ANTICOAGULATION TREATMENTS are one of the most commonly encountered therapeutic areas, which health care professionals are actively engaged with each day. There are numerous commercially available anticoagulants that act via inhibition of active clotting factors and/or inhibition of the formation of clotting factors. As newer anticoagulant agents are developed, targets of the clotting cascade are narrowed and treatments become much more specific. Each of these therapies, both old and new, have unique mechanisms of action and pharmacokinetic properties. These distinct mechanisms and properties are extremely advantageous for patients requiring anticoagulation.
Relatively common indications for anticoagulation include atrial fibrillation, venous thromboembolism, acute coronary syndromes, and genetic coagulation abnormalities. For some of these indications, anticoagulation is necessary for only short periods of time such as four weeks. Others require months to years of therapeutic dosing and even life-long therapy in many situations. Medical anticoagulation effectively offers both mortality and morbidity benefits for these patients. However, these benefits are not without risks.
One of the major risks of therapy is excessive anticoagulation and associated bleeding. Major bleeding associated with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) has an incremental risk between 0% and 2%, with this incremental risk depending on underlying disease, concomitant medications, and the intensity and duration of treatment (Schulman, Beyth, Kearon, & Levine, 2008). Treatment with Vitamin K antagonist (VKA) therapy increases the risk of major bleeding by 0.3%–0.5% per year and the risk of intracranial hemorrhage by 0.2% per year compared with controls in clinical studies, with careful monitoring (Schulman et al., 2008). Similar to UFH and LMWH, major determinants of oral VKA bleeding are the intensity of anticoagulation, patient characteristics, concomitant medications, and duration of treatment (Schulman et al., 2008).
Excessive anticoagulation may require treatment with a pharmacologic reversal agent. The emergency department is often the first location where a patient experiencing bleeding associated with anticoagulation will present for treatment. With the evolution of newer anticoagulants now targeting more specific sites of the coagulation cascade, reversal therapies and their use must also evolve. The choice of which reversal agent to initiate must be carefully considered to promote safe and effective treatment. Knowledge of the unique aspects of each reversal agent and the anticoagulant that was administered must be reflected upon when selecting or recommending pharmacologic anticoagulation reversal.
The intent of this review is to discuss the relevant management issues associated with anticoagulant reversal in the emergency department. Some of the common reversal agents include Vitamin K, protamine sulfate, desmopressin, recombinant Factor VIIa (rVIIa), and prothrombin complex concentrates (PCCs). Each of these agents has distinct indications and properties, which make them advantageous in certain situations. These agents and their properties will be reviewed, as well as some of the challenges associated with anticoagulant reversal in the emergency department.
PRODUCTS AND ADMINISTRATION
Vitamin K, also known as phytonadione or Aquamephyton, is a common reversal agent for patients with a supratherapeutic international normalized ratio (INR) and/or bleeding associated with VKA therapy. In the United States, warfarin is the most commonly used VKA. Warfarin inhibits activation of the Vitamin K-dependent clotting factors II, VII, IX, and X via inhibition of the Vitamin K epoxide reductase enzyme (Package Insert, 2007). Inhibition of this enzyme results in a deficiency of reduced Vitamin K, which is necessary for clotting factor activation. Administration of Vitamin K, orally or intravenously, reverses this effect of warfarin. Vitamin K is available commercially as both oral and intravenous formulations.
Recommendations for Vitamin K use are described in the American College of Chest Physician (CHEST) guidelines, which were last updated in 2008 (Ansell et al., 2008). The CHEST guidelines base their Vitamin K administration recommendations on the patient's current INR and the presence of any significant bleeding (Table 1). Vitamin K may be repeated in 12 hrs, depending on the INR. Patients with life-threatening bleeding should receive 10 mg Vitamin K by slow intravenous infusion, with the administration rate not exceeding 1 mg/min (Package Insert, 2002).
The efficacy and time to effect of Vitamin K are variables depending on the route of administration. The efficacy of oral Vitamin K at various doses has been demonstrated by numerous studies. A study published in 2,000 demonstrated the efficacy of only 1 mg of oral Vitamin K compared with placebo for patients with an INR of 4.5–10 with no immediate indication for reversal. Patients who received Vitamin K had a more rapid decrease in INR than those who received a placebo. Fifty-six percent of patients in the Vitamin K group compared with 20% in the placebo group had INR values of 1.8–3.2 on the day after treatment, p = 0.001 (Crowther et al., 2000). Oral Vitamin K therapy will likely correct the INR within 24–48 hrs (Zieve & Solomon, 1969). When given intravenously, the effect of Vitamin K is detectable in 1–2 hrs, and bleeding is usually controlled in 3–6 hrs (Package Insert, 2002).
A common consideration associated with the Vitamin K use is the preferred route of administration. The CHEST guidelines provide a Grade 1A recommendation for oral Vitamin K use being preferred over subcutaneous administration for mild to moderately elevated INRs without major bleeding (Ansell et al., 2008). Vitamin K is considered a fat-soluble vitamin. These lipophilic properties result in erratic absorption and extended durations of action when given via subcutaneous injection. Intramuscular administration should be avoided because of the increased risk of hematoma. As described previously, intravenous administration is preferred in emergent situations of serious or life-threatening bleeding. However, a concern with intravenous use of Vitamin K is the increased risk of hypersensitivity reactions. Anaphylactoid reactions with intravenous Vitamin K are relatively uncommon. However, anaphylactoid reactions can have serious adverse effects when they do occur. Because of these concerns, in nonsignificant bleeding situations, oral Vitamin K administration is preferred (Table 2).
Protamines are a mixture of polypeptides that occur naturally and are isolated from the sperm of certain fish species such as salmon (Weitz, 2011). These proteins are rich in arginine, strongly basic, and have a low molecular weight. Protamine sulfate is indicated for the reversal of heparin overdosage. Protamine sulfate, itself, has an anticoagulant effect; however, when administered with heparin, a stable salt forms, resulting in a loss of anticoagulant effect of both agents. This stable salt forms as a result of an interaction of the strongly basic protamine and the strongly acidic heparin. The onset of action of protamine sulfate is approximately 5 min after intravenous administration (Package Insert, 2008).
Intravenous protamine sulfate is beneficial for patients experiencing bleeding associated with UFH. Intravenous protamine sulfate fully neutralizes the effects of UFH rapidly. The half-life of intravenous heparin is approximately 60–90 min. Because of this short half-life, only intravenous heparin given during the few hours before the indication for reversal needs to be considered when calculating a protamine sulfate dose. (Hirsh et al., 2008) Protamine dosages should be adjusted, depending on the duration of time since heparin administration, to account for rapid declines in serum concentrations. If intravenous heparin was administered within the past few minutes, 1–1.5 mg of protamine should be used to reverse each 100 units of heparin administered. If 30–60 min have elapsed since administration of heparin, the protamine dose should be reduced by 50% to 0.5–0.75 mg for each 100 units of heparin. If greater than 2 hrs have elapsed since administration of heparin, the protamine dose should be reduced by 75% to 0.25–0.375 mg for every 100 units of heparin (Table 2).
Intravenous protamine sulfate may have beneficial effects for patients needing reversal associated with LMWH; however, the reversal of the anti-Xa activity associated with LMWH is incomplete. Because of the differences in effects of protamine sulfate on UFH and LMWH, dosing strategies differ on the basis of agent being reversed. One milligram of protamine sulfate will neutralize approximately 100 units of UFH. For LMWH given within 8 hrs, protamine sulfate should be dosed at 1 mg per 100 anti-Xa units of LMWH. If bleeding continues, a second dose of 0.5 mg per 100 anti-Xa units should be administered. For LMWH given longer than 8 hrs ago, smaller doses of protamine sulfate can be administered (Hirsh et al., 2008).
Protamine sulfate therapy is not without risks. Serious adverse effects include severe hypotension and bradycardia. Slow intravenous injection can minimize these risks. Intravenous protamine sulfate should not exceed 50 mg over a 10-min period (Package Insert, 2008). There are other common risk factors for adverse effects to protamine sulfate. A few examples include previous administration with protamine-containing medications, such as insulin, having a surgical history consisting of a vasectomy, or having an allergy to fish (Package Insert, 2008). Men who have undergone a vasectomy may develop antibodies against sperm antigens, including protamine. These antibodies may react to medicinal protamine and put these patients at an increased risk of having an allergic reaction (Watson, Ansbacher, Barry Deshon, & Agee, 1983). In these patients, the risk–benefit ratio must be considered.
Desmopressin is a synthetic analogue of antidiuretic hormone (Package Insert, 2007). Desmopressin is well known for its activity involving preservation of water in the renal collecting ducts in the kidney. In addition to the antidiuretic activity, desmopressin has also been shown to be an effective treatment for bleeding disorders by increasing plasma levels of von Willebrand factor and Factor VIII. Increasing plasma levels of Factor VIII is beneficial for patients with hemophilia and von Willebrand's disease Type I; however, desmopressin should be avoided in patients with von Willebrand's disease Type IIB due to the induction of platelet aggregation (Package Insert, 2007).
For patients with hemophilia A and von Willebrand's disease Type I, desmopressin is administered intravenously. An intravenous administration dosed at 0.3–0.4 mcg/kg and administered over 15–30 min is recommended. Repeat dosing may be necessary in patients but should be based on response to therapy. This response includes both laboratory response as well as clinical response. Laboratory tests for assessing status include Factor VIII coagulant activity, Factor VIII antigen, and von Willebrand factor (Package Insert, 2007). The beneficial effect of desmopressin is essentially immediate and can last for hours (Lethagen, 1997). In addition to these indications, desmopressin may be administered safely in other patients with unexpected bleeding during or after surgery (Lethagen, 1997).
In addition to the effects on Factor VIII, desmopressin is effective for patients with qualitative platelet defects (Levi, 2009). Desmopressin has been evaluated in reversing the antiplatelet effects of glycoprotein IIb/IIIa inhibitors and aspirin therapy (Reiter et al., 2003). Normalization of platelet function was shown to be accelerated with desmopressin administration. Based on their study and because of a lack of clinical studies in bleeding patients, Reiter and colleagues (2003) recommended that desmopressin be used if bleeding is suspected to be due to glycoprotein IIb/IIIa therapy (Table 2).
Monitoring of fluid status is important, and fluid restriction may be necessary for patients being treated with desmopressin. A reduction in desmopressin activity with dosing more often than every 48 hours may also occur and must be taken into consideration (Package Insert, 2007). Generally, desmopressin is well tolerated in the treatment of bleeding diatheses.
Recombinant Factor VIIa
Activated recombinant Factor VII (NovoSeven® RT, Novo Nordisk, Princeton, NJ) is a commercially available product that is structurally similar to human plasma-derived Factor VIIa and is Food and Drug Administration approved for the treatment of bleeding in patients with hemophilia A or B with inhibitors to Factor VIII or IX (Package Insert, 2010). Recombinant Factor VIIa has been evaluated for reversal of warfarin, fondaparinux, and the direct thrombin inhibitors (DTIs).
In the human body, injury to a blood vessel results in the expression of tissue factor, which binds with circulating Factor VIIa to begin the process of hemostasis. The resulting tissue factor–Factor VIIa complex promotes fibrin production, platelet activation, and the conversion of fibrinogen into a fibrin clot, which restores the integrity of the blood vessel. rVIIa works to promote hemostasis through a very similar mechanism and has been increasingly used for the treatment of non–hemophiliac-related bleeding, including anticoagulation reversal.
rVIIa (Novoseven® RT) is commercially available as a powder and should be reconstituted with the diluent included in the drug package to a final concentration of 1 mg/ml. The reconstituted solution should be administered intravenously over 2–5 min, and the intravenous catheter should be flushed with normal saline (Package Insert, 2010). Once administered, rVIIa has a rapid onset of action and corrects the INR to normal within 15 min (Table 2; Aguilar et al., 2007).
The optimal dose of rVIIa for anticoagulation reversal has not been well defined. The dosage of rVIIa evaluated in the initial case reports and randomized controlled trials was much larger than what is used in contemporary practice. For example, a case report from 2002 reported rapid anticoagulation reversal after a single 120 mcg/kg dose of rVIIa before surgery in a patient with an acute subdural hematoma (Veshchev, Elran, & Salame, 2002). Subsequent research was performed to determine the lowest effective dose that did not produce adverse effects, and a cumulative dose of 20–60 mcg/kg of rVIIa generally produces hemostasis (Table 2; Beshay, Morgan, Madden, Yu, & Sarode, 2010).
The ideal laboratory monitoring parameter has not been determined because the concentration of Factor VII, prothrombin time/INR, or activated partial thromboplastin time does not necessarily correlate with clinical response (Hoffman, 2003; Roberts, Monroe, & White, 2004; Key & Nelsestuen, 2004).
The major concerns with the use of rVIIa are the risk of thromboembolic events and the cost of therapy. Thromboembolic events are serious adverse effects associated with rVIIa and include acute myocardial infarction, cerebrovascular infraction, and venous thromboembolism. A recently published pooled analysis of studies using off-label rVIIa noted that 11.1% of patients had a subsequent thromboembolic complication and there was a significant increase in arterial thromboembolic events (5.5% vs. 3.2%; p = 0.003) when compared with placebo (Levi, Levy, Andersen, & Truloff, 2010). In addition, the average wholesale price of 1 mg of rVIIa is approximately $1000. Inappropriate off-label use of this high-cost, low-utilization therapy may result in adverse patient events and increased drug expenditures for the institution and patient.
Prothrombin Complex Concentrates
The PCCs are commercially available products that are produced through the pooling of human plasma and contain clotting Factors II, IX, and X with variable amounts of Factor VII. The two commercially available products in the United States are Bebulin® VH (Baxter Healthcare Corporation, Westlake Village, CA) and Profilnine® SD (Grifols Biologicals Inc., Los Angeles, CA), which contain relatively small concentrations of Factor VII compared with other products. Administration of PCCs replaces clotting factors that have been depleted by anticoagulation therapy. The PCCs are predominately used for the reversal of warfarin, fondaparinux, and the DTIs. Because these products contain a small amount of heparin, PCCs should be used with caution in patients with heparin-induced thrombocytopenia (Pindur & Morsdorf, 1999).
Several dosing strategies for PCCs have been evaluated, but the optimal dosing strategy has yet to be determined. Doses of 25–100 international units/kg, based on the Factor IX composition, have been evaluated and are effective for anticoagulation reversal (Warkentin & Crowther, 2002; Hanley, 2004). Alternatively, each international unit of PCC per kilogram of body weight raises the plasma concentration of Factor IX by 0.5–1 international unit/dl (Pindur & Morsdorf, 1999).
Bebulin® VH and Profilnine® SD are also available as a powder for reconstitution with the Factor IX concentration labeled on each drug product. Each drug package contains a single-use drug vial, sterile water, a double-ended transfer needle, and filter needle for reconstitution and withdrawal. The drug powder should be reconstituted aseptically after the double-ended transfer needle has been inserted into the sterile water vial. Bebulin® and Profilnine® should be administered at a maximum rate of 2 ml/min and 10 ml/min, respectively (Table 2; Package Insert, 2006; Package Insert, 2004).
During the infusion, patients should be monitored for the development of a headache, flushing, or changes in heart rate and blood pressure. If any of these events occur, the infusion rate should be decreased. Similar to rVIIa, correction of the INR occurs approximately 15 min after infusion of a PCC (Table 2; Aguilar et al., 2007).
The PCCs are most similar in blood clotting factor composition to fresh frozen plasma (FFP), which is plasma that has been separated from whole blood and frozen blood. However, there are several advantages of administering PCCs compared to FFP. As the name implies, FFP must be thawed before administration, whereas PCCs are available as a powder for reconstitution and should be refrigerated. In addition, a patient's blood does not have to be typed and matched before administration of a PCC. The volume of PCC to be infused varies from 5–20 ml, depending on the Factor IX content of the product, which is significantly less than the 1000 ml of FFP that is often needed to achieve hemostasis (Package Insert, 2006; Package Insert, 2004; Lankiewics, Hays, Friedman, Tinkoff, & Blatt, 2006). Finally, the administration of a PCC can be completed in as little as 15 min compared with several hours with FFP.
The two major concerns with the administration of PCCs are product sterility and the potential for a subsequent thrombotic event. The PCCs are pooled from human plasma of thousands of blood donors; all donors are screened for HIV and hepatitis B and C viruses; and the product undergoes heat sterilization to kill other viruses (Makris, 2003; Warkentin & Crowther, 2002). Thrombotic events have been reported with the administration of PCC for anticoagulation reversal, but the overall risk appears to be low compared to the potential deleterious effects of life-threatening hemorrhage (McNeill, Ewing, Wallace, & Stewart, 1998; Preston, Laidlaw, Sampson, & Kitchen, 2002).
PHARMACOLOGIC ANTICOAGULATION REVERSAL CHALLENGES
There are several anticoagulants that have no true reversal agent available or the reversal agent has limited efficacy or variable success. Pharmacologic reversal therapy may have limited utility in the management of severe, life-threatening hemorrhage due to these anticoagulants, thus alternative therapies such as blood products, local hemostatic agents, and hemodialysis should be considered.
Although protamine sulfate binds to and neutralizes UFH, it has a variable reversal effect on LMWH and may result in treatment failure (Crowther & Warkentin, 2008; Kessler, 2004). It has been proposed that this incomplete neutralization is because of the inability of protamine sulfate to bind to the very low molecular weight components of LMWH (Hirsh & Levine, 1992). The unclear efficacy of protamine sulfate on LMWH reversal is because of a lack of human studies demonstrating a benefit or lack thereof. Several animal-model studies have demonstrated the incomplete ability of protamine sulfate to reverse bleeding associated with LMWH (Bang, Berstad, & Talstad, 1991; Van Ryn-McKenna, Cai, Ofosu, Hirsh, & Buchanan, 1990). It is also important to note the short half-life of protamine sulfate when compared with either UFH or LMWH, and thus, repeated doses of protamine may be necessary.
Fondaparinux, a selective Factor Xa inhibitor, does not have an antidote and has a relatively long duration of action. In addition, protamine sulfate is ineffective in reversing the anticoagulation effect of fondaparinux. Administration of rVIIa and PCCs has been shown to reverse the anticoagulation effects of fondaparinux in small studies and may be considered as an option (Bijsterveld et al., 2002; Desmurs-Clavel, Huchon, Chatard, Negrier, & Dargaud, 2009).
Another barrier to effective anticoagulation reversal is the lack of an antidote for the DTIs. Until recently, the DTIs (lepirudin, argatroban, and bivalirudin) were only available as intravenous preparations. However, the newest DTI, dabigatran is available as a capsule for oral administration. Measures to avoid overanticoagulation with DTI therapy include careful monitoring of activated partial thromboplastin time and selection of the optimal agent for each patient on the basis of the patient's comorbid conditions and the route of elimination of the drug product. In addition, the relatively short half-life of the intravenous DTIs may be advantageous when life-threatening hemorrhage occurs as the effect of the drug is quickly terminated when the infusion is stopped. However, the half-life of dabigatran is significantly longer compared with that of the intravenous DTIs, and discontinuation of dabigatran therapy alone is unlikely to result in hemostasis in the setting of severe, life-threatening hemorrhage. Administration of rVIIa, PCCs, and desmopressin has shown mixed results but may be considered in life-threatening hemorrhage in addition to nonpharmacologic hemostatic therapies (Butler, Dolan, Talbot, & Wallis, 1993; Irani, White, & Sexon, 1995; Malherbe, Tsui, Stobart, & Koller, 2004; Oh, Akers, Lewis, Ramaiah, & Flynn, 2006).
Anticoagulation agents act by directly inhibiting or preventing the production of clotting factors or a component of the clotting process. Life-threatening hemorrhage due to anticoagulation therapy is a common challenge faced by emergency department health care professionals. Fortunately, several pharmacologic therapies exist to act as reversal agents or replace blood coagulation factors. Knowledge of the unique aspects of each reversal agent and the anticoagulation therapy must be considered when selecting or recommending pharmacologic anticoagulation reversal. However, the optimal strategy for anticoagulation reversal remains unknown, and the selection of pharmacologic anticoagulation reversal therapy must be determined on a case-by-case basis through a protocol-driven, multidisciplinary approach.
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