There are both parenteral and oral anticoagulants. The parenteral anticoagulants include heparin, low-molecular-weight heparin (LMWH), fondaparinux (a synthetic pentasaccharide), lepirudin, desirudin, bivalirudin, and argatroban. Currently available oral anticoagulants include warfarin; dabigatran etexilate, an oral thrombin inhibitor; and rivaroxaban and apixaban, oral factor Xa inhibitors. Edoxaban, a third oral factor Xa inhibitor, is undergoing regulatory review.
A sulfated polysaccharide, heparin is isolated from mammalian tissues rich in mast cells. Most commercial heparin is derived from porcine intestinal mucosa and is a polymer of alternating d-glucuronic acid and N-acetyl-d-glucosamine residues.
Heparin acts as an anticoagulant by activating antithrombin (previously known as antithrombin III) and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa. Antithrombin, the obligatory plasma cofactor for heparin, is a member of the serine protease inhibitor (serpin) superfamily. Synthesized in the liver and circulating in plasma at a concentration of 2.6 ± 0.4 μM, antithrombin acts as a suicide substrate for its target enzymes.
To activate antithrombin, heparin binds to the serpin via a unique pentasaccharide sequence that is found on one-third of the chains of commercial heparin (Fig. 24-5). Heparin chains without this pentasaccharide sequence have little or no anticoagulant activity. Once bound to antithrombin, heparin induces a conformational change in the reactive center loop of antithrombin that renders it more readily accessible to its target proteases. This conformational change enhances the rate at which antithrombin inhibits factor Xa by at least two orders of magnitude but has little effect on the rate of thrombin inhibition. To catalyze thrombin inhibition, heparin serves as a template that binds antithrombin and thrombin simultaneously. Formation of this ternary complex brings the enzyme in close apposition to the inhibitor, thereby promoting the formation of a stable covalent thrombin-antithrombin complex.
Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux, a synthetic pentasaccharide. A. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains composed of at least 18 saccharide units, which corresponds to a molecular weight of 5400, are of sufficient length to perform this bridging function. With a mean molecular weight of 15,000, all of the heparin chains are long enough to do this. B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because, with a mean molecular weight of 4500–5000, at least half of the LMWH chains are too short to bridge antithrombin to thrombin. C. The pentasaccharide only accelerates factor Xa inhibition by antithrombin because the pentasaccharide is too short to bridge antithrombin to thrombin.
Only pentasaccharide-containing heparin chains composed of at least 18 saccharide units (which correspond to a molecular weight of 5400) are of sufficient length to bridge thrombin and antithrombin together. With a mean molecular weight of 15,000, and a range of 5000–30,000, almost all of the chains of unfractionated heparin are long enough to do so. Consequently, by definition, heparin has equal capacity to promote the inhibition of thrombin and factor Xa by antithrombin and is assigned an anti-factor Xa to anti-factor IIa (thrombin) ratio of 1:1.
Heparin causes the release of tissue factor pathway inhibitor (TFPI) from the endothelium. A factor Xa–dependent inhibitor of tissue factor–bound factor VIIa, TFPI may contribute to the antithrombotic activity of heparin. Longer heparin chains induce the release of more TFPI than shorter ones.
Heparin must be given parenterally. It is usually administered SC or by continuous IV infusion. When used for therapeutic purposes, the IV route is most often employed. If heparin is given SC for treatment of thrombosis, the dose of heparin must be high enough to overcome the limited bioavailability associated with this method of delivery.
In the circulation, heparin binds to the endothelium and to plasma proteins other than antithrombin. Heparin binding to endothelial cells explains its dose-dependent clearance. At low doses, the half-life of heparin is short because it binds rapidly to the endothelium. With higher doses of heparin, the half-life is longer because heparin is cleared more slowly once the endothelium is saturated. Clearance is mainly extrarenal; heparin binds to macrophages, which internalize and depolymerize the long heparin chains and secrete shorter chains back into the circulation. Because of its dose-dependent clearance mechanism, the plasma half-life of heparin ranges from 30 to 60 min with bolus IV doses of 25 and 100 units/kg, respectively.
Once heparin enters the circulation, it binds to plasma proteins other than antithrombin, a phenomenon that reduces its anticoagulant activity. Some of the heparin-binding proteins found in plasma are acute-phase reactants whose levels are elevated in ill patients. Others, such as high-molecular-weight multimers of VWF, are released from activated platelets or endothelial cells. Activated platelets also release platelet factor 4 (PF4), a highly cationic protein that binds heparin with high affinity. The large amounts of PF4 found in the vicinity of platelet-rich arterial thrombi can neutralize the anticoagulant activity of heparin. This phenomenon may attenuate heparin’s capacity to suppress thrombus growth.
Because the levels of heparin-binding proteins in plasma vary from person to person, the anticoagulant response to fixed or weight-adjusted doses of heparin is unpredictable. Consequently, coagulation monitoring is essential to ensure that a therapeutic response is obtained. This is particularly important when heparin is administered for treatment of established thrombosis because a subtherapeutic anticoagulant response may render patients at risk for recurrent thrombosis, whereas excessive anticoagulation increases the risk of bleeding.
Monitoring the anticoagulant effect
Heparin therapy can be monitored using the activated partial thromboplastin time (aPTT) or anti-factor Xa level. Although the aPTT is the test most often used for this purpose, there are problems with this assay. aPTT reagents vary in their sensitivity to heparin, and the type of coagulometer used for testing can influence the results. Consequently, laboratories must establish a therapeutic aPTT range with each reagent-coagulometer combination by measuring the aPTT and anti-factor Xa level in plasma samples collected from heparin-treated patients. For most of the aPTT reagents and coagulometers in current use, therapeutic heparin levels are achieved with a two- to threefold prolongation of the aPTT.
Anti-factor Xa levels also can be used to monitor heparin therapy. With this test, therapeutic heparin levels range from 0.3 to 0.7 units/mL. Although this test is gaining in popularity, anti-factor Xa assays have yet to be standardized, and results can vary widely between laboratories.
Up to 25% of heparin-treated patients with venous thromboembolism require >35,000 units/d to achieve a therapeutic aPTT. These patients are considered heparin resistant. It is useful to measure anti-factor Xa levels in heparin-resistant patients because many will have a therapeutic anti-factor Xa level despite a subtherapeutic aPTT. This dissociation in test results occurs because elevated plasma levels of fibrinogen and factor VIII, both of which are acute-phase proteins, shorten the aPTT but have no effect on anti-factor Xa levels. Heparin therapy in patients who exhibit this phenomenon is best monitored using anti-factor Xa levels instead of the aPTT. Patients with congenital or acquired antithrombin deficiency and those with elevated levels of heparin-binding proteins may also need high doses of heparin to achieve a therapeutic aPTT or anti-factor Xa level. If there is good correlation between the aPTT and the anti-factor Xa levels, either test can be used to monitor heparin therapy.
For prophylaxis, heparin is usually given in fixed doses of 5000 units SC two or three times daily. With these low doses, coagulation monitoring is unnecessary. In contrast, monitoring is essential when the drug is given in therapeutic doses. Fixed-dose or weight-based heparin nomograms are used to standardize heparin dosing and to shorten the time required to achieve a therapeutic anticoagulant response. At least two heparin nomograms have been validated in patients with venous thromboembolism and reduce the time required to achieve a therapeutic aPTT. Weight-adjusted heparin nomograms have also been evaluated in patients with acute coronary syndromes. After an IV heparin bolus of 5000 units or 70 units/kg, a heparin infusion rate of 12–15 units/kg per hour is usually administered. In contrast, weight-adjusted heparin nomograms for patients with venous thromboembolism use an initial bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/kg per h. Thus, patients with venous thromboembolism appear to require higher doses of heparin to achieve a therapeutic aPTT than do patients with acute coronary syndromes. This may reflect differences in the thrombus burden. Heparin binds to fibrin, and the amount of fibrin in patients with extensive DVT is greater than that in those with coronary thrombosis.
Heparin manufacturers in North America have traditionally measured heparin potency in USP units, with a unit defined as the concentration of heparin that prevents 1 mL of citrated sheep plasma from clotting for 1 h after calcium addition. In contrast, manufacturers in Europe measure heparin potency with anti-Xa assays using an international heparin standard for comparison. Because of problems with heparin contamination with oversulfated chondroitin sulfate, which the USP assay system does not detect, North American heparin manufacturers now use the anti-Xa assay to assess heparin potency. The use of international units in place of USP units results in a 10% reduction in heparin doses, which is a difference unlikely to affect patient care because monitoring will help to ensure that a therapeutic anticoagulant response has been achieved.
Heparin has pharmacokinetic and biophysical limitations (Table 24-2). The pharmacokinetic limitations reflect heparin’s propensity to bind in a pentasaccharide-independent fashion to cells and plasma proteins. Heparin binding to endothelial cells explains its dose-dependent clearance, whereas binding to plasma proteins results in a variable anticoagulant response and can lead to heparin resistance.
TABLE 24-2Pharmacokinetic and Biophysical Limitations of Heparin ||Download (.pdf) TABLE 24-2 Pharmacokinetic and Biophysical Limitations of Heparin
|Limitations ||Mechanism |
|Poor bioavailability at low doses ||Binds to endothelial cells and macrophages |
|Dose-dependent clearance ||Binds to macrophages |
|Variable anticoagulant response ||Binds to plasma proteins whose levels vary from patient to patient |
|Reduced activity in the vicinity of platelet-rich thrombi ||Neutralized by platelet factor 4 released from activated platelets |
|Limited activity against factor Xa incorporated in the prothrombinase complex and thrombin bound to fibrin ||Reduced capacity of heparin-antithrombin complex to inhibit factor Xa bound to activated platelets and thrombin bound to fibrin |
The biophysical limitations of heparin reflect the inability of the heparin-antithrombin complex to inhibit factor Xa when it is incorporated into the prothrombinase complex, the complex that converts prothrombin to thrombin, and to inhibit thrombin bound to fibrin. Consequently, factor Xa bound to activated platelets within platelet-rich thrombi has the potential to generate thrombin, even in the face of heparin. Once this thrombin binds to fibrin, it too is protected from inhibition by the heparin-antithrombin complex. Clot-associated thrombin can then trigger thrombus growth by locally activating platelets and amplifying its own generation through feedback activation of factors V, VIII, and XI. Further compounding the problem is the potential for heparin neutralization by the high concentrations of PF4 released from activated platelets within the platelet-rich thrombus.
The most common side effect of heparin is bleeding. Other complications include thrombocytopenia, osteoporosis, and elevated levels of transaminases.
The risk of bleeding rises as the dose of heparin is increased. Concomitant administration of drugs that affect hemostasis, such as antiplatelet or fibrinolytic agents, increases the risk of bleeding, as does recent surgery or trauma. Heparin-treated patients with serious bleeding can be given protamine sulfate to neutralize the heparin. Protamine sulfate, a mixture of basic polypeptides isolated from salmon sperm, binds heparin with high affinity, and the resultant protamine-heparin complexes are then cleared. Typically, 1 mg of protamine sulfate neutralizes 100 units of heparin. Protamine sulfate is given IV. Anaphylactoid reactions to protamine sulfate can occur, and drug administration by slow IV infusion is recommended to reduce the risk.
Heparin can cause thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is an antibody-mediated process that is triggered by antibodies directed against neoantigens on PF4 that are exposed when heparin binds to this protein. These antibodies, which are usually of the IgG isotype, bind simultaneously to the heparin-PF4 complex and to platelet Fc receptors. Such binding activates the platelets and generates platelet microparticles. Circulating microparticles are prothrombotic because they express anionic phospholipids on their surface and can bind clotting factors and promote thrombin generation.
The clinical features of HIT are illustrated in Table 24-3. Typically, HIT occurs 5–14 days after initiation of heparin therapy, but it can manifest earlier if the patient has received heparin within the past 3 months. A platelet count below 100,000/μL or a 50% decrease in the platelet count from the pretreatment value should raise the suspicion of HIT in those receiving heparin. HIT is more common in surgical patients than in medical patients and, like many autoimmune disorders, occurs more frequently in females than in males.
TABLE 24-3Features of Heparin-Induced Thrombocytopenia ||Download (.pdf) TABLE 24-3 Features of Heparin-Induced Thrombocytopenia
|Features ||Details |
|Thrombocytopenia ||Platelet count of ≤100,000/μL or a decrease in platelet count of ≥50% |
|Timing ||Platelet count falls 5–10 days after starting heparin |
|Type of heparin ||More common with unfractionated heparin than low-molecular-weight heparin |
|Type of patient ||More common in surgical patients and patients with cancer than general medical patients; more common in women than in men |
|Thrombosis ||Venous thrombosis more common than arterial thrombosis |
HIT can be associated with thrombosis, either arterial or venous. Venous thrombosis, which manifests as DVT and/or PE, is more common than arterial thrombosis. Arterial thrombosis can manifest as ischemic stroke or acute MI. Rarely, platelet-rich thrombi in the distal aorta or iliac arteries can cause critical limb ischemia.
The diagnosis of HIT is established using enzyme-linked assays to detect antibodies against heparin-PF4 complexes or with platelet activation assays. Enzyme-linked assays are sensitive but can be positive in the absence of any clinical evidence of HIT. The most specific diagnostic test is the serotonin release assay. This test is performed by quantifying serotonin release when washed platelets loaded with labeled serotonin are exposed to patient serum in the absence or presence of varying concentrations of heparin. If the patient serum contains the HIT antibody, heparin addition induces platelet activation and serotonin release.
Management of HIT is outlined in Table 24-4. Heparin should be stopped in patients with suspected or documented HIT, and an alternative anticoagulant should be administered to prevent or treat thrombosis. The agents most often used for this indication are parenteral direct thrombin inhibitors, such as lepirudin, argatroban, or bivalirudin, or factor Xa inhibitors, such as fondaparinux.
TABLE 24-4Management of Heparin-Induced Thrombocytopenia ||Download (.pdf) TABLE 24-4 Management of Heparin-Induced Thrombocytopenia
|Stop all heparin. |
|Give an alternative anticoagulant, such as lepirudin, argatroban, bivalirudin, or fondaparinux. |
|Do not give platelet transfusions. |
|Do not give warfarin until the platelet count returns to its baseline level. If warfarin was administered, give vitamin K to restore the INR to normal. |
|Evaluate for thrombosis, particularly deep vein thrombosis. |
Patients with HIT, particularly those with associated thrombosis, often have evidence of increased thrombin generation that can lead to consumption of protein C. If these patients are given warfarin without a concomitant parenteral anticoagulant to inhibit thrombin or thrombin generation, the further decrease in protein C levels induced by the vitamin K antagonist can trigger skin necrosis. To avoid this problem, patients with HIT should be treated with a direct thrombin inhibitor or fondaparinux until the platelet count returns to normal levels. At this point, low-dose warfarin therapy can be introduced, and the thrombin inhibitor can be discontinued when the anticoagulant response to warfarin has been therapeutic for at least 2 days.
Treatment with therapeutic doses of heparin for >1 month can cause a reduction in bone density. This complication has been reported in up to 30% of patients given long-term heparin therapy, and symptomatic vertebral fractures occur in 2–3% of these individuals.
Heparin causes bone loss both by decreasing bone formation and by enhancing bone resorption. Thus, heparin affects the activity of both osteoblasts and osteoclasts.
Elevated levels of transaminases
Therapeutic doses of heparin are frequently associated with modest elevations in the serum levels of hepatic transaminases without a concomitant increase in the level of bilirubin. The levels of transaminases rapidly return to normal when the drug is stopped. The mechanism responsible for this phenomenon is unknown.
Consisting of smaller fragments of heparin, LMWH is prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. The mean molecular weight of LMWH is about 5000, one-third the mean molecular weight of unfractionated heparin. LMWH has advantages over heparin (Table 24-5) and has replaced heparin for most indications.
TABLE 24-5Advantages of LMWH Over Heparin ||Download (.pdf) TABLE 24-5 Advantages of LMWH Over Heparin
|Advantage ||Consequence |
|Better bioavailability and longer half-life after subcutaneous injection ||Can be given subcutaneously once or twice daily for both prophylaxis and treatment |
|Dose-independent clearance ||Simplified dosing |
|Predictable anticoagulant response ||Coagulation monitoring is unnecessary in most patients |
|Lower risk of heparin-induced thrombocytopenia ||Safer than heparin for short- or long-term administration |
|Lower risk of osteoporosis ||Safer than heparin for extended administration |
Like heparin, LMWH exerts its anticoagulant activity by activating antithrombin. With a mean molecular weight of 5000, which corresponds to about 17 saccharide units, at least half of the pentasaccharide-containing chains of LMWH are too short to bridge thrombin to antithrombin (Fig. 24-5). However, these chains retain the capacity to accelerate factor Xa inhibition by antithrombin because this activity is largely the result of the conformational changes in antithrombin evoked by pentasaccharide binding. Consequently, LMWH catalyzes factor Xa inhibition by antithrombin more than thrombin inhibition. Depending on their unique molecular weight distributions, LMWH preparations have anti-factor Xa to anti-factor IIa ratios ranging from 2:1 to 4:1.
Although usually given SC, LMWH also can be administered IV if a rapid anticoagulant response is needed. LMWH has pharmacokinetic advantages over heparin. These advantages reflect the fact that shorter heparin chains bind less avidly to endothelial cells, macrophages, and heparin-binding plasma proteins. Reduced binding to endothelial cells and macrophages eliminates the rapid, dose-dependent, and saturable mechanism of clearance that is a characteristic of unfractionated heparin. Instead, the clearance of LMWH is dose-independent and its plasma half-life is longer. Based on measurement of anti-factor Xa levels, LMWH has a plasma half-life of ~4 h. LMWH is cleared almost exclusively by the kidneys, and the drug can accumulate in patients with renal insufficiency.
LMWH exhibits about 90% bioavailability after SC injection. Because LMWH binds less avidly to heparin-binding proteins in plasma than heparin, LMWH produces a more predictable dose response, and resistance to LMWH is rare. With a longer half-life and more predictable anticoagulant response, LMWH can be given SC once or twice daily without coagulation monitoring, even when the drug is given in treatment doses. These properties render LMWH more convenient than unfractionated heparin. Capitalizing on this feature, studies in patients with venous thromboembolism have shown that home treatment with LMWH is as effective and safe as in-hospital treatment with continuous IV infusions of heparin. Outpatient treatment with LMWH streamlines care, reduces health care costs, and increases patient satisfaction.
In the majority of patients, LMWH does not require coagulation monitoring. If monitoring is necessary, anti-factor Xa levels must be measured because most LMWH preparations have little effect on the aPTT. Therapeutic anti-factor Xa levels with LMWH range from 0.5 to 1.2 units/mL when measured 3–4 h after drug administration. When LMWH is given in prophylactic doses, peak anti-factor Xa levels of 0.2–0.5 units/mL are desirable.
Indications for LMWH monitoring include renal insufficiency and obesity. LMWH monitoring in patients with a creatinine clearance of ≤50 mL/min is advisable to ensure that there is no drug accumulation. Although weight-adjusted LMWH dosing appears to produce therapeutic anti-factor Xa levels in patients who are overweight, this approach has not been extensively evaluated in those with morbid obesity. It may also be advisable to monitor the anticoagulant activity of LMWH during pregnancy because dose requirements can change, particularly in the third trimester. Monitoring should also be considered in high-risk settings, such as in patients with mechanical heart valves who are given LMWH for prevention of valve thrombosis, and when LMWH is used in treatment doses in infants or children.
The doses of LMWH recommended for prophylaxis or treatment vary depending on the LMWH preparation. For prophylaxis, once-daily SC doses of 4000–5000 units are often used, whereas doses of 2500–3000 units are given when the drug is administered twice daily. For treatment of venous thromboembolism, a dose of 150–200 units/kg is given if the drug is administered once daily. If a twice-daily regimen is used, a dose of 100 units/kg is given. In patients with unstable angina, LMWH is given SC on a twice-daily basis at a dose of 100–120 units/kg.
The major complication of LMWH is bleeding. Meta-analyses suggest that the risk of major bleeding is lower with LMWH than with unfractionated heparin. HIT and osteoporosis are less common with LMWH than with unfractionated heparin.
Like the situation with heparin, bleeding with LMWH is more common in patients receiving concomitant therapy with antiplatelet or fibrinolytic drugs. Recent surgery, trauma, or underlying hemostatic defects also increase the risk of bleeding with LMWH.
Although protamine sulfate can be used as an antidote for LMWH, protamine sulfate incompletely neutralizes the anticoagulant activity of LMWH because it only binds the longer chains of LMWH. Because longer chains are responsible for catalysis of thrombin inhibition by antithrombin, protamine sulfate completely reverses the anti-factor IIa activity of LMWH. In contrast, protamine sulfate only partially reverses the anti-factor Xa activity of LMWH because the shorter pentasaccharide-containing chains of LMWH do not bind to protamine sulfate. Consequently, patients at high risk for bleeding may be more safely treated with continuous IV unfractionated heparin than with SC LMWH.
The risk of HIT is about fivefold lower with LMWH than with heparin. LMWH binds less avidly to platelets and causes less PF4 release. Furthermore, with lower affinity for PF4 than heparin, LMWH is less likely to induce the conformational changes in PF4 that trigger the formation of HIT antibodies.
LMWH should not be used to treat HIT patients because most HIT antibodies exhibit cross-reactivity with LMWH. This in vitro cross-reactivity is not simply a laboratory phenomenon because there are case reports of thrombosis when HIT patients were switched from heparin to LMWH.
Because the risk of osteoporosis is lower with LMWH than with heparin, LMWH is the better choice for extended treatment.
A synthetic analogue of the antithrombin-binding pentasaccharide sequence, fondaparinux differs from LMWH in several ways (Table 24-6). Fondaparinux is licensed for thromboprophylaxis in general medical or surgical patients and in high-risk orthopedic patients and as an alternative to heparin or LMWH for initial treatment of patients with established venous thromboembolism. Although widely used in Europe, as an alternative to heparin or LMWH in patients with acute coronary syndromes, fondaparinux is not licensed for this indication in the United States.
TABLE 24-6Comparison of LMWH and Fondaparinux ||Download (.pdf) TABLE 24-6 Comparison of LMWH and Fondaparinux
|Features ||LMWH ||Fondaparinux |
|Number of saccharide units ||15–17 ||5 |
|Catalysis of factor Xa inhibition ||Yes ||Yes |
|Catalysis of thrombin inhibition ||Yes ||No |
|Bioavailability after subcutaneous administration (%) ||90 ||100 |
|Plasma half-life (h) ||4 ||17 |
|Renal excretion ||Yes ||Yes |
|Induces release of tissue factor pathway inhibitor ||Yes ||No |
|Neutralized by protamine sulfate ||Partially ||No |
As a synthetic analogue of the antithrombin-binding pentasaccharide sequence found in heparin and LMWH, fondaparinux has a molecular weight of 1728. Fondaparinux binds only to antithrombin (Fig. 24-5) and is too short to bridge thrombin to antithrombin. Consequently, fondaparinux catalyzes factor Xa inhibition by antithrombin and does not enhance the rate of thrombin inhibition.
Fondaparinux exhibits complete bioavailability after SC injection. With no binding to endothelial cells or plasma proteins, the clearance of fondaparinux is dose independent and its plasma half-life is 17 h. The drug is given SC once daily. Because fondaparinux is cleared unchanged via the kidneys, it is contraindicated in patients with a creatinine clearance <30 mL/min and should be used with caution in those with a creatinine clearance <50 mL/min.
Fondaparinux produces a predictable anticoagulant response after administration in fixed doses because it does not bind to plasma proteins. The drug is given at a dose of 2.5 mg once daily for prevention of venous thromboembolism. For initial treatment of established venous thromboembolism, fondaparinux is given at a dose of 7.5 mg once daily. The dose can be reduced to 5 mg once daily for those weighing <50 kg and increased to 10 mg for those >100 kg. When given in these doses, fondaparinux is as effective as heparin or LMWH for initial treatment of patients with DVT or PE and produces similar rates of bleeding.
Fondaparinux is used at a dose of 2.5 mg once daily in patients with acute coronary syndromes. When this prophylactic dose of fondaparinux was compared with treatment doses of enoxaparin in patients with non-ST-segment elevation acute coronary syndrome, there was no difference in the rate of cardiovascular death, MI, or stroke at 9 days. However, the rate of major bleeding was 50% lower with fondaparinux than with enoxaparin, a difference that likely reflects the fact that the dose of fondaparinux was lower than that of enoxaparin. In acute coronary syndrome patients who require percutaneous coronary intervention, there is a risk of catheter thrombosis with fondaparinux unless adjunctive heparin is given.
Fondaparinux does not cause HIT because it does not bind to PF4. In contrast to LMWH, there is no cross-reactivity of fondaparinux with HIT antibodies. Consequently, fondaparinux appears to be effective for treatment of HIT patients, although large clinical trials supporting its use are lacking.
The major side effect of fondaparinux is bleeding. There is no antidote for fondaparinux. Protamine sulfate has no effect on the anticoagulant activity of fondaparinux because it fails to bind to the drug. Recombinant activated factor VII reverses the anticoagulant effects of fondaparinux in volunteers, but it is unknown whether this agent controls fondaparinux-induced bleeding.
Parenteral direct thrombin inhibitors
Direct thrombin inhibitors bind directly to thrombin and block its interaction with its substrates. Approved parenteral direct thrombin inhibitors include recombinant hirudins (lepirudin and desirudin), argatroban, and bivalirudin (Table 24-7). Lepirudin and argatroban are licensed for treatment of patients with HIT, desirudin is licensed for thromboprophylaxis after elective hip arthroplasty, and bivalirudin is approved as an alternative to heparin in patients undergoing percutaneous coronary intervention, including those with HIT.
TABLE 24-7Comparison of the Properties of Lepirudin, Bivalirudin, and Argatroban ||Download (.pdf) TABLE 24-7 Comparison of the Properties of Lepirudin, Bivalirudin, and Argatroban
| ||Lepirudin/Desirudin ||Bivalirudin ||Argatroban |
|Molecular mass ||7000 ||1980 ||527 |
|Site(s) of interaction with thrombin ||Active site and exosite 1 ||Active site and exosite 1 ||Active site |
|Renal clearance ||Yes ||No ||No |
|Hepatic metabolism ||No ||No ||Yes |
|Plasma half-life (min) || |
|25 ||45 |
Recombinant forms of hirudin, lepirudin, and desirudin are bivalent direct thrombin inhibitors that interact with the active site and exosite 1, the substrate-binding site on thrombin. For rapid anticoagulation, lepirudin is given by continuous IV infusion, but the drug can be given SC. Lepirudin has a plasma half-life of 60 min after IV infusion and is cleared by the kidneys. Consequently, lepirudin accumulates in patients with renal insufficiency. For thromboprophylaxis, desirudin is given SC twice daily in fixed doses; the half-life of desirudin is 2–3 h after SC injection.
A high proportion of lepirudin-treated patients develop antibodies against the drug; antibody formation is rare with SC desirudin. Although lepirudin-directed antibodies rarely cause problems, in a small subset of patients, they can delay lepirudin clearance and enhance its anticoagulant activity. Serious bleeding has been reported in some of these patients.
Lepirudin is usually monitored using the aPTT, and the dose is adjusted to maintain an aPTT that is 1.5–2.5 times the control. The aPTT is not an ideal test for monitoring lepirudin therapy because the clotting time plateaus with higher drug concentrations. Although the clotting time with ecarin, a snake venom that converts prothrombin to meizothrombin, provides a better index of lepirudin dose than the aPTT, the ecarin clotting time has yet to be standardized. When used for thromboprophylaxis, desirudin does not require monitoring.
A univalent inhibitor that targets the active site of thrombin, argatroban is metabolized in the liver. Consequently, this drug must be used with caution in patients with hepatic insufficiency. Argatroban is not cleared via the kidneys, so this drug is safer than lepirudin for HIT patients with renal insufficiency.
Argatroban is administered by continuous IV infusion and has a plasma half-life of ~45 min. The aPTT is used to monitor its anticoagulant effect, and the dose is adjusted to achieve an aPTT 1.5–3 times the baseline value, but not to exceed 100 s. Argatroban also prolongs the international normalized ratio (INR), a feature that can complicate the transitioning of patients to warfarin. This problem can be circumvented by using the levels of factor X to monitor warfarin in place of the INR. Alternatively, argatroban can be stopped for 2–3 h before INR determination.
A synthetic 20-amino-acid analogue of hirudin, bivalirudin is a divalent thrombin inhibitor. Thus, the N-terminus of bivalirudin interacts with the active site of thrombin, whereas its C-terminus binds to exosite 1. Bivalirudin has a plasma half-life of 25 min, the shortest half-life of all the parenteral direct thrombin inhibitors. Bivalirudin is degraded by peptidases and is partially excreted via the kidneys. When given in high doses in the cardiac catheterization laboratory, the anticoagulant activity of bivalirudin is monitored using the activated clotting time. With lower doses, its activity can be assessed using the aPTT.
Bivalirudin is licensed as an alternative to heparin in patients undergoing percutaneous coronary intervention. Bivalirudin also has been used successfully in HIT patients who require percutaneous coronary intervention or cardiac bypass surgery.
Current oral anticoagulant practice dates back almost 60 years to when the vitamin K antagonists were discovered as a result of investigations into the cause of hemorrhagic disease in cattle. Characterized by a decrease in prothrombin levels, this disorder is caused by ingestion of hay containing spoiled sweet clover. Hydroxycoumarin, which was isolated from bacterial contaminants in the hay, interferes with vitamin K metabolism, thereby causing a syndrome similar to vitamin K deficiency. Discovery of this compound provided the impetus for development of other vitamin K antagonists, including warfarin.
For many years, the vitamin K antagonists were the only available oral anticoagulants. This situation changed with the introduction of new oral anticoagulants, including dabigatran, which targets thrombin, and rivaroxaban, apixaban, and edoxaban, which target factor Xa.
A water-soluble vitamin K antagonist initially developed as a rodenticide, warfarin is the coumarin derivative most often prescribed in North America. Like other vitamin K antagonists, warfarin interferes with the synthesis of the vitamin K–dependent clotting proteins, which include prothrombin (factor II) and factors VII, IX, and X. The synthesis of the vitamin K–dependent anticoagulant proteins, proteins C and S, is also reduced by vitamin K antagonists.
All of the vitamin K–dependent clotting factors possess glutamic acid residues at their N termini. A posttranslational modification adds a carboxyl group to the γ-carbon of these residues to generate γ-carboxyglutamic acid. This modification is essential for expression of the activity of these clotting factors because it permits their calcium-dependent binding to negatively charged phospholipid surfaces. The γ-carboxylation process is catalyzed by a vitamin K–dependent carboxylase. Thus, vitamin K from the diet is reduced to vitamin K hydroquinone by vitamin K reductase (Fig. 24-6). Vitamin K hydroquinone serves as a cofactor for the carboxylase enzyme, which in the presence of carbon dioxide replaces the hydrogen on the γ-carbon of glutamic acid residues with a carboxyl group. During this process, vitamin K hydroquinone is oxidized to vitamin K epoxide, which is then reduced to vitamin K by vitamin K epoxide reductase.
Mechanism of action of warfarin. A racemic mixture of S- and R-enantiomers, S-warfarin is most active. By blocking vitamin K epoxide reductase, warfarin inhibits the conversion of oxidized vitamin K into its reduced form. This inhibits vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X because reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes the γ-carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium and interacting with anionic phospholipid surfaces. S-warfarin is metabolized by CYP2C9. Common genetic polymorphisms in this enzyme can influence warfarin metabolism. Polymorphisms in the C1 subunit of vitamin K reductase (VKORC1) also can affect the susceptibility of the enzyme to warfarin-induced inhibition, thereby influencing warfarin dosage requirements.
Warfarin inhibits vitamin K epoxide reductase (VKOR), thereby blocking the γ-carboxylation process. This results in the synthesis of vitamin K–dependent clotting proteins that are only partially γ-carboxylated. Warfarin acts as an anticoagulant because these partially γ-carboxylated proteins have reduced or absent biologic activity. The onset of action of warfarin is delayed until the newly synthesized clotting factors with reduced activity gradually replace their fully active counterparts.
The antithrombotic effect of warfarin depends on a reduction in the functional levels of factor X and prothrombin, clotting factors that have half-lives of 24 and 72 h, respectively. Because the antithrombotic effect of warfarin is delayed, patients with established thrombosis or at high risk for thrombosis require concomitant treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux, for at least 5 days.
Warfarin is a racemic mixture of R and S isomers. Warfarin is rapidly and almost completely absorbed from the gastrointestinal tract. Levels of warfarin in the blood peak about 90 min after drug administration. Racemic warfarin has a plasma half-life of 36–42 h, and more than 97% of circulating warfarin is bound to albumin. Only the small fraction of unbound warfarin is biologically active.
Warfarin accumulates in the liver where the two isomers are metabolized via distinct pathways. CYP2C9 mediates oxidative metabolism of the more active S isomer (Fig. 24-6). Two relatively common variants, CYP2C9*2 and CYP2C9*3, encode an enzyme with reduced activity. Patients with these variants require lower maintenance doses of warfarin. Approximately 25% of Caucasians have at least one variant allele of CYP2C9*2 or CYP2C9*3, whereas those variant alleles are less common in African Americans and Asians (Table 24-8). Heterozygosity for CYP2C9*2 or CYP2C9*3 decreases the warfarin dose requirement by 20–30% relative to that required in subjects with the wild-type CYP2C9*1/*1 alleles, whereas homozygosity for the CYP2C9*2 or CYP2C9*3 alleles reduces the warfarin dose requirement by 50–70%.
Consistent with their decreased warfarin dose requirement, subjects with at least one CYP2C9 variant allele are at increased risk for bleeding. Compared with individuals with no variant alleles, the relative risks for warfarin-associated bleeding in CYP2C9*2 or CYP2C9*3 carriers are 1.9 and 1.8, respectively.
Polymorphisms in VKORC1 also can influence the anticoagulant response to warfarin. Several genetic variations of VKORC1 are in strong linkage disequilibrium and have been designated as non-A haplotypes. VKORC1 variants are more prevalent than variants of CYP2C9. Asians have the highest prevalence of VKORC1 variants, followed by Caucasians and African Americans (Table 24-8). Polymorphisms in VKORC1 likely explain 30% of the variability in warfarin dose requirements. Compared with VKORC1 non-A/non-A homozygotes, the warfarin dose requirement decreases by 25 and 50% in A haplotype heterozygotes and homozygotes, respectively. These findings prompted the Food and Drug Administration to amend the prescribing information for warfarin to indicate that lower initiation doses should be considered for patients with CYP2C9 and VKORC1 genetic variants. In addition to genotype data, other pertinent patient information has been incorporated into warfarin dosing algorithms. Although such algorithms help predict suitable warfarin doses, it remains unclear whether better dose identification improves patient outcome in terms of reducing hemorrhagic complications or recurrent thrombotic events.
TABLE 24-8Frequencies of CYP2C9 enotypes and VKORC1 Haplotypes in Different Populations and Their Effect on Warfarin Dose Requirements ||Download (.pdf) TABLE 24-8 Frequencies of CYP2C9 enotypes and VKORC1 Haplotypes in Different Populations and Their Effect on Warfarin Dose Requirements
| || ||Frequency, % || |
|Genotype/Haplotype ||Caucasians ||African Americans (A/A) ||Asians (A) ||Dose Reduction Compared with Wild-Type |
|*1/*1 ||70 ||90 ||95 ||– |
|*1/*2 ||17 ||2 ||0 ||22 |
|*1/*3 ||9 ||3 ||4 ||34 |
|*2/*2 ||2 ||0 ||0 ||43 |
|*2/*3 ||1 ||0 ||0 ||53 |
|*3/*3 ||0 ||0 ||1 ||76 |
|Non-A/non-A ||37 ||82 ||7 ||– |
|Non-A/A ||45 ||12 ||30 ||26 |
|A/A ||18 ||6 ||63 ||50 |
In addition to genetic factors, the anticoagulant effect of warfarin is influenced by diet, drugs, and various disease states. Fluctuations in dietary vitamin K intake affect the activity of warfarin. A wide variety of drugs can alter absorption, clearance, or metabolism of warfarin. Because of the variability in the anticoagulant response to warfarin, coagulation monitoring is essential to ensure that a therapeutic response is obtained.
Warfarin therapy is most often monitored using the prothrombin time, a test that is sensitive to reductions in the levels of prothrombin, factor VII, and factor X. The test is performed by adding thromboplastin, a reagent that contains tissue factor, phospholipid, and calcium, to citrated plasma and determining the time to clot formation. Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors. Thus, less sensitive thromboplastins will trigger the administration of higher doses of warfarin to achieve a target prothrombin time. This is problematic because higher doses of warfarin increase the risk of bleeding.
The INR was developed to circumvent many of the problems associated with the prothrombin time. To calculate the INR, the patient’s prothrombin time is divided by the mean normal prothrombin time, and this ratio is then multiplied by the international sensitivity index (ISI), which is an index of the sensitivity of the thromboplastin used for prothrombin time determination to reductions in the levels of the vitamin K–dependent clotting factors. Highly sensitive thromboplastins have an ISI of 1.0. Most current thromboplastins have ISI values that range from 1.0 to 1.4.
Although the INR has helped to standardize anticoagulant practice, problems persist. The precision of INR determination varies depending on reagent-coagulometer combinations. This leads to variability in the INR results. Also complicating INR determination is unreliable reporting of the ISI by thromboplastin manufacturers. Furthermore, every laboratory must establish the mean normal prothrombin time with each new batch of thromboplastin reagent. To accomplish this, the prothrombin time must be measured in fresh plasma samples from at least 20 healthy volunteers using the same coagulometer that is used for patient samples.
For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0. An exception is patients with mechanical heart valves, particularly those in the mitral position or older ball and cage valves in the aortic position, where a target INR of 2.5–3.5 is recommended. Studies in atrial fibrillation demonstrate an increased risk of cardioembolic stroke when the INR falls to <1.7 and an increase in bleeding with INR values >4.5. These findings highlight the fact that vitamin K antagonists have a narrow therapeutic window. In support of this concept, a study in patients receiving long-term warfarin therapy for unprovoked venous thromboembolism demonstrated a higher rate of recurrent venous thromboembolism with a target INR of 1.5–1.9 compared with a target INR of 2.0–3.0.
Warfarin is usually started at a dose of 5–10 mg. Lower doses are used for patients with CYP2C9 or VKORC1 polymorphisms, which affect the pharmacodynamics or pharmacokinetics of warfarin and render patients more sensitive to the drug. The dose is then titrated to achieve the desired target INR. Because of its delayed onset of action, patients with established thrombosis or those at high risk for thrombosis are given concomitant initial treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux. Early prolongation of the INR reflects reduction in the functional levels of factor VII. Consequently, concomitant treatment with the parenteral anticoagulant should be continued until the INR has been therapeutic for at least 2 consecutive days. A minimum 5-day course of parenteral anticoagulation is recommended to ensure that the levels of factor Xa and prothrombin have been reduced into the therapeutic range with warfarin.
Because warfarin has a narrow therapeutic window, frequent coagulation monitoring is essential to ensure that a therapeutic anticoagulant response is maintained. Even patients with stable warfarin dose requirements should have their INR determined every 3–4 weeks. More frequent monitoring is necessary when new medications are introduced because so many drugs enhance or reduce the anticoagulant effects of warfarin.
Like all anticoagulants, the major side effect of warfarin is bleeding. A rare complication is skin necrosis. Warfarin crosses the placenta and can cause fetal abnormalities. Consequently, warfarin should not be used during pregnancy.
At least half of the bleeding complications with warfarin occur when the INR exceeds the therapeutic range. Bleeding complications may be mild, such as epistaxis or hematuria, or more severe, such as retroperitoneal or gastrointestinal bleeding. Life-threatening intracranial bleeding can also occur.
To minimize the risk of bleeding, the INR should be maintained in the therapeutic range. In asymptomatic patients whose INR is between 3.5 and 10, warfarin should be withheld until the INR returns to the therapeutic range. If the INR is over 10, oral vitamin K should be administered, at a dose of 2.5–5 mg, although there is no evidence that doing so reduces the bleeding risk. Higher doses of oral vitamin K (5–10 mg) produce more rapid reversal of the INR but may render patients temporarily resistant to warfarin when the drug is restarted. Patients with serious bleeding need more aggressive treatment. These patients should be given 5–10 mg of vitamin K by slow IV infusion. Additional vitamin K should be given until the INR is in the normal range. Treatment with vitamin K should be supplemented with fresh-frozen plasma as a source of the vitamin K–dependent clotting proteins. Four factor prothrombin complex concentrates, which contain all four vitamin K–dependent clotting proteins, are the treatment of choice for (1) life-threatening bleeds, (2) rapid restoration of the INR into the normal range in patients requiring urgent surgery or intervention, and (3) patients who cannot tolerate the volume load of fresh-frozen plasma.
Warfarin-treated patients who experience bleeding when their INR is in the therapeutic range require investigation into the cause of the bleeding. Those with gastrointestinal or genitourinary bleeding often have an underlying lesion.
A rare complication of warfarin, skin necrosis usually is seen 2–5 days after initiation of therapy. Well-demarcated erythematous lesions form on the thighs, buttocks, breasts, or toes. Typically, the center of the lesion becomes progressively necrotic. Examination of skin biopsies taken from the border of these lesions reveals thrombi in the microvasculature.
Warfarin-induced skin necrosis is seen in patients with congenital or acquired deficiencies of protein C or protein S. Initiation of warfarin therapy in these patients produces a precipitous fall in plasma levels of proteins C or S, thereby eliminating this important anticoagulant pathway before warfarin exerts an antithrombotic effect through lowering of the functional levels of factor X and prothrombin. The resultant procoagulant state triggers thrombosis. Why the thrombosis is localized to the microvasculature of fatty tissues is unclear.
Treatment involves discontinuation of warfarin and reversal with vitamin K, if needed. An alternative anticoagulant, such as heparin or LMWH, should be given in patients with thrombosis. Protein C concentrate can be given to protein C–deficient patients to accelerate healing of the skin lesions; fresh-frozen plasma may be of value if protein C concentrate is unavailable and for those with protein S deficiency. Occasionally, skin grafting is necessary when there is extensive skin loss.
Because of the potential for skin necrosis, patients with known protein C or protein S deficiency require overlapping treatment with a parenteral anticoagulant when initiating warfarin therapy. Warfarin should be started in low doses in these patients, and the parenteral anticoagulant should be continued until the INR is therapeutic for at least 2–3 consecutive days.
Warfarin crosses the placenta and can cause fetal abnormalities or bleeding. The fetal abnormalities include a characteristic embryopathy, which consists of nasal hypoplasia and stippled epiphyses. The risk of embryopathy is highest if warfarin is given in the first trimester of pregnancy. Central nervous system abnormalities can also occur with exposure to warfarin at any time during pregnancy. Finally, maternal administration of warfarin produces an anticoagulant effect in the fetus that can cause bleeding. This is of particular concern at delivery when trauma to the head during passage through the birth canal can lead to intracranial bleeding. Because of these potential problems, warfarin is contraindicated in pregnancy, particularly in the first and third trimesters. Instead, heparin, LMWH, or fondaparinux can be given during pregnancy for prevention or treatment of thrombosis.
Warfarin does not pass into the breast milk. Consequently, warfarin can safely be given to nursing mothers.
Patients with a lupus anticoagulant and those who need urgent or elective surgery present special challenges. Although observational studies suggested that patients with thrombosis complicating the antiphospholipid antibody syndrome required higher intensity warfarin regimens to prevent recurrent thromboembolic events, two randomized trials showed that targeting an INR of 2.0–3.0 is as effective as higher intensity treatment and produces less bleeding. Monitoring warfarin therapy can be problematic in patients with antiphospholipid antibody syndrome if the lupus anticoagulant prolongs the baseline INR; factor X levels can be used instead of the INR in such patients.
There is no need to stop warfarin before procedures associated with a low risk of bleeding; these include dental cleaning, simple dental extraction, cataract surgery, or skin biopsy. For procedures associated with a moderate or high risk of bleeding, warfarin should be stopped 5 days before the procedure to allow the INR to return to normal levels. Patients at high risk for thrombosis, such as those with mechanical heart valves, can be bridged with once-or twice-daily SC injections of LMWH when the INR falls to <2.0. The last dose of LMWH should be given 12–24 h before the procedure, depending on whether LMWH is administered twice or once daily. After the procedure, treatment with warfarin can be restarted.
New oral anticoagulants are now available as alternatives to warfarin. These include dabigatran, which targets thrombin, and rivaroxaban, apixaban, and edoxaban, which target factor Xa. All of these drugs have a rapid onset and offset of action and have half-lives that permit once- or twice-daily administration. Designed to produce a predictable level of anticoagulation, the new oral agents are more convenient to administer than warfarin because they are given in fixed doses without routine coagulation monitoring.
The new oral anticoagulants are small molecules that bind reversibly to the active site of their target enzyme. Table 24-9 summarizes the distinct pharmacologic properties of these agents.
TABLE 24-9Comparison of the Pharmacologic Properties of the New Oral Anticoagulants ||Download (.pdf) TABLE 24-9 Comparison of the Pharmacologic Properties of the New Oral Anticoagulants
|Characteristic ||Rivaroxaban ||Apixaban ||Edoxaban ||Dabigatran |
|Target ||Factor Xa ||Factor Xa ||Factor Xa ||Thrombin |
|Prodrug ||No ||No ||No ||Yes |
|Bioavailability ||80% ||60% ||50% ||6% |
|Dosing ||qd (bid) ||bid ||qd ||bid (qd) |
|Half-life ||7–11 h ||12 h ||9–11 h ||12–17 h |
|Renal ||33% (66%) ||25% ||35% ||80% |
|Monitoring ||No ||No ||No ||No |
|Interactions ||3A4/P-gp ||3A4/P-gp ||P-gp ||P-gp |
The new oral anticoagulants have been compared with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation in four randomized trials that enrolled 71,683 patients. A meta-analysis of these data demonstrates that compared with warfarin, the new agents significantly reduce stroke or systemic embolism by 19% (p = .001), primarily driven by a 51% reduction in hemorrhagic stroke (p <.0001), and are associated with a 10% reduction in mortality (p <.0001). New oral anticoagulants reduce intracranial hemorrhage by 52% compared with warfarin (p <.0001), but increase gastrointestinal bleeding by about 24% (p = .04). Overall, the new agents demonstrate a favorable benefit-to-risk profile compared with warfarin, and their relative efficacy and safety are maintained across a wide spectrum of atrial fibrillation patients, including those over the age of 75 years and those with a prior history of stroke. Based on these findings, dabigatran, rivaroxaban, and apixaban are licensed as alternatives to warfarin for stroke prevention in nonvalvular atrial fibrillation, and edoxaban is under regulatory consideration for this indication. Nonvalvular atrial fibrillation is defined as that occurring in patients without mechanical heart valves or severe rheumatic valvular disease, particularly mitral stenosis and/or regurgitation.
Dabigatran, rivaroxaban, and apixaban have been compared with enoxaparin for thromboprophylaxis after elective hip or knee arthroplasty. Currently, only rivaroxaban and apixaban are licensed for this indication in the United States. Rivaroxaban and dabigatran are also licensed for treatment of DVT or PE. Apixaban and edoxaban have also been investigated for treatment of patients with venous thromboembolism, but have not yet been approved for this indication. Rivaroxaban is licensed in Europe for prevention of recurrent ischemic events in patients who have been stabilized after an acute coronary syndrome. In this setting, rivaroxaban is usually administered in conjunction with dual antiplatelet therapy with aspirin and clopidogrel.
For stroke prevention in patients with nonvalvular atrial fibrillation, rivaroxaban is given at a dose of 20 mg once daily with a dose reduction to 15 mg once daily in patients with a creatinine clearance of 15–49 mL/min; dabigatran is given at a dose of 150 mg twice daily with a dose reduction to 75 mg twice daily in those with a creatinine clearance of 15–30 mL/min; and apixaban is given at a dose of 5 mg twice daily with a dose reduction to 2.5 mg twice daily for patients with a creatinine >1.5 g/dL, for those 80 years of age or older, or for patients who weigh <60 kg.
For thromboprophylaxis after elective hip or knee replacement surgery, rivaroxaban is given at a dose of 10 mg once daily, whereas apixaban is given at a dose of 2.5 mg twice daily. For treatment of patients with DVT or PE, rivaroxaban is started at a dose of 15 mg twice daily for 3 weeks; the dose is then reduced to 20 mg once daily thereafter. After a minimum of a 5 day course of treatment with heparin or LMWH, dabigatran is given at a dose of 150 mg twice daily.
Although designed to be administered without routine monitoring, there are situations where determination of the anticoagulant activity of the new oral anticoagulants can be helpful. These include assessment of adherence, detection of accumulation or overdose, identification of bleeding mechanisms, and determination of activity prior to surgery or intervention. For qualitative assessment of anticoagulant activity, the prothrombin time can be used for factor Xa inhibitors and the aPTT for dabigatran. Rivaroxaban and edoxaban prolong the prothrombin time more than apixaban. In fact, because apixaban has such a limited effect on the prothrombin time, anti-factor Xa assays are needed to assess its activity. The effect of the drugs on tests of coagulation varies depending on the time that the blood is drawn relative to the timing of the last dose of the drug and the reagents used to perform the tests. Chromogenic anti-factor Xa assays and a dilute thrombin clotting time with appropriate calibrators provide quantitative assays to measure the plasma levels of the factor Xa inhibitors and dabigatran, respectively.
Like all anticoagulants, bleeding is the most common side effect of the new oral anticoagulants. The new agents are associated with less intracranial bleeding than warfarin. The increased risk of intracranial bleeding with warfarin likely reflects the reduction in functional levels of factor VII, which precludes efficient thrombin generation at sites of microvascular bleeding in the brain. Because the new oral anticoagulants target downstream coagulation enzymes, they produce less impairment of hemostatic plug formation at sites of vascular injury.
A downside of the new oral anticoagulants is the increased risk of gastrointestinal bleeding. This likely occurs because unabsorbed active drug in the gut exacerbates bleeding from lesions. Although dabigatran etexilate is a prodrug, only 7% is absorbed. Although the remainder passes through the gut, at least two-thirds is metabolically activated to dabigatran by gut esterases.
Dyspepsia occurs in up to 10% of patients treated with dabigatran; this problem improves with time and can be minimized by administering the drug with food. Dyspepsia is rare with rivaroxaban, apixaban, and edoxaban.
Like warfarin, the new oral anticoagulants must be stopped before procedures associated with a moderate or high risk of bleeding. The drugs should be held for 1–2 days, or longer if renal function is impaired. Assessment of residual anticoagulant activity before procedures associated with a high bleeding risk is prudent.
There are no specific antidotes for the new oral anticoagulants. With minor bleeding, holding one or two doses of drug is usually sufficient. The approach to serious bleeding is similar to that with warfarin except that vitamin K administration is of no benefit. Thus, the anticoagulant and antiplatelet drugs should be held, the patient should be resuscitated with fluids and blood products as necessary, and, if possible, the bleeding site should be identified and managed. Coagulation testing will determine the extent of anticoagulation. and renal function should be assessed so that the half-life of the drug can be calculated. Timing of the last dose of anticoagulant is important; administration of oral activated charcoal may help to prevent absorption of drug administered in the past 2–4 h. If bleeding continues or is life-threatening, procoagulants, such as prothrombin complex concentrate (either unactivated or activated) or factor VIIa, can be administered, although the evidence of their effectiveness is limited. Dialysis removes dabigatran from the circulation in patients with renal impairment; dialysis does not remove rivaroxaban, apixaban, or edoxaban because unlike dabigatran, these drugs are highly protein-bound.
As small molecules, the new oral anticoagulants can all pass through the placenta. Consequently, these agents are contraindicated in pregnancy, and when used by women of childbearing potential, appropriate contraception is important.
Although the lack of antidotes has created concern about the risk of bleeding events in patients taking the new oral anticoagulants, emerging postmarketing data suggest that the rates of bleeding in the real-world setting are similar to those reported in the trials. Nonetheless, specific antidotes are under development. These include a humanized mouse monoclonal antibody fragment against dabigatran and a recombinant variant of factor Xa that serves as a decoy for the oral factor Xa inhibitors. Neither agent is currently available for clinical use.