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The new oral anticoagulants: Reasonable alternatives to warfarin
Author(s)
Bernardino Roca, MD, PhD
Manuel Roca, MD

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).1,2 Other factor Xa inhibitors, including edoxaban3 (available in the United States and Japan) and betrixaban,4 may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.5 Indications for these new agents are expected to expand as new clinical trial results become available.6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Characteristics of thrombin inhibitors and factor Xa inhibitors

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Approved indications for and doses of the new oral anticoagulants

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

  • Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
  • Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Selected steps in the blood coagulation pathway
Figure 1. Selected steps in the blood coagulation pathway. Sites of action of thrombin inhibitors and factor Xa inhibitors are denoted by blue slashes.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,11 but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,12 Dyspepsia is common and may be severe enough to require stopping treatment.13 Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.1

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.16 No other selective thrombin inhibitors are currently in an advanced stage of development.

 

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.17 These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.18

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).19

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.20–23 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
  • Preventing deep vein thrombosis after hip or knee replacement surgery
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.1 Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.24 Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).25  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.26–28 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.29

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.31

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.33

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.38 Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.25 These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran40 but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

  • Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans41
  • Activated prothrombin complex concentrate for reversing thrombin inhibitors
  • Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents42–44
  • Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.45

More research is needed to assess the efficacy and safety of these measures.46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.39

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation48 appears as effective and safe as anticoagulation with warfarin.49 There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer54 and critical illnesses,55 and in treating acute coronary syndrome56–58 and other conditions.59 However, their role in these settings is not well established.60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.65

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.66

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.18

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.17,69,70 However, there are factors to consider when choosing a drug:

  • Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
  • Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.13
  • Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.1,71
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Bernardino Roca, MD, PhD
Hospital General, University Jaume I, Castellon, Spain

Manuel Roca, MD
Hospital Provincial, University Jaume I, Castellon, Spain

Address: Bernardino Roca, MD, PhD, Hospital General, University Jaume I, Catalunya, 33-4, 12004 Castellon, Spain; e-mail: [email protected]

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Cleveland Clinic Journal of Medicine - 82(12)
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Cleveland Clinic Journal of Medicine
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Neurology
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anticoagulant, oral anticoagulant, target-specific oral anticoagulant, thrombin inhibitor, factor IIa inhibitor, factor Xa inhibitor, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Bernardino Roca, Manuel Roca
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Bernardino Roca, MD, PhD
Manuel Roca, MD
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Bernardino Roca, MD, PhD
Manuel Roca, MD
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Author and Disclosure Information

Bernardino Roca, MD, PhD
Hospital General, University Jaume I, Castellon, Spain

Manuel Roca, MD
Hospital Provincial, University Jaume I, Castellon, Spain

Address: Bernardino Roca, MD, PhD, Hospital General, University Jaume I, Catalunya, 33-4, 12004 Castellon, Spain; e-mail: [email protected]

Author and Disclosure Information

Bernardino Roca, MD, PhD
Hospital General, University Jaume I, Castellon, Spain

Manuel Roca, MD
Hospital Provincial, University Jaume I, Castellon, Spain

Address: Bernardino Roca, MD, PhD, Hospital General, University Jaume I, Catalunya, 33-4, 12004 Castellon, Spain; e-mail: [email protected]

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Roca_NewOralAnticoagulants.pdf
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When patients on target-specific oral anticoagulants need surgery
Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).1,2 Other factor Xa inhibitors, including edoxaban3 (available in the United States and Japan) and betrixaban,4 may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.5 Indications for these new agents are expected to expand as new clinical trial results become available.6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Characteristics of thrombin inhibitors and factor Xa inhibitors

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Approved indications for and doses of the new oral anticoagulants

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

  • Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
  • Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Selected steps in the blood coagulation pathway
Figure 1. Selected steps in the blood coagulation pathway. Sites of action of thrombin inhibitors and factor Xa inhibitors are denoted by blue slashes.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,11 but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,12 Dyspepsia is common and may be severe enough to require stopping treatment.13 Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.1

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.16 No other selective thrombin inhibitors are currently in an advanced stage of development.

 

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.17 These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.18

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).19

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.20–23 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
  • Preventing deep vein thrombosis after hip or knee replacement surgery
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.1 Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.24 Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).25  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.26–28 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.29

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.31

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.33

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.38 Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.25 These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran40 but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

  • Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans41
  • Activated prothrombin complex concentrate for reversing thrombin inhibitors
  • Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents42–44
  • Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.45

More research is needed to assess the efficacy and safety of these measures.46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.39

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation48 appears as effective and safe as anticoagulation with warfarin.49 There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer54 and critical illnesses,55 and in treating acute coronary syndrome56–58 and other conditions.59 However, their role in these settings is not well established.60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.65

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.66

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.18

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.17,69,70 However, there are factors to consider when choosing a drug:

  • Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
  • Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.13
  • Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.1,71

For decades, vitamin K antagonists such as warfarin, acenocoumarol, phenindione, and phenprocoumon have been the only available oral anticoagulants. These drugs have similar pharmacologic profiles and share significant drawbacks in clinical use: a narrow therapeutic window, food and drug interactions, and the need for repeated blood testing to ensure the desired international normalized ratio.

Such problems have fostered research in the field of coagulation, and new oral agents that selectively target coagulation factors have become available. At least three such products are already available in most countries: dabigatran (a thrombin or factor IIa inhibitor) and rivaroxaban and apixaban (factor Xa inhibitors).1,2 Other factor Xa inhibitors, including edoxaban3 (available in the United States and Japan) and betrixaban,4 may also soon become available worldwide. 

The new oral anticoagulants are more effective than vitamin K antagonists in preventing several thromboembolic conditions, have fewer drug interactions, and likely have fewer side effects.5 Indications for these new agents are expected to expand as new clinical trial results become available.6,7

This review summarizes the clinically relevant characteristics of the new oral anticoagulants (Table 1) and provides guidance on their usage (Table 2).

THROMBIN (FACTOR IIa) INHIBITORS

Dabigatran

Characteristics of thrombin inhibitors and factor Xa inhibitors

Dabigatran etexilate is a prodrug that is rapidly and completely converted by esterases in the plasma and liver into its active metabolite, dabigatran. It competitively and reversibly binds to freely circulating and clot-bound thrombin, thereby blocking thrombin’s pro­coagulant properties (Figure 1).

Approved indications for and doses of the new oral anticoagulants

Clinical trials have shown dabigatran to be similar to warfarin and enoxaparin in efficacy and safety in preventing and treating thromboembolic disease.8–10

Indications. Dabigatran is approved by the US Food and Drug Administration (FDA) for:

  • Preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism in patients who have been treated with a parenteral anticoagulant for 5 to 10 days
  • Preventing recurrence of deep vein thrombosis and pulmonary embolism in patients who have previously been treated with other medications.

Selected steps in the blood coagulation pathway
Figure 1. Selected steps in the blood coagulation pathway. Sites of action of thrombin inhibitors and factor Xa inhibitors are denoted by blue slashes.

Precautions. Dabigatran should not be used, or should be used only in a reduced dosage, in patients with renal failure. It can be used in patients with moderate liver impairment but should be avoided in patients with advanced liver disease (cirrhosis), especially if they have coagulopathy. Its use in pregnant and nursing women is not recommended.

Adverse effects. Bleeding, including gastrointestinal and intracranial hemorrhage, is the most important adverse effect,11 but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,12 Dyspepsia is common and may be severe enough to require stopping treatment.13 Other possible effects are pain or burning in the throat, skin rash, and syncope. The risk of acute coronary syndrome is slightly increased but is outweighed by the benefit of ischemic stroke prevention.14,15

Drug interactions. Normally, permeability (P)-glycoprotein intestinal transporter extrudes substrate drugs back into the gut lumen after initial absorption, thereby interfering with drug bioavailability. Strong P-glycoprotein inhibitors (eg, ketoconazole, cyclosporine, tacrolimus, dronedarone, amiodarone, verapamil, clarithromycin) increase the plasma concentration of dabigatran. Despite that, giving these drugs with dabigatran is generally safe except in patients with renal failure (and especially with ketoconazole and dronedarone). To reduce interaction with verapamil, dabigatran should be taken at least 2 hours before this drug.

Potent P-glycoprotein transporter inducers such as rifampicin, carbamazepine, and phenytoin reduce the plasma concentration of dabigatran, and concomitant use of dabigatran with these drugs should be avoided.1

Another selective thrombin inhibitor

Ximelagatran was extensively investigated and approved in several countries in 2006. However, it was withdrawn after reports of severe hepatotoxicity.16 No other selective thrombin inhibitors are currently in an advanced stage of development.

 

 

FACTOR Xa INHIBITORS

Factor Xa is an ideal target for anticoagulants because of its important role in thrombin formation (Figure 1). Selective or direct factor Xa inhibitors significantly reduce the number of strokes and systemic embolic events compared with warfarin in patients with atrial fibrillation. They also may cause fewer major bleeding events than warfarin, although evidence supporting this is less robust.17 These agents have shown an advantage over enoxaparin for thromboprophylaxis after elective hip or knee replacement surgery and after hip fracture surgery without increasing the rate of bleeding events.18

Rivaroxaban

Rivaroxaban is an oral direct factor Xa inhibitor. It  reversibly binds to factor Xa with high specificity and inhibits free and clot-bound factor Xa as well as factor Xa in the prothrombinase complex (which catalyzes the conversion of prothrombin to thrombin).19

Indications. Clinical trials have shown rivaroxaban to have suitable efficacy and safety in several clinical situations.20–23 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in nonvalvular atrial fibrillation
  • Preventing deep vein thrombosis after hip or knee replacement surgery
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrence of deep vein thrombosis and pulmonary embolism.

In addition, the European Medicines Agency has approved the use of rivaroxaban together with antiplatelet medications to prevent atherothrombotic events after an acute coronary syndrome with elevated cardiac biomarkers.

Precautions. Rivaroxaban should be taken with food to maximize its absorption. Like dabigatran, it should be avoided or used cautiously in patients with renal failure and liver disease, and it is not recommended for pregnant and nursing women. 

Adverse effects. The most common adverse event is bleeding, although the incidence of major hemorrhage is similar to that with vitamin K antagonists and low-molecular-weight heparins.1 Other effects include osteoarticular pain, weakness, wound secretion, skin rash, pruritus, abdominal pain, and syncope.

Drug interactions. Inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes can alter the metabolism of rivaroxaban, making its levels too high. Rivaroxaban is not recommended for patients receiving systemic treatment with azole-antimycotics (eg, ketoconazole) or protease inhibitors to treat human immunodeficiency virus (HIV) infection (eg, ritonavir), as these drugs are strong inhibitors of both systems and may considerably increase plasma rivaroxaban concentrations.24 Interactions of rivaroxaban with most other inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes are considered clinically inconsequential, but caution is still recommended, especially in patients already at risk of bleeding (eg, those taking antiplatelet agents).25  

Strong inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes (eg, rifampicin, phenytoin) can reduce plasma rivaroxaban concentrations and thus decrease its efficacy. Caution is needed if rivaroxaban is taken with these drugs.

Apixaban

Apixaban also selectively and reversibly inhibits free and clot-bound factor Xa, as well as factor Xa in the prothrombinase complex.

Indications. Apixaban has a suitable efficacy and safety profile, and in clinical trials fewer patients died while taking it than those taking warfarin.26–28 It is FDA-approved for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Prophylaxis of deep vein thrombosis and pulmonary embolism in patients who have undergone hip or knee replacement
  • Treating deep vein thrombosis and pulmonary embolism
  • Reducing the risk of recurrent deep vein thrombosis and pulmonary embolism after initial therapy.

Precautions. Apixaban can be used in most patients with renal failure, but at a lower dosage in some circumstances (Table 2). It can be used without dosage adjustment for patients with mild hepatic impairment but should be avoided in those with moderate or advanced liver failure. It is contraindicated in pregnant and nursing women.

Adverse effects. As with other anticoagulants, the most common adverse effect is bleeding, but the incidence is similar to that with vitamin K antagonists and low-molecular-weight heparins.1,26–28 Other adverse reactions, such as nausea, skin rash, and liver enzyme elevation, are uncommon.

Drug interactions are similar to those of rivaroxaban but are generally less intense. Concomitant use with strong dual inhibitors of the P-glycoprotein transporter or the cytochrome P450 enzymes, especially azole-antimycotics and HIV protease inhibitors, should be avoided, but if used, the apixaban dosage may be halved. Caution is also recommended if using apixaban with dual inducers of the P-glycoprotein transporter and the cytochrome P450 enzymes.29

Edoxaban

Edoxaban, another direct factor Xa inhibitor, has a rapid onset of action. It is taken orally once daily and has antithrombotic efficacy similar to other agents in this group.1,30

Indications. Edoxaban has been approved by the Japanese Pharmaceuticals and Medical Devices Agency and the FDA for:

  • Reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation
  • Treating deep vein thrombosis and pulmonary embolism after 10 days of initial therapy with a parenteral anticoagulant.

Precautions. Edoxaban should not be used in patients with creatinine clearance above 95 mL/min because patients with this excellent level of renal function may clear the drug too well and therefore have a higher risk of ische­mic stroke than those receiving warfarin.31

Adverse effects and drug interactions are similar to those of other factor Xa inhibitors.

Other factor Xa inhibitors

Betrixaban is similar to other factor Xa inhibitors but has some unique pharmacokinetic characteristics, including minimal metabolism through the cytochrome P450 system, limited renal excretion, and a long half-life. This profile may have the advantages of fewer drug interactions and greater flexibility for use in patients with poor renal function, as well as the convenience of once-daily dosing.4,32 The drug has not yet been approved for clinical use by the FDA or the European Medicines Agency.

Additional oral factor Xa inhibitors, including letaxaban, darexaban, and eribaxaban, are being developed with the aim of overcoming the limitations of available drugs in the group.33

COAGULATION MONITORING

Given their rapid onset of action, stable pharmacokinetic properties, and few significant drug interactions, the new oral anticoagulants do not generally require coagulation monitoring. However, these drugs may produce alterations in coagulation tests: thrombin inhibitors tend to prolong the activated partial thromboplastin time, and factor Xa inhibitors tend to prolong the prothrombin time. These alterations vary from laboratory to laboratory, depending on the reagents used.34,35

The new agents have also been reported to cause false-positive results on lupus anticoagulant assays and falsely elevated activated protein C ratio assays, misclassifying patients with the factor V Leiden mutation as normal.36,37

Anticoagulation from dabigatran therapy can be monitored with the ecarin clotting time test, which yields a dose-dependent prolongation of clotting time.38 Rivaroxaban, apixaban, and edoxaban can be monitored using modified chromogenic anti-Xa assays.25 These tests may help manage overdoses, bleeding events, and emergency perioperative situations, but their usefulness in clinical practice is limited at this time because they are not widely available and they are not validated for this use.

 

 

SWITCHING FROM VITAMIN K ANTAGONISTS TO THE NEW AGENTS

Important issues to consider when switching anticoagulant agents are the delayed onset of action after initiating treatment and the persistent anticoagulant effect after stopping it. In both cases, the international normalized ratio can be used to monitor the anticoagulant effect of the drugs. Renal failure should also be considered, as it can prolong the plasma half-life of the agents.1,39

MANAGING BLEEDING

Dabigatran is the only new anticoagulant with an antidote commercially available: idaruciz­umab can completely reverse the anticoagulant effect of dabigatran within minutes.

The other new oral anticoagulants lack antidotes, which can present a major problem if a patient has a major bleed or needs emergency surgery. Giving vitamin K is probably useless in this situation. In general, patients taking one of the new oral anticoagulants who present with bleeding should be treated with traditional measures—eg, oral activated charcoal to retard absorption of recently ingested drugs and cauterization and packing of localized bleeding sites. Dialysis may be useful for patients taking dabigatran40 but probably not the other drugs, because they are more highly protein-bound.

Other measures to consider include giving:

  • Fresh frozen plasma, which may have some potential for reversing the action of thrombin inhibitors and factor Xa inhibitors but lacks data in humans41
  • Activated prothrombin complex concentrate for reversing thrombin inhibitors
  • Nonactivated prothrombin complex concentrates and factor Xa analogues for reversing anti-factor Xa agents42–44
  • Recombinant factor VIIa, but serious adverse effects—disseminated intravascular coagulation and systemic thrombosis— limit its usefulness.45

More research is needed to assess the efficacy and safety of these measures.46,47

STOPPING THERAPY BEFORE SURGERY

How long to withhold a new oral anticoagulant before patients undergo surgery depends on the type and urgency of the procedure, the indication for anticoagulation, the patient’s renal function, and the drug used.

For procedures with a low risk of bleeding (eg, laparoscopy, colonoscopy), dabigatran should be stopped at least 48 hours before the procedure, and factor Xa inhibitors at least 24 hours before. More time should be allowed for patients with renal failure to clear the drug, according to creatinine clearance.

For procedures entailing a high bleeding risk (eg, major surgery, insertion of pacemaker or defibrillator, neurosurgery, spinal puncture), any new oral anticoagulant should be stopped at least 48 hours before the procedure, with a longer time needed for patients with renal failure.

If urgent surgery is needed and performed within a few hours after the last dose of a drug, bleeding complications should be anticipated.

Resuming anticoagulation therapy after surgery should also be individualized depending on the procedure, the indication for anticoagulation, and renal function. In most patients, if good hemostasis is achieved, the drug may be resumed 4 to 6 hours after surgery. Generally, the first dose should be reduced by 50%, after which the usual maintenance dose can be resumed.39

OTHER POSSIBLE USES

Cardioversion. Anticoagulation with da­big­­atran before and after cardioversion in patients with atrial fibrillation48 appears as effective and safe as anticoagulation with warfarin.49 There are insufficient data for the other new oral anticoagulants.

Heparin-induced thrombocytopenia. The new oral anticoagulants do not affect the interaction of platelets with platelet factor 4 or antibodies to the platelet factor 4-heparin complex, indicating that they may be an appropriate option for anticoagulation in patients with heparin-induced thrombocytopenia.50–53

Other conditions. The new oral anticoagulants have demonstrated efficacy in preventing or treating thromboembolic disease in patients with cancer54 and critical illnesses,55 and in treating acute coronary syndrome56–58 and other conditions.59 However, their role in these settings is not well established.60,61

SITUATIONS TO AVOID

Valvular heart disease. The new oral anticoagulants should not be prescribed for patients with a prosthetic heart valve or other significant valvular heart disease because of an increased risk of thrombotic complications with dabigatran and the lack of evidence of efficacy and safety of factor Xa inhibitors.62–64

Concurrent thrombolytic therapy along with any of the new oral anticoagulants poses a very high risk of bleeding. Some cases in which dabigatran was used successfully in this situation have been reported, but definitive recommendations are lacking.65

Elderly patients. The safety of the new oral anticoagulants in the elderly is of concern because of the high prevalence of renal failure and other comorbidities and the underrepresentation of this population in many clinical trials assessing these drugs. Data on interactions with foods or other drugs in this population are also scant.66

CHOOSING AN ORAL ANTICOAGULANT

New oral anticoagulants are now a viable alternative to vitamin K antagonists for preventing and treating thromboembolic disease.67,68

When oral anticoagulation is indicated, the choice of drug should be individualized. Cost is an important consideration: direct costs of the new drugs are substantially higher than those of vitamin K antagonists and heparin, but their cost-effectiveness may be comparable or superior to that of warfarin or enoxaparin when clinical efficacy and savings in avoiding coagulation tests are considered.18

Many experts estimate that the new oral anticoagulants are not remarkably superior to vitamin K antagonists, and thus patients whose coagulation is well controlled and stable on a traditional drug would probably not benefit much from changing.1,18

There is currently no conclusive evidence to determine which new oral anticoagulant drug is more effective and safe for long-term treatment, as head-to-head studies of the different medications have not yet been performed.17,69,70 However, there are factors to consider when choosing a drug:

  • Rivaroxaban and edoxaban can be taken once daily and so may be better choices for patients who may have difficulties with compliance.
  • Dabigatran should be avoided in patients with dyspepsia because of gastrointestinal adverse effects.13
  • Dabigatran should be avoided in patients at risk of myocardial infarction because of a possible additional increase in risk.1,71
References
  1. Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc 2013; 88:495–511.
  2. Rognoni C, Marchetti M, Quaglini S, Liberato NL. Apixaban, dabigatran, and rivaroxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis. Clin Drug Investig 2014; 34:9–17.
  3. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406–1415.
  4. Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor - betrixaban. Expert Opin Investig Drugs 2013; 22:1465–1472.
  5. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013; 52:69–82.
  6. Turagam MK, Addepally NS, Velagapudi P. Novel anticoagulants for stroke prevention in atrial fibrillation and chronic kidney disease. Expert Rev Cardiovasc Ther 2013; 11:1297–1299.
  7. Biondi-Zoccai G, Malavasi V, D’Ascenzo F, et al. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth 2013; 5:40–54.
  8. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–1151.
  9. Eriksson BI, Dahl OE, Huo MH, et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*): a randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105:721–729.
  10. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709–718.
  11. Donaldson M, Norbeck AO. Adverse events in patients initiated on dabigatran etexilate therapy in a pharmacist-managed anticoagulation clinic. Pharm Pract (Granada) 2013; 11:90–95.
  12. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368:1272–1274.
  13. Bytzer P, Connolly SJ, Yang S, et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013; 11:246–252.
  14. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397–402.
  15. Artang R, Rome E, Nielsen JD, Vidaillet HJ. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol 2013; 112:1973–1979.
  16. Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol 2010; 196:407–418.
  17. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2013; 8:CD008980.
  18. Capranzano P, Miccichè E, D’Urso L, Privitera F, Tamburino C. Personalizing oral anticoagulant treatment in patients with atrial fibrillation. Expert Rev Cardiovasc Ther 2013; 11:959-973.
  19. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol 2012; 26:27-32.
  20. EINSTEIN–PE Investigators; Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287–1297.
  21. EINSTEIN Investigators; Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499–2510.
  22. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–891.
  23. Cohen AT, Spiro TE, Büller HR, et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368:513–523.
  24. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76:455–466.
  25. Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108:876–886.
  26. Agnelli G, Buller HR, Cohen A, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368:699–708.
  27. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981–992.
  28. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363:2487–2498.
  29. Keating GM. Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Drugs 2013; 73:825–843.
  30. Giugliano RP, Ruff CT, Braunwald E, et al; NGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093–2104.
  31. Traynor K. Edoxaban approved for embolism prevention. Am J Health Syst Pharm 2015; 72:258.
  32. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013; 34:1498–1505.
  33. Bondarenko M, Curti C, Montana M, Rathelot P, Vanelle P. Efficacy and toxicity of factor Xa inhibitors. J Pharm Pharm Sci 2013; 16:74–88.
  34. Funk DM. Coagulation assays and anticoagulant monitoring. Hematology Am Soc Hematol Educ Program 2012; 2012:460–465.
  35. Gouin-Thibault I, Flaujac C, Delavenne X, et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb Haemost 2014; 111:240–248.
  36. Halbmayer WM, Weigel G, Quehenberger P, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med 2012; 50:1601–1615.
  37. Merriman E, Kaplan Z, Butler J, Malan E, Gan E, Tran H. Rivaroxaban and false positive lupus anticoagulant testing. Thromb Haemost 2011; 105:385–386.
  38. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–1127.
  39. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012; 119:3016–3023.
  40. Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013; 8:1533–1539.
  41. Akwaa F, Spyropoulos AC. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med 2013; 15:288–298.
  42. Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol 2013; 26:191–202.
  43. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19:446–451.
  44. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111:189–198.
  45. Holster IL, Hunfeld NG, Kuipers EJ, Kruip MJ, Tjwa ET. On the treatment of new oral anticoagulant-associated gastrointestinal hemorrhage. J Gastrointestin Liver Dis 2013; 22:229–231.
  46. Nitzki-George D, Wozniak I, Caprini JA. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Ann Pharmacother 2013; 47:841–855.
  47. Nutescu EA, Dager WE, Kalus JS, Lewin JJ 3rd, Cipolle MD. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm 2013; 70:1914–1929.
  48. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:1935–1944.
  49. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011; 123:131–136.
  50. Warkentin TE. HIT: treatment easier, prevention harder. Blood 2012; 119:1099–1100.
  51. Mirdamadi A. Dabigatran, a direct thrombin inhibitor, can be a life-saving treatment in heparin-induced thrombocytopenia. ARYA Atheroscler 2013; 9:112–114.
  52. Walenga JM, Prechel M, Hoppensteadt D, et, al. Apixaban as an alternate oral anticoagulant for the management of patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2013; 19:482–487.
  53. Bakchoul T, Greinacher A. Recent advances in the diagnosis and treatment of heparin-induced thrombocytopenia. Ther Adv Hematol 2012; 3:237–251.
  54. Den Exter PL, Kooiman J, van der Hulle T, Huisman MV. New anticoagulants in the treatment of patients with cancer-associated venous thromboembolism. Best Pract Res Clin Haematol 2013; 26:163–169.
  55. Adriance SM, Murphy CV. Prophylaxis and treatment of venous thromboembolism in the critically ill. Int J Crit Illn Inj Sci 2013; 3:143–151.
  56. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366:9–19.
  57. Chatterjee S, Sharma A, Uchino K, Biondi-Zoccai G, Lichstein E, Mukherjee D. Rivaroxaban and risk of myocardial infarction: insights from a meta-analysis and trial sequential analysis of randomized clinical trials. Coron Artery Dis 2013; 24:628–635.
  58. Liew A, Darvish-Kazem S, Douketis JD. Is there a role for the novel oral anticoagulants in patients with an acute coronary syndrome? A review of the clinical trials. Pol Arch Med Wewn 2013; 123:617–622.
  59. Säily VM, Pétas A, Joutsi-Korhonen L, Taari K, Lassila R, Rannikko AS. Dabigatran for thromboprophylaxis after robotic assisted laparoscopic prostatectomy: retrospective analysis of safety profile and effect on blood coagulation. Scand J Urol 2014; 48:153–159.
  60. Kearon C, Akl EA, Comerota AJ, et al; ; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2):e419S–e494S.
  61. Cove CL, Hylek EM. An updated review of target-specific oral anticoagulants used in stroke prevention in atrial fibrillation, venous thromboembolic disease, and acute coronary syndromes. J Am Heart Assoc 2013; 2:e000136.
  62. Eikelboom JW, Connolly SJ, Brueckmann M, et al; RE-ALIGN Investigators. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369:1206–1214.
  63. Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol 2013; 69:1617–1633.
  64. Heidbuchel H, Verhamme P, Alings M, et al. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 2013; 34:2094–2106.
  65. Matute MC, Guillan M, Garcia-Caldentey J, et al. Thrombolysis treatment for acute ischaemic stroke in a patient on treatment with dabigatran. Thromb Haemost 2011; 106:178–179.
  66. Stöllberger C, Finsterer J. Concerns about the use of new oral anticoagulants for stroke prevention in elderly patients with atrial fibrillation. Drugs Aging 2013; 30:949–958.
  67. Mantha S. Target-specific oral anticoagulants in atrial fibrillation: results of phase III trials and comments on sub-analyses. J Thromb Thrombolysis 2013; 36:155–162.
  68. Prandoni P, Dalla Valle F, Piovella C, Tormene D, Pesavento R. New anticoagulants for the treatment of venous thromboembolism. Minerva Med 2013; 104:131–139.
  69. Chatterjee S, Sardar P, Biondi-Zoccai G, Kumbhani DJ. New oral anticoagulants and the risk of intracranial hemorrhage: traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fibrillation. JAMA Neurol 2013; 70:1486–1490.
  70. Weitz JI. Anticoagulation therapy in 2015: where we are and where we are going. J Thromb Thrombolysis 2015; 39:264–272.
  71. Weitz JI, Gross PL. New oral anticoagulants: which one should my patient use? Hematology Am Soc Hematol Educ Program 2012; 2012:536–540.
References
  1. Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin Proc 2013; 88:495–511.
  2. Rognoni C, Marchetti M, Quaglini S, Liberato NL. Apixaban, dabigatran, and rivaroxaban versus warfarin for stroke prevention in non-valvular atrial fibrillation: a cost-effectiveness analysis. Clin Drug Investig 2014; 34:9–17.
  3. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369:1406–1415.
  4. Palladino M, Merli G, Thomson L. Evaluation of the oral direct factor Xa inhibitor - betrixaban. Expert Opin Investig Drugs 2013; 22:1465–1472.
  5. Scaglione F. New oral anticoagulants: comparative pharmacology with vitamin K antagonists. Clin Pharmacokinet 2013; 52:69–82.
  6. Turagam MK, Addepally NS, Velagapudi P. Novel anticoagulants for stroke prevention in atrial fibrillation and chronic kidney disease. Expert Rev Cardiovasc Ther 2013; 11:1297–1299.
  7. Biondi-Zoccai G, Malavasi V, D’Ascenzo F, et al. Comparative effectiveness of novel oral anticoagulants for atrial fibrillation: evidence from pair-wise and warfarin-controlled network meta-analyses. HSR Proc Intensive Care Cardiovasc Anesth 2013; 5:40–54.
  8. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361:1139–1151.
  9. Eriksson BI, Dahl OE, Huo MH, et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*): a randomised, double-blind, non-inferiority trial. Thromb Haemost 2011; 105:721–729.
  10. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368:709–718.
  11. Donaldson M, Norbeck AO. Adverse events in patients initiated on dabigatran etexilate therapy in a pharmacist-managed anticoagulation clinic. Pharm Pract (Granada) 2013; 11:90–95.
  12. Southworth MR, Reichman ME, Unger EF. Dabigatran and postmarketing reports of bleeding. N Engl J Med 2013; 368:1272–1274.
  13. Bytzer P, Connolly SJ, Yang S, et al. Analysis of upper gastrointestinal adverse events among patients given dabigatran in the RE-LY trial. Clin Gastroenterol Hepatol 2013; 11:246–252.
  14. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012; 172:397–402.
  15. Artang R, Rome E, Nielsen JD, Vidaillet HJ. Meta-analysis of randomized controlled trials on risk of myocardial infarction from the use of oral direct thrombin inhibitors. Am J Cardiol 2013; 112:1973–1979.
  16. Keisu M, Andersson TB. Drug-induced liver injury in humans: the case of ximelagatran. Handb Exp Pharmacol 2010; 196:407–418.
  17. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2013; 8:CD008980.
  18. Capranzano P, Miccichè E, D’Urso L, Privitera F, Tamburino C. Personalizing oral anticoagulant treatment in patients with atrial fibrillation. Expert Rev Cardiovasc Ther 2013; 11:959-973.
  19. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol 2012; 26:27-32.
  20. EINSTEIN–PE Investigators; Büller HR, Prins MH, Lensin AW, et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366:1287–1297.
  21. EINSTEIN Investigators; Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499–2510.
  22. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365:883–891.
  23. Cohen AT, Spiro TE, Büller HR, et al; MAGELLAN Investigators. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368:513–523.
  24. Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013; 76:455–466.
  25. Turpie AG, Kreutz R, Llau J, Norrving B, Haas S. Management consensus guidance for the use of rivaroxaban—an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108:876–886.
  26. Agnelli G, Buller HR, Cohen A, et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368:699–708.
  27. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365:981–992.
  28. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363:2487–2498.
  29. Keating GM. Apixaban: a review of its use for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Drugs 2013; 73:825–843.
  30. Giugliano RP, Ruff CT, Braunwald E, et al; NGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369:2093–2104.
  31. Traynor K. Edoxaban approved for embolism prevention. Am J Health Syst Pharm 2015; 72:258.
  32. Connolly SJ, Eikelboom J, Dorian P, et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur Heart J 2013; 34:1498–1505.
  33. Bondarenko M, Curti C, Montana M, Rathelot P, Vanelle P. Efficacy and toxicity of factor Xa inhibitors. J Pharm Pharm Sci 2013; 16:74–88.
  34. Funk DM. Coagulation assays and anticoagulant monitoring. Hematology Am Soc Hematol Educ Program 2012; 2012:460–465.
  35. Gouin-Thibault I, Flaujac C, Delavenne X, et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb Haemost 2014; 111:240–248.
  36. Halbmayer WM, Weigel G, Quehenberger P, et al. Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests. Clin Chem Lab Med 2012; 50:1601–1615.
  37. Merriman E, Kaplan Z, Butler J, Malan E, Gan E, Tran H. Rivaroxaban and false positive lupus anticoagulant testing. Thromb Haemost 2011; 105:385–386.
  38. van Ryn J, Stangier J, Haertter S, et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103:1116–1127.
  39. Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012; 119:3016–3023.
  40. Singh T, Maw TT, Henry BL, et al. Extracorporeal therapy for dabigatran removal in the treatment of acute bleeding: a single center experience. Clin J Am Soc Nephrol 2013; 8:1533–1539.
  41. Akwaa F, Spyropoulos AC. Treatment of bleeding complications when using oral anticoagulants for prevention of strokes. Curr Treat Options Cardiovasc Med 2013; 15:288–298.
  42. Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol 2013; 26:191–202.
  43. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 2013; 19:446–451.
  44. Dickneite G, Hoffman M. Reversing the new oral anticoagulants with prothrombin complex concentrates (PCCs): what is the evidence? Thromb Haemost 2014; 111:189–198.
  45. Holster IL, Hunfeld NG, Kuipers EJ, Kruip MJ, Tjwa ET. On the treatment of new oral anticoagulant-associated gastrointestinal hemorrhage. J Gastrointestin Liver Dis 2013; 22:229–231.
  46. Nitzki-George D, Wozniak I, Caprini JA. Current state of knowledge on oral anticoagulant reversal using procoagulant factors. Ann Pharmacother 2013; 47:841–855.
  47. Nutescu EA, Dager WE, Kalus JS, Lewin JJ 3rd, Cipolle MD. Management of bleeding and reversal strategies for oral anticoagulants: clinical practice considerations. Am J Health Syst Pharm 2013; 70:1914–1929.
  48. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:1935–1944.
  49. Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 2011; 123:131–136.
  50. Warkentin TE. HIT: treatment easier, prevention harder. Blood 2012; 119:1099–1100.
  51. Mirdamadi A. Dabigatran, a direct thrombin inhibitor, can be a life-saving treatment in heparin-induced thrombocytopenia. ARYA Atheroscler 2013; 9:112–114.
  52. Walenga JM, Prechel M, Hoppensteadt D, et, al. Apixaban as an alternate oral anticoagulant for the management of patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2013; 19:482–487.
  53. Bakchoul T, Greinacher A. Recent advances in the diagnosis and treatment of heparin-induced thrombocytopenia. Ther Adv Hematol 2012; 3:237–251.
  54. Den Exter PL, Kooiman J, van der Hulle T, Huisman MV. New anticoagulants in the treatment of patients with cancer-associated venous thromboembolism. Best Pract Res Clin Haematol 2013; 26:163–169.
  55. Adriance SM, Murphy CV. Prophylaxis and treatment of venous thromboembolism in the critically ill. Int J Crit Illn Inj Sci 2013; 3:143–151.
  56. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366:9–19.
  57. Chatterjee S, Sharma A, Uchino K, Biondi-Zoccai G, Lichstein E, Mukherjee D. Rivaroxaban and risk of myocardial infarction: insights from a meta-analysis and trial sequential analysis of randomized clinical trials. Coron Artery Dis 2013; 24:628–635.
  58. Liew A, Darvish-Kazem S, Douketis JD. Is there a role for the novel oral anticoagulants in patients with an acute coronary syndrome? A review of the clinical trials. Pol Arch Med Wewn 2013; 123:617–622.
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  60. Kearon C, Akl EA, Comerota AJ, et al; ; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141(suppl 2):e419S–e494S.
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Issue
Cleveland Clinic Journal of Medicine - 82(12)
Issue
Cleveland Clinic Journal of Medicine - 82(12)
Page Number
847-854
Page Number
847-854
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
Cardiology
Drug Therapy
Hospital Medicine
Neurology
Article Type
Article
Display Headline
The new oral anticoagulants: Reasonable alternatives to warfarin
Display Headline
The new oral anticoagulants: Reasonable alternatives to warfarin
Legacy Keywords
anticoagulant, oral anticoagulant, target-specific oral anticoagulant, thrombin inhibitor, factor IIa inhibitor, factor Xa inhibitor, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Bernardino Roca, Manuel Roca
Legacy Keywords
anticoagulant, oral anticoagulant, target-specific oral anticoagulant, thrombin inhibitor, factor IIa inhibitor, factor Xa inhibitor, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Bernardino Roca, Manuel Roca
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Inside the Article

KEY POINTS

  • The new oral anticoagulants have favorable pharmacologic properties and similar efficacy and safety as vitamin K antagonists.
  • The new agents are indicated for preventing stroke and systemic embolism in patients with nonvalvular atrial fibrillation and preventing and treating deep vein thrombosis and pulmonary embolism (the indications regarding venous thromboembolism differ somewhat among agents).
  • Except for dabigatran, lack of an antidote in case of bleeding or emergency surgery is a major drawback.
  • Be cautious when using these drugs in patients with renal or liver disease and in those taking an inhibitor or inducer of the P-glycoprotein transporter or the cytochrome P450 enzymes.
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