Anticoagulation in Long-Term Care

Author Affiliations: Dr. Jacobs is Professor of Clinical Medicine & Division Chief, Geriatrics, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY.

Abstract: Although anticoagulants have been a part of the medical armamentarium for more than 50 years, their use is complex, and new agents and regimens are being added. It is critically important that each facility consider the issues surrounding the use of anticoagulants in LTC settings, as these agents have significant risks and benefits, and are in frequent use. Monitoring of anticoagulants is a frequent area of error and adverse outcomes in the LTC setting. Policies and procedures should address drug administration; bedside monitoring for bleeding by nurses and aides; policy recommendations for the minimum frequency of laboratory monitoring, if required; and administrative systems for obtaining laboratory monitoring in a timely fashion, including obtaining and reporting of laboratory testing results to the facility and to the physicians in a timely manner. (Annals of Long-Term Care: Clinical Care and Aging 2009;17[1]:34-38)
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Introduction
A recent study of adverse events with warfarin use in long-term care (LTC) residents highlights several important issues for anticoagulant use in nursing homes in general.¹ The rate of serious, life-threatening, or fatal events was 2.49 per 100 resident-months, and 57% of these events were considered preventable. Twenty-nine percent of all of the adverse events identified may have been prevented, and most were related to prescribing and monitoring, such as incorrect dosing, a known drug interaction, insufficient monitoring, or a delayed or no response to test results.

Anticoagulants inhibit both venous and arterial thromboses, which is the incipient event in many cardiovascular diseases. They are frequently prescribed for older adults in the acute care and LTC settings. Although anticoagulants have been a part of the medical armamentarium for more than 50 years, their use is complex, and new agents and regimens are being added.

Clot Formation and the Coagulation Pathways
The incidence of both venous and arterial thromboses increases significantly with age.² Clot formation (and dissolution) is a carefully regulated cascade of events initiated when tissue factor is generated or exposed at a site of injury. In the high-pressure arterial system, atherosclerotic plaque rupture exposes a thrombogenic lipid core to which platelets adhere, activate, and aggregate, to form a platelet plug. Clot formation is further propagated by activation of the coagulation cascade. Venous clots occur in low-flow sites and are predominantly comprised of fibrin, the final product of the coagulation cascade, and red cells, in contrast to the platelet core of arterial clots. Other agents that are used to prevent clotting, but are not anticoagulants, include antiplatelet agents such as aspirin and clopidogrel, and thrombolytic agents.

Clotting or coagulation factors are precursor proteins or proenzymes, which become activated as the cascade proceeds. Classically, the coagulation sequence is separated into the “intrinsic” and “extrinsic” pathways, although this may not be the actual sequence of events in vivo. Both result in a final common pathway in which factor Xa mediates the conversion of prothrombin to thrombin (factor IIa). Factor Xa catalyzes the formation of fibrin from fibrinogen, as well as activating other clotting factors through feedback mechanisms. Fibrin reinforces the platelet plug. Anticoagulant agents used in clinical practice act either indirectly through a plasma cofactor, such as the heparins, or directly interfere with the action of thrombin (IIa).

Heparins, Low-Molecular-Weight Heparins, and Pentasaccharides

Pharmacology
Heparin is found in animal tissue and is composed of a mixture of long chains of glycosaminoglycans. A specific five-sugar (pentasaccharide) sequence of heparin binds to antithrombin (AT). The heparin-AT complex binds and inhibits serine protease coagulation factors, particularly thrombin (IIa) and Xa, although to inhibit thrombin, the heparin chain must contain about 18 saccharide units to span the thrombin-AT complex. In contrast, the ability of the heparin-AT complex to inhibit factor Xa is not dependent on chain length. Unfractionated heparin inhibits thrombin and Xa in equal amounts.

Low-molecular-weight heparins (LMWHs)—enoxaparin, dalteparin, and tinzaparin—are derived from heparin by enzymatic or chemical degradation and have shorter chain lengths, which do not bind to thrombin efficiently. LMWH inhibits Xa to thrombin in a 3:1 or 4:1 ratio as a result (the three LMWHs differ somewhat). The pentasaccharide sequence responsible for AT binding has been synthesized to produce a potent anticoagulant, fondaparinux, which is too small to bind to thrombin; its anticoagulant action is only against factor Xa.

The glycosaminoglycan chains of unfractionated heparin bind to other plasma proteins, endothelial cells, and platelet factor 4, as well as inhibiting osteoblast formation and activating osteoclasts. This nonspecific binding is the cause of pharmacokinetic unpredictability in its anticoagulant effect and mandates the need for close monitoring (with the active partial thromboplastin time [aPTT]). LMWH does not exhibit this extent of nonspecific binding and has more predictable kinetics so that monitoring is not required. For special circumstances, factor Xa levels are used. Fondaparinux does not require monitoring either.

Dosing and Administration
Unfractionated heparin is administered intravenously or parenterally. For venous thromboembolic prophylaxis, the dosage is usually 5000 U subcutaneously every 8 hours.³ Treatment dosing is ultimately based on results from monitoring. Initial dosing⁴ is estimated based upon weight. For treatment of venous thromboembolism, an 80 U/kg initial bolus is followed by an 18 U/kg/h infusion. Fixed-dose weight-adjusted subcutaneous dosing of unfractionated heparin can also be used for acute treatment of venous thromboembolism.^5,6

LMWHs are administered subcutaneously in fixed or body-weight–adjusted doses once or twice daily for prophylaxis or treatment. Clearance is inversely related to chain length. The half-life of unfractionated heparin is approximately 1 hour following an intravenous bolus, and longer with subcutaneous administration. LMWH excretion is much slower, allowing less frequent dosing, due to the shorter chain length. For patients with significant renal insufficiency (Cr Cl £ 30 mL/min), LMWH is not usually recommended. Fondaparinux is administered subcutaneously as well, reaching peak plasma levels in 2 hours. It has a 17-hour half-life due to its small size, allowing once-daily dosing.⁷ Caution is required with elderly patients with renal insufficiency.

The most important adverse effect of these agents is bleeding. However, heparin is also associated with an immune-mediated thrombocytopenia (type II heparin-induced thrombocytopenia [HIT]), in which IgG-antibody to platelets begins as an antibody directed against the complex of heparin and platelet factor 4. HIT is a growing concern in acute and LTC settings since patients are more frequently being exposed to heparin. HIT is associated with significant morbidity from arterial and venous thromboses. Although benign nonimmune thrombocytopenia (type I) occurs more frequently, HIT should be suspected in patients in whom the platelet count falls by greater than 50% within 5 to 14 days of initiating heparin, or in patients presenting with thromboses who have recently been treated with heparin. HIT occurs less often with LMWHs, perhaps due to reduced binding to platelet factor 4, and does not occur with fondaparinux.

Monitoring platelet counts every other day until day 14, or until therapy is discontinued, is recommended for patients receiving therapeutic doses of unfractionated heparin.⁸ For those restarting unfractionated heparin within 100 days of prior treatment, a platelet count should be obtained prior to treatment and repeated after 24 hours. No monitoring is required for LMWH if the use of unfractionated heparin has not preceded it.

Monitoring and Reversal
Anticoagulant agents are designed to interfere with the synthesis or activity of clotting factors to disrupt thrombosis. Some of these agents may be monitored by use of the intrinsic and extrinsic pathways, or specific factor levels. The aPTT test uses the intrinsic pathway and is used to monitor unfractionated heparin; the therapeutic range is 1.5 to 2.5 times the control result based upon a historic study. The aPTT is usually obtained 6 hours after the therapy is begun and the heparin infusion adjusted. It is critical for both efficacy and safety that therapeutic levels be achieved quickly. When intravenous unfractionated heparin is used to treat an acute venous thromboembolism, the risk of recurrence is greatly increased for those who have not achieved a therapeutic aPTT level within 24 hours.^9,10

Reversal of the anticoagulant effects of heparin may be required for a procedure or in the event of bleeding, whether or not the dosage is therapeutic. This can be achieved by discontinuation and obtaining an aPTT after 4-6 hours to determine whether normal clotting has been reinstated. If clinically significant bleeding is present, immediate reversal can be achieved with the use of protamine, support of the patient with transfusion, fluid support, and other interventions. Protamine must be infused slowly because it can be associated with severe adverse reactions such as hypotension or bradycardia. LMWHs cannot easily be monitored. Normal coagulation will resume more slowly with discontinuation of LMWH, and particularly fondaparinux, due to slower excretion. No agent is available to rapidly reverse the activity of these agents, other than support with transfusions and fresh frozen plasma.

Vitamin K Antagonists: Warfarin

Warfarin remains the most widely used anticoagulant agent in the United States, largely due to the ability to administer it orally, despite its many drug interactions, challenges in dosing, narrow therapeutic index, and requirement for close monitoring.

Pharmacology
Warfarin inhibits the vitamin K-induced g-carboxylation of coagulation factors II (prothrombin), VII, IX, and X, and endogenous anticoagulant proteins C, S, and Z. Its antithrombotic effect is thought to be most dependent on the reduction of factors II and X. Warfarin is a racemic mixture of R and S enantiomers (greater intrinsic activity), is easily absorbed with peak concentration within 4 hours, and is approximately 99% plasma protein-bound. S-warfarin is metabolized stereoselectively by the hepatic microsomal enzymes CYP2C9, which have several variants, as does the vitamin K epoxide reductase (VKORC1) gene, which are associated with variations in warfarin sensitivity. Warfarin has an effective half-life of 40 hours.

Drug interactions¹¹ may occur through dietary intake of vitamin K, liver disease, smoking, comorbid disease, and the use of other medications by changes in liver metabolism, and for antibiotics, by affecting the vitamin K2 production by intestinal flora, in addition to other less frequent mechanisms. The timing and intensity of these interactions is not clearly predictable. Vitamin K intake may occur through dietary supplement drinks or chewables, or through dietary changes which can, if not taken on a regular basis, cause perturbations in the international normalized ratio (INR).

Dosing
Warfarin’s anticoagulant and antithrombotic effects require several days to achieve due to the long half-life of some of the critical vitamin K-dependent clotting factors. Thus, if anticoagulation is required immediately, heparin or LMWH should be used simultaneously until the warfarin is therapeutic for 24 hours. There is evidence of a pharmacodynamic increase in activity with age such that older adults require a lower dosage. For elderly patients, an initial dose of 5 mg or less is recommended.

In a study of dosage by age, the average dose for patients age 75-84 years was 4.0 mg of warfarin to maintain the INR in the therapeutic range (INR of 2-3), and for those age 85 years and older, it was 3.5 mg.¹² Several practical suggestions can be made about warfarin dosing. Dosages should be altered if two consecutive INR results are more than 0.3 above/below the target level, or if the INR is substantially out of range (> 0.4 points). The dosage should be adjusted by 5% to 20% of the weekly total dose. Consistent daily dosing is preferable. Warfarin is available as 1-mg, 2-mg, 2.5-mg, 3-mg, 4-mg, 5-mg, 6-mg, 7.5-mg, and 10-mg tablets. If the INR varies considerably and is not due to other factors, the influence of dietary vitamin K can be blunted with administration of 100-200 µg of supplemental vitamin K.

Monitoring and Reversal
Thromboplastin, a tissue-like factor, is used in the prothrombin time (PT) test to measure the activity of the extrinsic pathway proteins. As the activity of thromboplastins varies across laboratories, INR was developed as a standardized method, and is calculated from the PT, used as the test to monitor warfarin. The method of monitoring, either serum INR or a point-of-care fingerstick, should be consistent because the results may vary between these methods.

A therapeutic range of INR for each indication, usually 2-3 except for some mechanical prosthetic valve use (where it is 2.5-3.5), has been established by widely accepted guidelines.¹³ For many indications, efficacy is reduced when the INR falls below 2.0 so that “low-intensity” therapy is not recommended. The risk of bleeding begins to increase exponentially in patients in whom the INR is above 4.0,¹⁴ leading to the upper limit for therapeutic range recommendations.

INR monitoring should be done at initiation of therapy, then daily or every few days, until a therapeutic INR has been achieved. Monitoring is done frequently thereafter until the therapeutic INR appears sustained, which usually occurs within 5-7 days, after which an INR can be obtained weekly, then biweekly, and, finally, no less often than every 4 weeks for patients who are relatively well-controlled with regard to variability in INR results.¹³

Guidelines for management of over-anticoagulation of warfarin are based upon consensus.¹³ Options for reversal, in order of intensity, include withholding warfarin therapy, administration of vitamin K, fresh frozen plasma, or factor concentrates. For patients with a supratherapeutic INR below 5, without bleeding, the dose of warfarin may be reduced or withheld until the INR has fallen to within the therapeutic range, which may take 3 to 5 days. For patients without bleeding and an INR of 5 or greater, but less than 9, omit one to two doses, monitor more frequently, and resume therapy at a lower dosage; or alternatively, omit a dose and administer vitamin K1 to 2.5 mg orally. Vitamin K is usually available as 5-mg scored tablets. For patients without bleeding and an INR above 9, 5-10 mg of vitamin K is usually required. Oral vitamin K is fat-soluble, readily absorbed, and preferred to subcutaneous administration. It will begin to correct the INR within several hours but will not be completely effective until 24 hours.

Direct Thrombin Inhibitors: Lepirudin, Bivalirudin, and Argatroban, and New Anticoagulants

The direct thrombin inhibitors interact directly with thrombin, do not exhibit the nonspecific binding to plasma proteins seen with heparin, and do not appear to be associated with immune thrombocytopenia. They are useful when anticoagulant therapy is indicated in a patient with HIT. Currently, three direct thrombin inhibitors are approved for use: lepirudin, bivalirudin, and argatroban, all of which are parenterally administered. Dosing and monitoring is complex and is usually done in the acute care setting, often by a specialist. Several new anticoagulants, including oral agents, are currently under development or in clinical trials. This includes indirect agents that act through antithrombin and direct agents acting upon factors IXa, Xa, and thrombin.

Indications for Anticoagulation Therapy  

Warfarin is usually the anticoagulant used for chronic therapy in arterial disease to prevent thromboembolization for the following: (1) atrial fibrillation (target INR, 2.5); (2) the first 12 hours in an acute ST-elevation myocardial infarction (target INR, 2.5); (3) rheumatic mitral valve disease with a history of systemic embolization, atrial fibrillation, or a left atrial diameter greater than 5.5 cm (target INR, 2.5); (4) porcine valves when atrial fibrillation is present or for the first 3 months after placement (target INR, 2.5); and (5) prosthetic mechanical valves (bileaflet or Medtronic [target INR, 2.5]), mitral position tilting disk, bileaflet tilting disk, or caged ball or disk (target INR, 3.0).

For venous disease, anticoagulants can be used for primary and secondary prevention of venous thromboembolic disease—deep venous thrombosis (DVT) and pulmonary embolism (PE). Primary prevention may be considered in high-risk patients, including postoperatively for those with total hip or knee replacement or hip fracture surgery, for up to 35 days; other postoperative surgical patients; patients with stroke with a hemiparesis; patients with cancer; and acutely ill medical patients with severe respiratory disease, infections, heart failure exacerbations, or who have become bedfast acutely. The need for anticoagulant prophylaxis is not usually ongoing in these patients. Anticoagulants are also used to prevent secondary thromboembolic events in patients with a current DVT or PE. In these circumstances, treatment duration varies from 3 months at a minimum to ongoing treatment, with a target INR of 2.5 if warfarin is used.

Anticoagulation Policies and Procedures in LTC
It is critically important that each facility consider the issues surrounding the use of anticoagulants in LTC settings, as these agents have significant risks and benefits, and are in frequent use. The development of policies and procedures should involve all departments: nursing, the medical director and medical staff, pharmacy, and administrative. Strategies for anticoagulant prescribing, monitoring, and the education and training of staff to understand the action of these agents and recognize high-risk situations and bleeding must be developed.

Policies should include procedures for patients admitted on anticoagulants and for those who initiate therapy in the facility. An institutional policy regarding prophylaxis for DVT should also be in place, to assess patients on admission and with significant changes in clinical status, particularly for postoperative patients transferred to the facility and others at high risk. These policies and procedures are often reviewed during Medicare surveys, when the care of a patient on an anticoagulant is examined. Policies should address expectations for documentation in the medical record, including the indication for therapy, dosing orders, expected duration of therapy, monitoring plan, and desired therapeutic range (if appropriate). One method to achieve this is to use a standard form and flow sheet. Materials and information are available from the American Medical Directors Association (www.amda.com). Anticoagulant prescriptions should be carefully reviewed by nursing staff. In addition, a timely and careful review by pharmacists is also essential. Medication review should include indication, dosing, potential drug interactions, the monitoring plan, duration, and whether the laboratory testing indicates that the drug is in therapeutic range.

Monitoring of anticoagulants is a frequent area of error and adverse outcomes in the LTC setting. Policies and procedures should address drug administration; bedside monitoring for bleeding by nurses and aides; policy recommendations for the minimum frequency of laboratory monitoring, if required; and administrative systems for obtaining laboratory monitoring in a timely fashion, including obtaining and reporting of laboratory testing results to the facility and to the physicians in a timely manner.

Finally, the entire staff requires education and training to understand the action of these agents, to recognize high-risk situations and bleeding. The nurses and aides must understand that signs of bleeding or risk, including the ability to identify ecchymosis, which may indicate a high intensity of anticoagulation; petechiae, as a sign of low platelet counts associated with heparin use; and black stools and melena as an indication of upper-gastrointestinal bleeding.

The author has been on the speakers’ bureau for Sanofi-Aventis.