Prevention of Thromboembolism: Is There Hope?
Abstract & Commentary
By Dara G. Jamieson, MD Associate Professor of Clinical Neurology, Department of Neurology and Neuroscience, Weill Medical College, Cornell University Dr. Jamieson reports that she is a retained consultant for Boehringer Ingelheim, Merck, and Ortho-McNeil; and that she is on the speaker's bureau for Boehringer Ingelheim and Merck.
Synopsis: Anticoagulation for the prevention of venous thromboembolization is underutilized worldwide. Risk of short-term interruption of warfarin therapy appears small. Treatment with idraparinux increases hemorrhage risk, as compared with vitamin K antagonists.
Sources: Cohen AT, et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE) study: a multinational cross-sectional study. Lancet 2008;371:387-394; The Amadeus Investigators. Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomized, open-label, non-inferiority trial. Lancet 2008;371:315-321; Garcia DA, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med 2008;168:63-69.
Prevention of clotting in persons at risk of arterial or venous thromboembolism is imperfect and fraught with the hazard of hemorrhage. These three recently published articles evaluate the prevalence of thrombotic risk in the acute hospital setting, the risk of interruption of chronic anticoagulation, and the efficacy and safety of a new agent for chronic anticoagulation. The articles demonstrate the difficulty of implementing and maintaining appropriate anticoagulation without risk of either a breakthrough ischemic event or a hemorrhagic complication.
Even transient causes of immobility, such as the middle seat on a transatlantic red-eye flight or bed rest after orthopedic surgery, may result in venous thrombosis with risk of embolization to the lungs or brain. Venous thromboembolism (VTE) during hospitalization for acute medical or surgical illness is the most common preventable cause of in-hospital death. Despite the clear risk, guidelines for VTE prophylaxis often are not observed.
The investigators for the multinational, observational, cross-sectional "Epidemiologic International Day for the Evaluation of Patients at Risk for Venous Thromboembolism in the Acute Hospital Care Setting" (ENDORSE) study did a chart audit of medical and surgical patients in 358 hospitals in 32 countries. The investigators evaluated the various countries' adherence to the American College of Chest Physicians (ACCP) guidelines for anticoagulant prophylaxis that were published in Chest in 2004 for the 35,329 patients found to be at risk for VTE. While about 10% of at-risk patients were not treated because of justifiable contraindications, only about 50% of all patients at risk for VTE received ACCP-recommended prophylaxis. Orthopedic surgery patients were more likely than medical patients to be given appropriate prophylaxis. Only 37% of patients with active malignancy or ischemic stroke received proper prophylaxis. Adherence to ACCP guidelines ranged widely by country, with high percentages (approximately 60-90%) of medical and surgical patients appropriately treated in Germany and Switzerland and very low percentages (less than 5%) treated in Bangladesh and Thailand. The percentage of compliance often varied widely between medical and surgical patients. In the United States, 48% of at-risk medical and 71% of at-risk surgical patients received ACCP-recommended prophylaxis. Globally, including in the United States, a large proportion of hospitalized patients are at risk for VTE and recommended prophylaxis is underutilized.
Non-valvular atrial fibrillation (AF) is the leading cause of cardioembolic ischemic stroke. Most patients with AF are chronically treated with the vitamin K antagonist warfarin to decrease the risk of ischemic stroke. However the necessary dose adjustments and frequent monitoring, along with the not-insignificant risk of hemorrhagic complications, limits the use of warfarin, especially in the elderly or infirm. The Amadeus Investigators compared the efficacy and safety of idraparinux, a synthetic inhibitor of activated factor X, in a randomized, open-label, non-inferiority trial in patients with AF. Patients were randomized to receive either subcutaneous idraparinux (2.5 mg weekly) or vitamin K antagonists (warfarin or acenocoumarol), with a target INR of 2-3. With a mean follow-up period of less than a year, after approximately 2300 patients were randomized into each arm, the study was prematurely terminated because of an excess of clinically relevant bleeding in the subcutaneous idraparinux group. Treatment with subcutaneous idraparinux satisfied the non-inferiority criteria for efficacy as compared to vitamin K antagonists; however, treatment also was associated with a statistically significant increased risk of intracranial bleeding. Renal insufficiency and advanced age were associated with an elevated risk of hemorrhage with idraparinux.
Although warfarin remains the standard therapy for chronic anticoagulation, its use poses risk for patients who need an elective procedure or minor surgery. Continuing anticoagulation through the procedure risks bleeding, but interruption of therapy may result in thrombosis. If the possibility of thromboembolism is low, warfarin therapy may be withheld up to a week with minimal danger. However, ischemic stroke occurring after an anticoagulation hiatus is not uncommon. Bridging the interruption of warfarin with a short-acting anticoagulant, such as unfractionated heparin or low-molecular-weight heparin, may decrease the ischemic stroke risk, but adds to the cost and complexity of the procedure.
Garcia and colleagues performed a prospective, observational cohort study of patients whose warfarin therapy was temporarily withheld for an outpatient invasive procedure. In the 1024 individuals, generally at low to intermediate thromboembolic risk, from 101 sites in the United States, the most common indications for anticoagulation therapy were AF, VTE, or mechanical heart valve. The most common reasons for interruption of therapy were colonoscopy and oral and ophthalmic surgeries. Periprocedural bridging therapy was only used in around 8% of cases overall, and was more often associated with prosthetic valves than with AF. Seven patients, none with bridging, sustained 4 arterial and 3 venous thromboembolic events in the 30-day post procedural period. While 85% of the interruptions of therapy were for < 5 days, a longer interval was associated with an increased thromboembolic risk. Bleeding, both major (6 patients) and non-major (17 patients), occurred in the 30-day post-procedural period; 14 of these 23 patients received periprocedural heparin or low-molecular-weight heparin. With interruption of therapy in patients at low to intermediate thromboembolic risk, the risk of periprocedural bleeding from bridging therapy must be weighed against the likelihood of thromboembolism.
Commentary
Patients who are at risk of arterial or venous thromboembolism present challenges to physicians of multiple specialties. While high-dose anticoagulation may be temporarily suspended prior to surgery, low-dose prophylaxis against VTE should be standard for most immobilized post-operative patients, as well as for immobilized medical patients. The ACCP recommends that prophylactic low-dose subcutaneous heparin or low-molecular-weight heparins or heparinoids be used for the prevention of deep vein thrombosis and pulmonary emboli in patients with restricted mobility. Unfortunately, observance of these guidelines in the United States lags behind other countries. Unintentional oversight and unwarranted fear of bleeding decreases compliance with the recommendations and increases the risk of hospitalization of bed-bound patients. Stricter adherence to these guidelines should reduce the mortality and morbidity due to thromboembolism in hospitalized patients.
Temporary interruption of anticoagulation portends a period of peril for patients who are at risk of thromboembolism; however, with bridging therapy, risk may cross from an ischemic event to a hemorrhagic event. Discontinuation of anticoagulation for up to 5 days seems to confer minimal risk; however, unexpected periprocedural complications that prolong the break in therapy may increase thromboembolic risk.
As baby boomers age, their risk of AF and resultant arterial thromboembolism is increasing and cardioembolic stroke is becoming more prevalent. Options for chronic anticoagulation are currently limited and fraught with hazard. The chronic use of idraparinux as a substitute for warfarin is unlikely because of excess bleeding. The disappointing results with antagonists of activated factor X increases the interest in other alternatives to vitamin K antagonists including oral direct thrombin inhibitors, currently under investigation. The ongoing Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial comparing the efficacy and safety of two blinded doses of dabigatran with open label warfarin for the prevention of stroke and systemic embolism in patients with non-valvular AF may offer an alternative to customary treatment of these patients.
For now however, no tenable alternative to long-term warfarin anticoagulation has shown equivalent efficacy and safety. More assiduous observance of VTE prophylaxis guidelines and the continuing search for alternatives to warfarin should decrease the major morbidity and mortality associated with arterial and venous thromboembolism. While the results of current investigation may be disappointing, there is hope for improved prevention of thromboembolism in the future.
Anticoagulation for the prevention of venous thromboembolization is underutilized worldwide. Risk of short-term interruption of warfarin therapy appears small. Treatment with idraparinux increases hemorrhage risk, as compared with vitamin K antagonists.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content