New insight into anticoagulation therapies

Dec 6 2004

Anticoagulation therapies, or treatments that reduce the amount of clotting factors in the blood, are quite common and used for a variety of reasons.

Typically, they are used to prevent major blood clotting complications, such as stroke and heart attack or blood clots brought on as a result of: trauma; major surgery, especially joint replacement surgery; or the presence of a mechanical heart valve. People at risk for one or more of these events are often administered a daily dose of anticoagulant medication. Anticoagulants may be administered orally, such as aspirin or warfarin, or intravenously or by subcutaneous injection (just under the skin), such as heparin and low-molecular-weight heparin (LMWH).

Despite improvements and standardization in the use of anticoagulants, many problems remain for clinicians. Two studies presented during the 46th Annual Meeting of the American Society of Hematology (ASH) help shed some light on anticoagulation therapy and add to the increasing knowledge necessary for the most effective application of this complex therapy.

"Millions of people successfully use anticoagulants every day, and several thousands of lives have been saved," said James George, M.D., President-Elect of the American Society of Hematology and Professor of Medicine at the University of Oklahoma Health Sciences Center, Oklahoma City. "However, there are a number of special populations that need to be cautious about the use of these treatments and need to be educated about how to properly take anticoagulants with other therapies."

Enoxaparin is Effective and Safe as Bridging Anticoagulation in Patients with a Mechanical Prosthetic Heart Valve Who Require Temporary Interruption of Warfarin Because of Surgery or an Invasive Procedure

People with severely damaged heart valves, which are prone to disease and malfunction, may have them replaced with prosthetic heart valves; too often, the body recognizes the prosthetics as foreign and attempts to protect itself from the invasion. As a result of this response, blood clots may form and cause serious problems if they travel to other parts of the body and become lodged in a blood vessel. To help counteract this problem, people with mechanical heart valves are often prescribed long-term warfarin, the most common oral-anticoagulation therapy, which reduces the amount of clotting factors in the blood, decreasing the incidence of blood clots. Warfarin is an oral anticoagulant that decreases the clotting ability of the blood and therefore helps to prevent harmful clots from forming in the blood vessels; it is more commonly known as a "blood thinner."

When patients on this maintenance therapy elect to undergo surgery or an invasive procedure of any type, they are at risk for a major bleeding event due to the warfarin therapy. It is standard procedure, therefore, to discontinue the warfarin and treat patients with enoxaparin (a low-molecular- weight heparin that is widely used in patients with acute coronary syndrome and venous thromboembolism) several days prior to the procedure and then resume the use of warfarin after the procedure. This is because the anticoagulant effect of enoxaparin is shorter than warfarin and therefore it can be adjusted to prevent excessive bleeding from the surgery. However, there is concern about enoxaparin's use in patients with mechanical prosthetic heart valves because of recent reports of fatal thromboembolism occurring in pregnant women with mechanical heart valves who received long-term enoxaparin therapy instead of warfarin, during pregnancy.

Researchers at McMaster University, Ontario, Canada, conducted a prospective study to assess the efficacy and safety of enoxaparin as a bridging anticoagulation therapy in patients with a mechanical prosthetic heart valve who require temporary interruption of warfarin therapy because of an elective surgical or other invasive procedure.

Results showed that enoxaparin appears to be effective and safe as a bridging anticoagulation therapy in patients with a mechanical prosthetic heart valve who require temporary interruption of warfarin therapy. After three months of clinical follow-up, only four patients developed non-fatal major bleeding events, one patient had a non-fatal stroke, and four patients died due to non-drug-related serious adverse events.

One hundred and seventy-four patients enrolled in this trial had warfarin interruption and bridging anticoagulation with subcutaneous enoxaparin, one mg/kg twice daily, and underwent clinical follow-up for three months after surgery. No patient was lost to follow-up. The incidence of major bleeding events, arterial thromboembolic events (such as stroke, transient ischemic attack, systemic embolism, valve thrombosis), and all-cause death were measured outcomes for this study. Warfarin therapy was resumed on the evening of or the day after the procedure.

Researchers concluded that enoxaparin is a practical approach to anticoagulant bridging in mechanical heart valve patients resulting in a low rate of bleeding and very low rates of thromboembolism. Patients who need to undergo anticoagulation bridging therapy, a standard medical practice with inherent risks now have a safe option available."

Effect of Non-Steroidal Anti-Inflammatory Drugs and COX-2 Inhibitors on Aspirin-Induced Platelet Inhibition

Low-dose aspirin is commonly used to reduce the risk of heart attack, stroke or sudden cardiac death for patients with heart disease. Aspirin is known to inhibit platelet aggregation and has become the foundation of preventive therapy for cardiovascular disease, used by an estimated 20 to 30 million Americans every day.

Aspirin inhibits platelet activation and aggregation through the COX-1 pathway that is responsible for conversion of arachidonic acid to thromboxane, a mediator of platelet aggregation. The benefits of aspirin, however, may be affected by short-term use of other drugs such as non-steroidal anti- inflammatory drugs (NSAIDs) and COX-2 inhibitors.

Researchers from Baylor College of Medicine, University of Texas Southwestern Medical Center, Houston Institute of Medical Research, and McNeil Consumer & Specialty Pharmaceuticals investigated the effects of acetaminophen, over-the-counter NSAIDs and COX-2 inhibitors on arachidonic acid induced platelet aggregation and thromboxane B(2) production. Eighty- seven healthy individuals were enrolled in the trial and given low-dose aspirin (81 mg) daily for eight days. Two hours after aspirin was administered, subjects received one of the following drugs: acetaminophen, ibuprofen, naproxen sodium, a higher dose of aspirin (2,600 mg), celecoxib, or rofecoxib. Control individuals received only low-dose aspirin (81 mg). Blood tests were performed before treatment and two, six, 12, and 24 hours after initial dosing on the first and eighth day of dosing. Platelet function was measured by arachidonic acid induced platelet aggregation and serum levels of thromboxane B(2).

Results showed that platelet inhibition occurred in 24 hours after initial aspirin (81 mg aspirin) dosing. It was observed at as early as six hours when aspirin was administered in combination with either ibuprofen or naproxen. In contrast, individuals receiving acetaminophen and the two COX-2 inhibitors did not appear to experience accelerated platelet inhibition. Consistent with aggregation studies, the inhibition of thromboxane B(2) production was accelerated for aspirin combined with ibuprofen or naproxen, but not for acetaminophen, celecoxib, and rofecoxib.

"It is important to discuss any potential side effects from concomitant drug use with your physician before taking any new drug, because, as our results and previous studies show, the order in which you take multiple drugs and the combined effects of two or more medications may aggravate or accelerate a given drug's desired effect," warns Jing-fei Dong, M.D., Ph.D., Associate Professor of Medicine, Baylor College of Medicine, and lead investigator of the study. "Without careful monitoring, a patient can suffer serious consequences."