properly and if the right anticoagulant level is obtained within a suitable amount of time,” said Dr. Nutescu. Its limitations include side effects such as bleeding complications, thrombocytopenia, osteopenia, alopecia, and poor bioavailability. “We’re not always doing a good job of obtaining therapeutic aPTTs within the first 24 hours of therapy,” she said. Without that, the rate of recurrent venous thromboembolic events is fairly high.

Dr. Nutescu described a study by Montalescot and colleagues, which compared unfractionated heparin to low-molecular-weight heparin (either enoxaparin or nadroparin) in 200 patients undergoing valve replacement surgery (Circulation 2000;101(10):1083-6). With unfractionated heparin, on day 2 of therapy only a small percent of patients attained a therapeutic PTT. By the last day of therapy this had risen to 30%. With low-molecular-weight heparin, on the other hand, close to 90% of patients attained anti-Xa levels within the therapeutic range by day 2, which were maintained until the last day of therapy. “These agents have a more predictable pharmacokinetic profile and more predictable anticoagulant response,” said Dr. Nutescu.

Three low-molecular-weight heparins are available in the United States: enoxaparin, dalteparin, and tinzaparin. “The main advantages of low-molecular-weight heparins are due to their decreased binding to certain proteins and cells, including macrophages, platelets, osteoblasts, and endothelial cells, which results in a more predictable anticoagulant response,” she said. These agents also have better side effect profiles and a longer plasma half-life, which allows once-a-day or twice-a-day dosing. Additionally, in most patients, routine monitoring of the anticoagulant effect is not necessary.

Due to different pharmacologic and clinical properties, low-molecular-weight heparins are not interchangeable on a unit by unit basis. They need to be studied individually for every indication. The FDA-approved indications for the three agents are listed in the table.

“For longer term therapy after deep vein thrombosis or pulmonary embolism, patients are transitioned from heparin to the oral anticoagulant warfarin,” said Dr. Nutescu. Advantages of warfarin include the oral route, once-a-day dosing, availability of international normalized ratio (INR) for monitoring, same INR ranges for prophylaxis and treatment, and the reversibility of the agent.

However, it is very difficult to monitor patients who receive warfarin because of the narrow therapeutic index and the fact that there is no linear dose response relationship. Also, warfarin inhibits the natural anticoagulants protein C and protein S in addition to the four vitamin K-dependent clotting factors. “When initiating therapy, this confers a paradoxical hypercoagulable effect, therefore it is essential that patients get cross-coverage with heparin or low-
molecular-weight-heparin,” said Dr. Nutescu.

Special concerns in the elderly
Dr. Nutescu turned to a discussion of special concerns when treating elderly patients with low-molecular-weight heparin. For example, these drugs are cleared renally, and older adults tend to have decreased renal function.

“We know from pharmacokinetic studies that as clearance drops below 30 mL/min, there is a 30% to 40% accumulation of the drug,” said Dr. Nutescu. So, if a patient has creatinine clearance that drops below this level, a 30% to 40% decrease in dose may be warranted.

In conclusion, Dr. Nutescu stated that the Chest Guidelines which came out in 2001 recommend low-molecular-weight heparins over unfractionated heparin for treatment of venous thrombosis (Grade 2B recommendation). “They offer convenient once-a-day dosing and allow for transitioning patients to the outpatient setting. There is a slightly lower recurrence rate and a lower mortality rate in cancer patients with low-molecular weight-heparin.”

DVT Prophylaxis and Treatment in Long-Term Care: An Evidence-Based Approach

Roger D. Yusen, MD, MPH, Assistant Professor, Department of Medicine, Washington School of Medicine, St. Louis, Missouri, discussed the epidemiology, prevention, and treatment of deep vein thrombosis.

Simply stated, a deep vein thrombosis (DVT) is a blood clot in any vein. “If the clot breaks loose and travels into the right atrium, the right ventricle, and out the pulmonary artery, lodging in the lungs, this is a pulmonary embolism (PE),” said Dr. Yusen. If blood flow to the lung is cut off, a pulmonary infarction results. Venous thromboembolic (VTE) disease encompasses both DVT and PE.

Some patients present with fatal pulmonary embolism resulting in sudden death. “This is the tip of the iceberg,” said Dr. Yusen. Many more patients—hundreds of thousands each year—present with symptomatic DVT or PE. But in the majority of patients with clots, they are not diagnosed.
About 60,000 people die each year from PE, 10% of hospital deaths are associated with PE, and the prevalence of DVT in nursing homes is 11-fold higher than in the community. Risk factors for venous thromboembolic disease fall into three categories: 1) stasis (from congestive heart failure, cor pulmonale, immobilization, obesity); 2) hypercoag- ulability (e.g., antiphospholipid Ab, homocysteine, deficiencies in ATIII and protein C and S, factor V leiden, factor XI excess, PF20210A, cancer); and 3) endothelial injury (from sepsis, hip fracture, IV catheter, and tumor).

Without prophylaxis, almost 100% of spinal cord injury patients will develop DVT, and over half of patients having hip or knee surgery will. Medical patients are also at risk. About 55% of stroke patients have DVT as do 30% of patients in the medical ICU. Dr. Yusen noted that most hospitalized patients have at least one risk factor for DVT.

Case study
Dr. Yusen presented the case of a 45-year-old male patient who resurfaced too quickly while scuba diving and developed an air embolism, which caused dense hemiplegia and blindness. He was treated in a hyperbaric chamber and his sight returned but his motor function did not. Because he was nonambulatory and hemiplegic he was given DVT prophylaxis (unfractionated heparin, 5,000 units subcutaneously every 12 hours). On the fifth hospital day he became short of breath. He was tachycardic, tachypneic, and borderline hypotensive. His oxygen levels dropped extremely low. His EKG showed no signs of cardiac ischemia and his chest x-ray was clear.

A perfusion scan showed there was no blood flow in the entire left lung or the right upper lobe, indicating a massive pulmonary embolism. The patient underwent thrombolytic therapy and survived. Dr. Yusen raised the following questions about this case: “Was unfractionated heparin the right treatment? How long should he be treated with this drug if he’s going to be hemiplegic for months or years?”

Prophylaxis for VTE
The goals of prophylaxis are to prevent DVT, PE, and their consequences, such as death from PE, post-phlebitic syndrome, and pulmonary hypertension. It’s also important to avoid complications of the therapy, such as bleeding and heparin-induced thrombocytopenia and thrombosis.

Mechanical methods of prophylaxis include early mobilization, graduated compression stockings, intermittent pneumatic compression, and inferior vena cava filter. Pharmacologic agents include low-dose unfractionated heparins, low-molecular-weight heparins, pentasaccharides, direct thrombin inhibitors, and vitamin K antagonists.

“Prophylaxis works,” Dr. Yusen emphasized. For patients undergoing orthopedic surgery, the incidence of DVT drops from 50-64% to 30-43% with prophylaxis. Similar reductions are achieved in patients with stroke, MI, or other medical conditions.

The American College of Chest Physicians recommends low-molecular-weight heparins or unfractionated heparin for prophylaxis in medical patients, typically for the duration of the hospital stay. Dr. Yusen suggested that some patients who are chronically immobilized may benefit from extended therapy. A clinical trial is underway to examine the usefulness of extended VTE prophylaxis in medical patients with prolonged immobilization.

Treatment for VTE
“Treatment of VTE is actually prevention,” said Dr. Yusen. Prophylaxis, as described above, is about primary prevention (preventing the first clot). Treatment is aimed at secondary prevention. The goals of treatment (secondary prevention) are to prevent pulmonary embolism, extension and recurrence of the existing clot, and post-thromboembolic complications (such as post-phlebitic syndrome).

Three months after a proximal lower extremity DVT that has not been treated, about half the patients will have a recurrence and 25% will have a PE. If DVT is treated, less than 5% of patients will have a symptomatic recurrence in three months and less than 1% will have a symptomatic PE. “Treatment clearly decreases clot rates,” said Dr. Yusen. He then weighed this against possible complications of treatment. Left untreated, 0-1% of DVT patients will have a major bleed. Among patients who are treated, less than 5% will have a major bleed. “I think the benefits from therapy outweigh the risks,” said Dr Yusen.

With heparin, there is a therapeutic threshold and a therapeutic window. “You have to give enough to avoid VTE without giving too much and inducing bleeding,” said Dr. Yusen. He went on to explain that the low-molecular-weight heparins (enoxaparin, tinzaparin, and dalteparin) are as good as unfractionated heparins in medical patients with DVT, which has been demonstrated in dozens of clinical trials.

“Once you confirm that a DVT is present, initially treat with either unfractionated heparin or low-molecular-weight heparin,” said Dr. Yusen. Warfarin therapy can be started on day 1 and then adjusted using the INR. “You want about 4 or 5 days of overlap therapy and an INR of at least 2 for two days in a row,” he said. “Then you can quit unfractionated heparin or low-molecular-weight heparin and treat the patient with long-term warfarin.”

In conclusion, Dr. Yusen stated: “We need to assess patients for the cause of DVT, risk factors for recurrence, consequences of embolism, and whether they are candidates for anticoagulation. In addition, we need to set up a treatment plan, including choosing the treatment regimen (dose, route, frequency, and duration) and monitoring the therapy.”

Pharmacoeconomic Issues in Long-Term Care Using LMWH

John E. Murphy, PharmD, Professor and Head, Department of Pharmacy Practice and Science, The University of Arizona College of Pharmacy, Tucson, discussed pharmacoeconomic issues regarding the low-molecular-weight heparin enoxaparin versus unfractionated heparin.

“In a pharmacoeconomic analysis, we need to consider the impact of new products on the entire system,” he said. Pharmacoeconomics can be defined as research that compares both the costs and consequences of two or more pharmaceutical interventions. Dr. Murphy added that the pharmacoeconomic triad includes efficacy, safety, and cost.

There are several tools for pharmacoeconomic analyses. Cost minimization assumes that two drugs have equal efficacy and safety, and therefore the least expensive drug will probably be the formulary choice. A cost-effectiveness approach compares costs relative to outcomes for two or more alternatives that do not have equal effects. Cost-benefit analyses measure dollars expended against dollars gained, meaning that outcomes must be valued financially. Cost-utility analyses compare outcomes adjusted according to the patient’s quality of life.

In cost-effectiveness analysis, cost and outcomes of two or more interventions are compared to determine which is of sufficient value to adopt or reimburse. Costs are measured in physical units and valued in monetary units. Effectiveness is measured in natural units of health improvement, such as clinical outcomes measures, years of added life, or prevention of a clinical event. Resources used include direct medical costs (costs of the drug, monitoring, and treatment of adverse events), direct non-medical costs (travel, lodging) and indirect costs (changes in productivity). Examples of effectiveness measures for thrombolytic agents include reductions in chronic venous insufficiencies, incidents of minor and major bleeding, pulmonary embolism, and mortality.

Dr. Murphy described a cost-effectiveness comparison of enoxaparin to unfractionated heparin, by Gould et al. (Ann Intern Med 1999;130:789-799). They looked at probabilities for clinical outcomes from a meta-analysis they had conducted; costs were determined from Medicare reimbursements. The population was a hypothetical cohort of 60-year-olds, and the intervention was fixed dose enoxaparin compared to adjusted dose unfractionated heparin.

The perspective was societal.
The total costs for inpatient treatment were $26,516 for enoxaparin and $26,361 for unfractionated heparin, a difference of $155 in favor of unfractionated heparin. However, patients treated with enoxaparin had a reduced risk for early major bleeding complications, recurrent DVT, and death.

Dr. Murphy provided the formula for calculating the incremental cost-effectiveness ratio, which is the total cost of one therapy minus the total cost of the other therapy divided by the differences in effectiveness. The incremental cost effectiveness of enoxaparin over unfractionated therapy was $7,820 per quality-adjusted life year gained. Gould and colleagues also performed a sensitivity analysis, which tested some of the assumptions made in building the model. The sensitivity analysis varied costs and probabilities in the model along a range of conservative to liberal estimates of variation. They used the following ranges: a 6-day hospitalization costs $2,100 to $3,500; unfractionated heparin costs $9 to $15 plus $33 to $55 for supplies and ancillary resources; enoxaparin costs $63 to $105 plus $8 to $14 for supplies and ancillary resources. There was a cost saving with enoxaparin when as few as 8% of patients were treated at home. “If you can move just 8% of patients out of the hospital to home treatment, the costs were equal,” said Dr. Murphy.

A study by Witter and colleagues compared enoxaparin to unfractionated heparin for DVT in a long-term care facility versus a hospital (Consult Pharm 2000;15:151-154, 157-159). Enoxa-parin was more cost effective. “The authors found that the pharmacoeconomic analysis was robust in favor of low-molecular-weight heparin, with a large degree of change necessary before unfractionated heparin would become beneficial,” said Dr. Murphy.

A study by Devlin et al. examined enoxaparin versus low-dose heparin for prophylaxis after major trauma (Pharmacotherapy 1998;18:1335-1342). Although enoxaparin increased overall health care costs, it was associated with an incremental cost per additional life-year saved of only $2,300, which is lower than the convention for “a good use of resources” of $30,000 for each life year saved.

“When we look at disease management, we need to understand the disease course and the cost drivers,” said Dr. Murphy. “Pharmacoeconomic evaluations require estimates of both costs and outcomes to evaluate the value of therapies. Sensitivity analysis should then be used to test the robustness of the assumptions,” he concluded.

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