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Future Cardiology
Review
Novel oral anticoagulants for the prevention and treatment of thromboembolism Carrie S Oliphant1,2, Anna Jacobs1,2, Rajesh Kabra3 & Pranab Das*4 Methodist University Hospital, Department of Pharmacy, 1265 Union Avenue, Memphis, TN 38104, USA University of Tennessee, College of Pharmacy, 920 Madison Avenue, Memphis, TN 38163, USA University of Tennessee, College of Medicine, 910 Madison Avenue, Memphis, TN 38163, USA 4 Cardiology Associates-Memphis, 6005 Park Avenue, #500B, Memphis, TN 38119, USA *Author for correspondence: [email protected] 1 2 3
Over the last 5 years, new oral anticoagulant options, including dabigatran, rivaroxaban and apixaban, have become available. Prior to this, vitamin K antagonists were the sole oral anticoagulants, which have been in use for more than 60 years. These novel agents have been studied in a variety of patient populations, including atrial fibrillation, acute coronary syndrome, treatment of venous thromboembolism and thromboprophylaxis. Compared with standard care, these agents have largely been found to be noninferior or superior for efficacy end points, with similar or improved rates of bleeding. As a result, these agents have become attractive alternatives to vitamin K antagonists for the prevention and treatment of thromboembolic disease. This article provides a summary of clinical trial data to help clinicians determine which agent is most appropriate for a given patient.
Arterial and venous thromboembolism (VTE) are common disorders that result in significant morbidity and mortality. The standard of care for the prevention and treatment of thrombo embolism includes both injectable and oral anti coagulants. Until recently, vitamin K antago nists (VKAs) were the only available oral anti coagulants. VKAs, namely warfarin, have many limitations, including a narrow therapeutic win dow, slow onset and offset, frequent laboratory monitoring, diet and drug interactions, genetic factors, and significant interpatient variability [1–3]. Many patients receiving warfarin remain at risk for embolic events, since it is difficult to maintain an international normalized ratio (INR) in the goal range of 2–3. Based on results from a meta-analysis including eight studies, warfarin patients in the USA have a therapeutic INR rate of 55% [4]. As a result, novel anti coagulants have been developed to overcome these limitations. The first novel oral anticoagulant to achieve regulatory approval was ximelagatran, a direct thrombin inhibitor. Owing to hepatotoxic ity, this agent was never approved for use in the USA and was withdrawn from the market in 2006 [5]. Dabigatran, also a direct throm bin inhibitor, has been available since 2010. Rivaroxaban and apixaban are both factor Xa inhibitors. These agents offer advantages over warfarin, including rapid onset of action, pre dictable pharmacokinetics, lack of required monitoring and minimal interactions [2]. The 10.2217/FCA.13.76 © 2013 Future Medicine Ltd
pharmacokinetic and pharmacodynamic prop erties of apixaban, dabigatran and rivaroxaban are outlined in Table 1. The three available agents have been stud ied in a variety of patient populations includ ing atrial fibrillation, treatment of VTE, acute coronary syndrome (ACS), thromboprophylaxis following orthopedic surgery and thrombo prophylaxis in the medically ill. On the basis of clinical trial data, these agents are approved for various conditions in both Europe and the USA. Table 2 outlines the approval status of each of these agents by indication. Currently, the only indication where all of the agents are widely available for use is atrial fibrillation. To describe the current literature on the pro phylaxis and treatment of thromboembolism, we conducted a MEDLINE search of the Eng lish language literature (1950–2013) to iden tify pertinent Phase III studies. The purpose of this article is to summarize the clinical trial data by patient population for each of these novel anticoagulants to aid the clinician in decision-making. Atrial fibrillation
Stroke prophylaxis in atrial fibrillation is the one indication where all of the agents are approved for use in both Europe and the USA. These approvals were based on large clinical trials where each agent was compared with warfarin in patients with nonvalvular atrial fibrillation. A summary of these clinical trials is provided Future Cardiol. (2013) 9(6), 849–861
Keywords acute coronary syndrome apixaban n atrial fibrillation n dabigatran n oral anticoagulant n rivaroxaban n venous thromboembolism n n
part of
ISSN 1479-6678
849
Review
Oliphant, Jacobs, Kabra & Das
Table 1. Pharmacokinetics and pharmacodynamics of apixaban, dabigatran and rivaroxaban. Drug
Onset of Half-life action (h) (h)
Metabolism/drug interaction potential
Renal elimination (%)
Apixaban
1–3
6–12
CYP3A4; P-gp substrate
25
[41]
Dabigatran
1.25–3
12–17
Prodrug; converted via hydrolysis; P-gp substrate
80
[39,40]
6–9 (young); 11–13 (elderly)
CYP3A4; P-gp substrate
36
[11]
Rivaroxaban 2–4
Ref.
P-gp: P-glycoprotein.
in Table 3. Both dabigatran 150 mg and apixa ban were found to be superior to warfarin, whereas rivaroxaban was noninferior in reduc ing the rates of stroke or systemic embolism. Major bleeding events were similar to warfarin, with the exception of dabigatran 110 mg and apixaban, which were found to have a signifi cant reduction. All of these agents significantly reduced the rates of hemorrhagic stroke and intracranial bleeding, some of the most feared effects of warfarin.
Apixaban
Dabigatran
Rivaroxaban
Europe USA
Europe USA
Europe USA
VTE prophylaxis following total knee or hip replacement
ü
ü
ü
ü
Stroke prophylaxis in atrial fibrillation
ü
ü
ü
ü
ü
ü
Compared with warfarin, major bleeding was significantly lower with the 110-mg dose and similar with the 150-mg dose. Both doses significantly reduced the rates of intracranial hemorrhage. Although the bleeding rates with dabigatran were favorable compared with war farin, there was a significantly higher rate of gastrointestinal (GI) bleeding seen with the 150-mg dose. A signal to an increased rate of myocardial infarction (MI) was identified in the RE‑LY trial, prompting a subsequent review of the data [7]. Although the rates of MI were found to be similar statistically, a higher rate persisted with dabigatran. In a recent meta-analysis of clini cal trials for dabigatran in numerous patient populations, a significantly higher rate of MIs (odds ratio: 1.33; p = 0.03) was found [8]. Based on this information, dabigatran may not be the most appropriate agent in patients with a history of ACS. Following completion of the RE‑LY trial, patients assigned to both dabigatran groups were eligible to continue therapy as part of a long-term study known as RELY‑ABLE [9]. A total of 5851 patients continued the dose of dab igatran they had received in the RE‑LY study (150 or 110 mg twice-daily) for up to 28 months. Patients assigned to warfarin were not eligible for this continuation study. Stroke or systemic embolism occurred at a rate of 1.46% in the 150-mg group and 1.60% in the 110-mg group (hazard ratio [HR]: 0.91; 95% CI: 0.69–1.20). The rate of major bleeding was higher in the 150-mg arm (3.74%) compared with 110 mg (2.99%; HR: 1.26; 95% CI: 1.04–1.53).
VTE treatment
ü
ü
Rivaroxaban
Acute coronary syndrome
ü
Under review
Based on the results of the ROCKET‑AF trial, rivaroxaban became the second agent available for the treatment of atrial fibrillation [10]. The ROCKET‑AF trial randomized 14,264 patients
Dabigatran
Dabigatran was the first novel anticoagulant to become available for use in atrial fibrillation patients. In the RE‑LY trial, 18,113 patients were randomized to receive dabigatran 110 mg twice-daily, dabigatran 150 mg twice-daily or open-label warfarin with a goal INR of 2–3 [6]. For the primary efficacy end points, stroke and systemic embolism, both doses of dabiga tran were found to be noninferior to warfarin. The 150-mg dose of dabigatran was found to be superior. Hemorrhagic stroke rates were sig nificantly lower with both doses, but only the 150-mg dose significantly reduced the rate of ischemic strokes. Table 2. Regulatory approval status. Indication
ü: Approval; VTE: Venous thromboembolism. Data taken from [105,106].
850
Future Cardiol. (2013) 9(6)
future science group
future science group
Review
§
‡
†
CHADS2: Stroke risk scoring system where 1 point is assigned to congestive heart failure, hypertension, age ≥75 years, diabetes and 2 points assigned for stroke/transient ischemic attack. Rivaroxaban 15 mg daily if creatinine clearance 30–49 ml/min. Apixaban 2.5 mg twice-daily if ≥two of the following: age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5. GI: Gastrointestinal; INR: International normalized ratio; TTR: Time in therapeutic range for warfarin patients.
[13]
Significant reduction: hemorrhagic stroke, stroke, intracranial hemorrhage and mortality 62.2 2.1
55 3.5
1.27 vs 1.60% (p = 0.01) Apixaban 5 mg twice-daily§ vs warfarin (blinded)
2.13 vs 3.09% (p
Future Cardiology
Review
Novel oral anticoagulants for the prevention and treatment of thromboembolism Carrie S Oliphant1,2, Anna Jacobs1,2, Rajesh Kabra3 & Pranab Das*4 Methodist University Hospital, Department of Pharmacy, 1265 Union Avenue, Memphis, TN 38104, USA University of Tennessee, College of Pharmacy, 920 Madison Avenue, Memphis, TN 38163, USA University of Tennessee, College of Medicine, 910 Madison Avenue, Memphis, TN 38163, USA 4 Cardiology Associates-Memphis, 6005 Park Avenue, #500B, Memphis, TN 38119, USA *Author for correspondence: [email protected] 1 2 3
Over the last 5 years, new oral anticoagulant options, including dabigatran, rivaroxaban and apixaban, have become available. Prior to this, vitamin K antagonists were the sole oral anticoagulants, which have been in use for more than 60 years. These novel agents have been studied in a variety of patient populations, including atrial fibrillation, acute coronary syndrome, treatment of venous thromboembolism and thromboprophylaxis. Compared with standard care, these agents have largely been found to be noninferior or superior for efficacy end points, with similar or improved rates of bleeding. As a result, these agents have become attractive alternatives to vitamin K antagonists for the prevention and treatment of thromboembolic disease. This article provides a summary of clinical trial data to help clinicians determine which agent is most appropriate for a given patient.
Arterial and venous thromboembolism (VTE) are common disorders that result in significant morbidity and mortality. The standard of care for the prevention and treatment of thrombo embolism includes both injectable and oral anti coagulants. Until recently, vitamin K antago nists (VKAs) were the only available oral anti coagulants. VKAs, namely warfarin, have many limitations, including a narrow therapeutic win dow, slow onset and offset, frequent laboratory monitoring, diet and drug interactions, genetic factors, and significant interpatient variability [1–3]. Many patients receiving warfarin remain at risk for embolic events, since it is difficult to maintain an international normalized ratio (INR) in the goal range of 2–3. Based on results from a meta-analysis including eight studies, warfarin patients in the USA have a therapeutic INR rate of 55% [4]. As a result, novel anti coagulants have been developed to overcome these limitations. The first novel oral anticoagulant to achieve regulatory approval was ximelagatran, a direct thrombin inhibitor. Owing to hepatotoxic ity, this agent was never approved for use in the USA and was withdrawn from the market in 2006 [5]. Dabigatran, also a direct throm bin inhibitor, has been available since 2010. Rivaroxaban and apixaban are both factor Xa inhibitors. These agents offer advantages over warfarin, including rapid onset of action, pre dictable pharmacokinetics, lack of required monitoring and minimal interactions [2]. The 10.2217/FCA.13.76 © 2013 Future Medicine Ltd
pharmacokinetic and pharmacodynamic prop erties of apixaban, dabigatran and rivaroxaban are outlined in Table 1. The three available agents have been stud ied in a variety of patient populations includ ing atrial fibrillation, treatment of VTE, acute coronary syndrome (ACS), thromboprophylaxis following orthopedic surgery and thrombo prophylaxis in the medically ill. On the basis of clinical trial data, these agents are approved for various conditions in both Europe and the USA. Table 2 outlines the approval status of each of these agents by indication. Currently, the only indication where all of the agents are widely available for use is atrial fibrillation. To describe the current literature on the pro phylaxis and treatment of thromboembolism, we conducted a MEDLINE search of the Eng lish language literature (1950–2013) to iden tify pertinent Phase III studies. The purpose of this article is to summarize the clinical trial data by patient population for each of these novel anticoagulants to aid the clinician in decision-making. Atrial fibrillation
Stroke prophylaxis in atrial fibrillation is the one indication where all of the agents are approved for use in both Europe and the USA. These approvals were based on large clinical trials where each agent was compared with warfarin in patients with nonvalvular atrial fibrillation. A summary of these clinical trials is provided Future Cardiol. (2013) 9(6), 849–861
Keywords acute coronary syndrome apixaban n atrial fibrillation n dabigatran n oral anticoagulant n rivaroxaban n venous thromboembolism n n
part of
ISSN 1479-6678
849
Review
Oliphant, Jacobs, Kabra & Das
Table 1. Pharmacokinetics and pharmacodynamics of apixaban, dabigatran and rivaroxaban. Drug
Onset of Half-life action (h) (h)
Metabolism/drug interaction potential
Renal elimination (%)
Apixaban
1–3
6–12
CYP3A4; P-gp substrate
25
[41]
Dabigatran
1.25–3
12–17
Prodrug; converted via hydrolysis; P-gp substrate
80
[39,40]
6–9 (young); 11–13 (elderly)
CYP3A4; P-gp substrate
36
[11]
Rivaroxaban 2–4
Ref.
P-gp: P-glycoprotein.
in Table 3. Both dabigatran 150 mg and apixa ban were found to be superior to warfarin, whereas rivaroxaban was noninferior in reduc ing the rates of stroke or systemic embolism. Major bleeding events were similar to warfarin, with the exception of dabigatran 110 mg and apixaban, which were found to have a signifi cant reduction. All of these agents significantly reduced the rates of hemorrhagic stroke and intracranial bleeding, some of the most feared effects of warfarin.
Apixaban
Dabigatran
Rivaroxaban
Europe USA
Europe USA
Europe USA
VTE prophylaxis following total knee or hip replacement
ü
ü
ü
ü
Stroke prophylaxis in atrial fibrillation
ü
ü
ü
ü
ü
ü
Compared with warfarin, major bleeding was significantly lower with the 110-mg dose and similar with the 150-mg dose. Both doses significantly reduced the rates of intracranial hemorrhage. Although the bleeding rates with dabigatran were favorable compared with war farin, there was a significantly higher rate of gastrointestinal (GI) bleeding seen with the 150-mg dose. A signal to an increased rate of myocardial infarction (MI) was identified in the RE‑LY trial, prompting a subsequent review of the data [7]. Although the rates of MI were found to be similar statistically, a higher rate persisted with dabigatran. In a recent meta-analysis of clini cal trials for dabigatran in numerous patient populations, a significantly higher rate of MIs (odds ratio: 1.33; p = 0.03) was found [8]. Based on this information, dabigatran may not be the most appropriate agent in patients with a history of ACS. Following completion of the RE‑LY trial, patients assigned to both dabigatran groups were eligible to continue therapy as part of a long-term study known as RELY‑ABLE [9]. A total of 5851 patients continued the dose of dab igatran they had received in the RE‑LY study (150 or 110 mg twice-daily) for up to 28 months. Patients assigned to warfarin were not eligible for this continuation study. Stroke or systemic embolism occurred at a rate of 1.46% in the 150-mg group and 1.60% in the 110-mg group (hazard ratio [HR]: 0.91; 95% CI: 0.69–1.20). The rate of major bleeding was higher in the 150-mg arm (3.74%) compared with 110 mg (2.99%; HR: 1.26; 95% CI: 1.04–1.53).
VTE treatment
ü
ü
Rivaroxaban
Acute coronary syndrome
ü
Under review
Based on the results of the ROCKET‑AF trial, rivaroxaban became the second agent available for the treatment of atrial fibrillation [10]. The ROCKET‑AF trial randomized 14,264 patients
Dabigatran
Dabigatran was the first novel anticoagulant to become available for use in atrial fibrillation patients. In the RE‑LY trial, 18,113 patients were randomized to receive dabigatran 110 mg twice-daily, dabigatran 150 mg twice-daily or open-label warfarin with a goal INR of 2–3 [6]. For the primary efficacy end points, stroke and systemic embolism, both doses of dabiga tran were found to be noninferior to warfarin. The 150-mg dose of dabigatran was found to be superior. Hemorrhagic stroke rates were sig nificantly lower with both doses, but only the 150-mg dose significantly reduced the rate of ischemic strokes. Table 2. Regulatory approval status. Indication
ü: Approval; VTE: Venous thromboembolism. Data taken from [105,106].
850
Future Cardiol. (2013) 9(6)
future science group
future science group
Review
§
‡
†
CHADS2: Stroke risk scoring system where 1 point is assigned to congestive heart failure, hypertension, age ≥75 years, diabetes and 2 points assigned for stroke/transient ischemic attack. Rivaroxaban 15 mg daily if creatinine clearance 30–49 ml/min. Apixaban 2.5 mg twice-daily if ≥two of the following: age ≥80 years, weight ≤60 kg or serum creatinine ≥1.5. GI: Gastrointestinal; INR: International normalized ratio; TTR: Time in therapeutic range for warfarin patients.
[13]
Significant reduction: hemorrhagic stroke, stroke, intracranial hemorrhage and mortality 62.2 2.1
55 3.5
1.27 vs 1.60% (p = 0.01) Apixaban 5 mg twice-daily§ vs warfarin (blinded)
2.13 vs 3.09% (p
