20.2 Anticoagulants

Heparin

Heparin is an injectable anticoagulant used primarily in the hospital setting. It is FDA approved for the treatment and prevention of thromboembolism. Heparin works by inactivating clotting factors in the coagulation cascade. It binds to antithrombin and the complex inactivates IIa (thrombin), Xa, IXa, XIa, and XIIa. Heparin is primarily administered via an intravenous or subcutaneous route. Subcutaneous use is limited because the absorption by that route is erratic and the bioavailability, or amount of drug that makes it into systemic circulation, is low. The dosing for heparin is complicated. For treatment of a thromboembolism, it is typically given as a weight-based continuous infusion that is titrated based on client response. Response is measured using either the PTT or anti-Xa level, depending on the institutional protocol.

The goal level of heparin varies based on the institution, indication, and client-specific doses. The goal level typically corresponds to 1.5–2.5 times the baseline PTT. Typically, monitoring of the anti-Xa level or PTT level is completed every 6 hours during an infusion. If the PTT or anti-Xa level is lower than the goal, it is described as subtherapeutic, meaning the blood is “too thick.” In this situation, a bolus dose may be given and/or the infusion rate increased with subsequent monitoring. If the PTT or anti-Xa level is higher than the goal, it is described as supratherapeutic, meaning the blood is “too thin.” The infusion may be held for a period of time and/or the infusion rate decreased. Some institutions have protocols for nurse-driven management of heparin. In these protocols, the nurse monitors the PTT or anti-Xa level as directed in the protocol, then adjusts the dose as directed without a new order from the provider.

An example of a heparin dosing protocol is shown in Table 20.1, utilizing PTT monitoring and potential dose adjustment every 6 hours.

Heparin can also be monitored using the ACT, although less frequently. This is typically limited to monitoring during procedures and surgeries by a point-of-care device. It allows for quick fine-tuning of the heparin dosage in real time.

If long-term anticoagulation is needed, an oral anticoagulant is usually started. The transition to oral anticoagulation depends on the agent being initiated. For example, warfarin takes several days to achieve therapeutic anticoagulation, so overlap with a parenteral agent (e.g., continuation of heparin or initiation of enoxaparin) is warranted until then. Other chronic agents may take action immediately; thus, heparin can be discontinued without overlap.

Heparin-induced thrombocytopenia (HIT) is a rare although major complication of heparin therapy. It is characterized by an immune-mediated decrease in platelets, often with concomitant thrombosis. Although the platelets are decreased, the client is in a highly hypercoagulable state. Heparin must be discontinued immediately, and alternative anticoagulation with a non-heparin-based anticoagulant is required. Argatroban, an intravenous direct thrombin inhibitor anticoagulant, is FDA approved to treat HIT. Bivalirudin is another intravenous direct thrombin inhibitor anticoagulant that has been studied for off-label use in treating clients with HIT. After the acute phase of HIT, clients can be transitioned to a long-term oral or subcutaneous non-heparin anticoagulant. Clients with a history of HIT should not receive heparin in the future. Other adverse effects of heparin include hyperkalemia and osteoporosis with prolonged use.

Enoxaparin

Enoxaparin is a derivative of heparin and is referred to as a low molecular weight heparin. It is FDA approved to treat thromboembolism and acute coronary syndromes. It is also approved to decrease the rate of thromboembolism after surgery and during prolonged immobilization. It works similarly to heparin; however, it targets factor Xa specifically. Enoxaparin can be administered intravenously and subcutaneously. A major advantage to using enoxaparin as compared to heparin is that it has more reliable subcutaneous absorption and a longer half-life; thus, it can more reliably be administered as an intermittent subcutaneous injection without continuous titration. It can be self-administrated by the client at home using a pre-filled syringe. Under most circumstances, specific monitoring is not required. A major disadvantage of enoxaparin is that it is eliminated by the kidneys and therefore the dose must be adjusted or the drug must be avoided in those with kidney dysfunction. Although enoxaparin can cause HIT, the incidence is less than therapy with heparin.

As enoxaparin can be self-administered by the client, there are many client education points to emphasize with its use. The client should:

• Learn appropriate injection technique. The manufacturer for Lovenox provides a client-education video for injection. The product labeling also includes pictorial representations of injection technique.
• Inject into subcutaneous abdomen and alternate injection sites between the left and right anterolateral and left and right posterolateral abdominal wall.
• Inject into a skin fold held between the thumb and forefinger, holding the skin fold throughout the injection.
• Avoid injecting through clothing or into skin that is bruised or scarred.
• Avoid ejecting the air bubble from the syringe.
• Avoid rubbing the injection site after administration.

Warfarin

Warfarin is an oral anticoagulant that is FDA approved to treat and prevent thromboembolism disorders. Warfarin inhibits the production of vitamin K in the body. Vitamin K is needed for production of clotting factors II, VII, IX, and X. When warfarin is administered, the production of those clotting factors is decreased, which leads to an anticoagulated state. It is available as an oral tablet in many strengths to allow for individualized dosing. Each tablet of the same dose is the same color regardless of manufacturer. For example, all warfarin 1 mg tablets are pink. (For more information, see this online chart of standard warfarin tablet colors and strengths. Dosing of warfarin is individualized, variable, and complicated by pharmacokinetic properties and food and drug interactions. Doses are titrated based on INR. The therapeutic goal INR varies per indication but is usually 2–3. Some clients with mechanical heart valves have an INR goal of 2.5–3.5. Clients are typically started on anywhere from 1–10 mg of warfarin depending on client-specific factors including genetic polymorphisms, if known. The full effect of warfarin is not apparent until 5–7 days after administration; thus, dose adjustments based on INR are limited before that time frame. Warfarin also has a long half-life, and effects can persist for 5 or more days after discontinuation. Many clients who take warfarin attend clinics that specialize in warfarin dose adjustments. For most clients, the INR is monitored frequently during initiation and during any lifestyle or medication changes.

Warfarin has numerous drug and food interactions. Drugs interacting with warfarin can cause an increase in bleeding risk via effects on the metabolism of warfarin through the cytochrome P450 enzyme or through a decrease in production of vitamin K. Some notable interacting drugs/drug classes are listed in Table 20.3; however, this list is not inclusive and merely points out a few examples. It is important for clients who take warfarin to maintain a consistent amount of vitamin K intake. Since warfarin decreases vitamin K production, dietary intake of vitamin K opposes the anticoagulant effect and can decrease warfarin’s effect. Conversely, if a client regularly consumes vitamin K foods but abruptly stops, their blood can quickly become over-anticoagulated.

Because of all the extra monitoring and food and drug interaction, warfarin requires in-depth client education. The nurse should instruct the client to:

• Maintain a consistent amount of vitamin K in their diet. It does not need to be avoided altogether, but a consistent amount is important. Green, leafy vegetables are known for their high vitamin K content. Some of these foods are broccoli, brussels sprouts, coleslaw, kale, and collard greens, and they should not be eaten in excess. The American Heart Association provides a list of foods that are high and low in vitamin K.
• Be educated on drug interactions that can occur. Any time a new medication is started, all involved providers should be notified so that the warfarin dose and monitoring can be proactively addressed. This is especially important with acute antibiotics that may otherwise go unnoticed when prescribed by a new provider.
• Send for a guide similar to this AHA warfarin guide to help them manage their medication.
• Have their liver enzymes monitored for early signs of hepatotoxicity and jaundice.
• Have their hemoglobin and hematocrit levels checked regularly.
• Abstain from alcohol to reduce risk of bleeding, as alcohol can thin the blood.
• Wear a medical alert bracelet indicating warfarin use.
• Use a soft-bristle toothbrush and an electric razor.

Direct-Acting Oral Anticoagulants

Direct-acting oral anticoagulants (DOACs) have the advantage of more standardized dosing than warfarin without the need for regular INR monitoring. They also have minimal food and drug interactions in comparison.

The first DOAC, dabigatran, was approved in 2010. It works by directly inhibiting thrombin in the coagulation cascade. It is an oral drug used for the treatment of DVT (deep vein thrombosis)/PE (pulmonary embolism), stroke prevention in atrial fibrillation, and thromboembolism prophylaxis after hip arthroplasty. The capsules must be swallowed whole and cannot be crushed, opened, or chewed. It also must be stored in the original packaging and discarded four months after opening. It has a high risk of gastrointestinal side effects. When treating a DVT/PE, an initial period of parenteral anticoagulation is required before initiating dabigatran. The other DOACs are all selective factor Xa inhibitors. These drugs include apixaban, rivaroxaban, and edoxaban.

Apixaban is FDA approved to reduce stroke risk in clients with atrial fibrillation, to treat DVT/PE both acutely and to reduce the risk of recurrent thromboembolism after the initial treatment period, and for prevention of DVT after hip or knee replacement surgery. It is administered twice daily, whereas the other anti-Xa DOACs are administered only once daily. When treating atrial fibrillation, the dosing must be adjusted if the client meets certain thresholds based on renal function, age, and weight. When treating an acute DVT, a higher dose of apixaban is required for the first week of therapy.

Rivaroxaban is FDA approved for several thromboembolic-related indications. Some of the approved indications are reduction of stroke risk in clients with atrial fibrillation, stable coronary artery disease, treatment of DVT/PE, reduction of risk for recurrent DVT/PE, prophylaxis of DVT in clients undergoing hip or knee surgery, treatment of peripheral artery disease, and venous thromboembolism prophylaxis in acutely ill medical clients. For most indications, rivaroxaban must be taken with food to improve absorption.

Edoxaban is the newest anti-Xa DOAC, approved in 2015. It is FDA approved for stroke prevention in clients with atrial fibrillation and treatment of DVT/PE. When treating an acute DVT, an initial period of parenteral anticoagulation for 5–10 days is required before initiation of edoxaban. The most noteworthy aspects of edoxaban treatment are the renal considerations. Edoxaban carries a black box warning because it should not be used in clients with a creatinine clearance over 95 mL/min. It also should not be used in clients with severe renal dysfunction (creatinine clearance under 15 mL/min). Dose adjustments should be made based on moderate renal dysfunction or low body weight.

Table 20.2 lists common anticoagulants and typical routes and dosing for adult clients. Dose adjustments may be necessary for renal or hepatic impairment. Package inserts should be consulted accordingly.