568550
research-article2015
AOPXXX10.1177/1060028014568550Annals of PharmacotherapyLekura
Review Article
The Safety and Efficacy of Target-Specific Anticoagulants in Patients With Venous Thromboembolism
Annals of Pharmacotherapy 1–10 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014568550 aop.sagepub.com
Jona Lekura1
Abstract Objective: To review the role of target-specific anticoagulants (TSACs) for the treatment of venous thromboembolism (VTE) and their associated efficacy and safety. Data Sources: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE (1966 to November 2014) using the following search terms: venous thromboembolism, vitamin K antagonist (VKA), target-specific anticoagulant, deep-vein thrombosis, pulmonary embolism. Results were limited to human trials published in English. Citations from articles were reviewed for additional references. Study Selection and Data Extraction: Clinical trials evaluating VTE treatment were included. Trials that evaluated alternative end points were excluded. Data Synthesis: Patients with VTE have a high risk of developing recurrent events and subsequent death if not treated in an appropriate manner. TSACs have been evaluated in several large clinical trials in patients with acute VTE. These trials have shown positive outcomes when compared with VKAs for treatment of VTE in the general population. Paralleled with these results, TSACs had similar or lower rates of bleeding compared with VKAs. Conclusions: Taken together, available evidence suggests that TSACs produce similar clinical benefits with less bleeding incidence when compared with VKAs in the treatment of VTE. There are significant differences between each study investigating this class of medication for VTE treatment. Each TSAC has potential advantages, and to date, there has been no head-to-head trial comparing them. Keywords anticoagulation, warfarin, pulmonary, pharmacology, basic, adult medicine, anticoagulants
Introduction Venous thromboembolism (VTE) is one of the most common cardiovascular conditions in the United States. According to the Centers for Disease Control and Prevention (CDC), the precise number of people affected by VTE is unknown, but estimates range from 300 000 to 600 000 each year in the United States. One-third of people with VTE will have a recurrence within 10 years.1 VTE is characterized by a variety of inciting factors that contribute to a diverse clinical presentation. The principal concept behind VTE is formation of a venous thrombin and fibrin clot, which holds together white blood cells, red blood cells and platelets. The venous clot can form in the peripheral extremities and cause a deep vein thrombosis (DVT) or embolize to the pulmonary arteries and cause a pulmonary embolism (PE). The goal of VTE treatment is prevention of thrombus extension, PE development, VTE reoccurrence, hemodynamic instability, and death. In the past, the mainstay of therapy for VTE has been the use of a parenteral anticoagulant for 5 to 7 days, used for bridging purposes with a vitamin K antagonist (VKA), while the international normalized ratio (INR) reached therapeutic levels, usually in the 2 to
3 range.2 Depending on the clinical situation, other potential options include thrombolysis and placement of vena cava filters.3 Guideline recommendations have recently updated the duration of treatment for anticoagulation, which varies from 3 months to lifelong therapy, depending on the presence or absence of inciting factors for VTE.2 With the availability of target-specific anticoagulants (TSACs) in the market, the past few years have been transformative in regard to VTE treatment options. This article will focus on the currently available evidence and clinical interpretation supporting the use of TSACs in VTE treatment.
Dabigatran The RECOVER study was a noninferiority trial involving patients with acute VTE who were initially given parenteral 1
Henry Ford Hospital, Detroit, MI, USA
Corresponding Author: Jona Lekura, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA. Email: [email protected]
Downloaded from aop.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on March 7, 2015
2
Annals of Pharmacotherapy
anticoagulation therapy for least 5 days with or without VKA, and the true or sham INR was recorded as 2 or higher on 2 consecutive days.4 Afterward, patients were randomized through a “double dummy phase” into the dabigatran arm (n = 1274), which was administered at a dose of 150 mg twice daily, or the warfarin arm (n = 1265), which was dose adjusted to achieve an INR of 2 to 3 for 6 months. The primary efficacy outcome was the occurrence of recurrent symptomatic VTE or death that was related to a VTE. The safety end points included bleeding events, acute coronary syndromes (ACSs), other adverse events, and results of liver function tests. The study involved a cohort of predominantly white male patients with an average age of 55 years. Creatinine clearance (CrCl) was >50 mL/min in >90% of the participants. The majority of the patients received lowmolecular-weight heparin (LMWH) as a parenteral agent, and the time in therapeutic range (TTR) in the warfarin arm was 60%. As illustrated in Table 1, among patients included in the intention-to-treat analysis, dabigatran was noninferior in the prevention of recurrent VTE or death. There was 1 death in each treatment arm. There was no statistical difference between groups; however, in the warfarin arm, there were numerically higher bleeding events into critical organs. Statistical differences were observed when major bleeding was combined with clinically relevant nonmajor bleeding events as well as any bleeding event. The dabigatran arm had numerically higher GI bleeding events, whereas the warfarin arm had higher urogenital and nasal bleeding events. These findings appear to support the use of dabigatran for the secondary prevention of VTE; however, as mentioned by the authors, the data cannot be applied to a patient population that differs from the one in RECOVER. In addition to the lack of a single drug approach, opponents of dabigatran use may cite the exclusion of patients at high risk of bleeding or on antiplatelet therapy as a drawback to the study design. In a similar manner, the investigators conducted RECOVER II to investigate the effect of extended dabigatran use in the treatment and secondary prevention of VTE after 3 months of conventional therapy.5 Patients were randomized to the dabigatran 150 mg twice-a-day arm (n = 1279) or to the warfarin arm (n = 1289), and similar inclusion and exclusion criteria were applied. Dabigatran was administered after 2 consecutive therapeutic INRs and a 5-day long duration of the parenteral agent in the “single dummy phase.” The “double-dummy phase,” where the study drugs were given to participants, lasted for 6 months from randomization. The primary efficacy outcome was a comparison of the time to first occurrence of the composite end point of symptomatic VTE or death associated with VTE in the 6 months after randomization. The safety outcomes included major bleeding, major or clinically relevant nonmajor bleeding,
and any bleeding. The RECOVER II cohort had more patients with Asian heritage and fewer patients with previous VTE than the RECOVER cohort. Similar to RECOVER, about 25% of the patients had a malignancy, and roughly 10% of patients were receiving acetylsalicylic acid. In RECOVER II, the majority of patients received LMWH as a parenteral agent, and TTR in the warfarin arm was 57%. Noninferiority was met, with fewer recurrent DVTs or PEs in patients treated with dabigatran compared with patients treated with warfarin. Although there was no difference in mortality rates and no difference in the rate of serious adverse events, the number of major bleeding events and any bleeding event was higher in the warfarin arm. Two additional studies were conducted to evaluate the efficacy and safety of dabigatran during long-term prophylaxis after VTE, an active-control study (RE-MEDY) and a placebo-control study (RE-SONATE).6 Both studies had a randomized, double-blind design but enrolled patients who had completed at least 3 months of treatment for VTE. In RE-MEDY, patients were assigned in a 1:1 ratio to receive active dabigatran 150 mg twice a day and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. In RE-SONATE, patients were assigned in a 1:1 ratio to receive dabigatran 150 mg twice a day or a matching placebo. Both studies shared a similar primary efficacy outcome, which was recurrent symptomatic and objectively verified VTE or death associated with VTE. Safety outcomes included major bleeding and clinically relevant nonmajor bleeding. RE-MEDY was designed to evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE or death related to VTE, whereas RE-SONATE was designed to evaluate whether dabigatran was superior to placebo for preventing recurrent VTE. In RE-MEDY, 2866 patients underwent randomization, and 1353 patients underwent randomization in RE-SONATE. TTR in RE-MEDY was 65%. In both trials, patients were on average 55-year-old men. The average weight was 85 kg, and estimated CrCl was >100 mL/min. In both studies, the number of patients with coronary artery disease, diabetes mellitus, and hypertension was higher in the dabigatran arms. In RE-MEDY, dabigatran had similar rates of recurrent or fatal VTE compared with warfarin and lower rates of major or clinically relevant bleeding events. There were more ACS events in the dabigatran group (n = 13) than in those taking warfarin (n = 3) during active treatment. In RE-SONATE, dabigatran had a 92% reduction in rates of recurrent or fatal VTE compared with placebo, and the active group was 3 times more likely to experience major or clinically relevant bleeding events. There were similar rates of ACS (n = 1) in each treatment arm. The investigators recognized the fact that prescribers have to assess the risk of ACS versus fewer rates of bleeding when deciding if dabigatran is an option for VTE treatment or prophylaxis.
Downloaded from aop.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on March 7, 2015
3
Lekura Table 1. Summary of Dabigatran Studies.
Number of patients Methodology Comparator
Time in therapeutic range Inclusion criteria
Exclusion criteria
Primary outcome
Duration of followup Efficacy results Recurrent VTE or fatal VTE
Safety results Major bleeding
Major or clinically relevant bleeding event
RECOVER
RECOVER-2
2539 Double-blind, double-dummy, randomized trial Parenteral agent, then dabigatran 150 mg twice daily vs parenteral agenta + warfarin 60%
2568 Double-blind, double-dummy, randomized trial Parenteral agent, then dabigatran 150 mg twice daily vs parenterala agent + warfarin 57%
2856 Randomized, double-blind, noninferiority trial Dabigatran 150 mg twice a day vs parenterala agent + warfarin
1343 Randomized, double-blind, superiority trial Dabigatran 150 mg twice a day vs placebo
65.3%
n/a
>18 Years old, acute, symptomatic, objectively verified proximal DVT or PE
>18 Years old, acute, symptomatic, objectively verified proximal DVT or PE
>18 Years old, objective >18 Years old, objective diagnosis of DVT or PE, diagnosis of DVT or PE, already treated with already treated with an anticoagulant or an anticoagulant or RECOVER and RECOVER II RECOVER and RECOVER II participants participants Symptomatic DVT or 3× ULN, CrCl 2× ULN, an endocarditis, active bleeding estimated CrCl 14 days, PE with hemodynamic days, PE with hemodynamic instability or requiring instability or requiring thrombolytic therapy, thrombolytic therapy, another indication for another indication for warfarin therapy, recent warfarin therapy, recent unstable CVD, a high risk unstable CVD, a high risk of bleeding, liver disease of bleeding, liver disease with an aminotransferase with an aminotransferase level that was >2× ULN, level that was >3× ULN, an estimated CrCl 165 mg daily, >2.5 mg/dL, elevated treatment with potent inhibitor LFTs, contraindications of CYP450-3A4, hemoglobin 80%. TTR was 63.5%. In the intention-to-treat population, which included all patients who underwent randomization and received at least 1 dose of the study drug, edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, regardless of administered dose. Edoxaban, regardless of administered dose, was superior in reducing clinically relevant bleeding when compared with warfarin. The types of bleeding that were most notably reduced with edoxaban in this study were intracranial and retroperitoneal bleeding. The authors concluded that edoxaban administered once daily after initial treatment with heparin was noninferior to parenteral VKA therapy and caused significantly less bleeding in a broad spectrum of patients with VTE. Although the primary safety outcome met statistical significance for superiority, the driving factor seems to have been the clinically relevant nonmajor bleeding.
Special Considerations These studies shed light on the efficacy and safety of TSACs and support their role as a new alternative for the treatment of acute VTE. However, it is important to highlight a few important concepts. Unlike the EINSTEIN and AMPLIFY programs, the studies that investigated dabigatran and edoxaban utilized parenteral agents before the initiation of TSACs. From a practicality standpoint, the necessity of a parenteral agent for at least 5 days as suggested by the study design might be considered inconvenient from a cost perspective and from the need to have patients learn and accept self-injections. Other significant differences between the studies include the variable TTR as well as inclusion and exclusion criteria. Doses of dabigatran, rivaroxaban, and apixaban in these studies were different from the ones in the atrial fibrillation study. Patients with CrCl
research-article2015
AOPXXX10.1177/1060028014568550Annals of PharmacotherapyLekura
Review Article
The Safety and Efficacy of Target-Specific Anticoagulants in Patients With Venous Thromboembolism
Annals of Pharmacotherapy 1–10 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014568550 aop.sagepub.com
Jona Lekura1
Abstract Objective: To review the role of target-specific anticoagulants (TSACs) for the treatment of venous thromboembolism (VTE) and their associated efficacy and safety. Data Sources: Peer-reviewed clinical trials, review articles, and relevant treatment guidelines were identified from MEDLINE (1966 to November 2014) using the following search terms: venous thromboembolism, vitamin K antagonist (VKA), target-specific anticoagulant, deep-vein thrombosis, pulmonary embolism. Results were limited to human trials published in English. Citations from articles were reviewed for additional references. Study Selection and Data Extraction: Clinical trials evaluating VTE treatment were included. Trials that evaluated alternative end points were excluded. Data Synthesis: Patients with VTE have a high risk of developing recurrent events and subsequent death if not treated in an appropriate manner. TSACs have been evaluated in several large clinical trials in patients with acute VTE. These trials have shown positive outcomes when compared with VKAs for treatment of VTE in the general population. Paralleled with these results, TSACs had similar or lower rates of bleeding compared with VKAs. Conclusions: Taken together, available evidence suggests that TSACs produce similar clinical benefits with less bleeding incidence when compared with VKAs in the treatment of VTE. There are significant differences between each study investigating this class of medication for VTE treatment. Each TSAC has potential advantages, and to date, there has been no head-to-head trial comparing them. Keywords anticoagulation, warfarin, pulmonary, pharmacology, basic, adult medicine, anticoagulants
Introduction Venous thromboembolism (VTE) is one of the most common cardiovascular conditions in the United States. According to the Centers for Disease Control and Prevention (CDC), the precise number of people affected by VTE is unknown, but estimates range from 300 000 to 600 000 each year in the United States. One-third of people with VTE will have a recurrence within 10 years.1 VTE is characterized by a variety of inciting factors that contribute to a diverse clinical presentation. The principal concept behind VTE is formation of a venous thrombin and fibrin clot, which holds together white blood cells, red blood cells and platelets. The venous clot can form in the peripheral extremities and cause a deep vein thrombosis (DVT) or embolize to the pulmonary arteries and cause a pulmonary embolism (PE). The goal of VTE treatment is prevention of thrombus extension, PE development, VTE reoccurrence, hemodynamic instability, and death. In the past, the mainstay of therapy for VTE has been the use of a parenteral anticoagulant for 5 to 7 days, used for bridging purposes with a vitamin K antagonist (VKA), while the international normalized ratio (INR) reached therapeutic levels, usually in the 2 to
3 range.2 Depending on the clinical situation, other potential options include thrombolysis and placement of vena cava filters.3 Guideline recommendations have recently updated the duration of treatment for anticoagulation, which varies from 3 months to lifelong therapy, depending on the presence or absence of inciting factors for VTE.2 With the availability of target-specific anticoagulants (TSACs) in the market, the past few years have been transformative in regard to VTE treatment options. This article will focus on the currently available evidence and clinical interpretation supporting the use of TSACs in VTE treatment.
Dabigatran The RECOVER study was a noninferiority trial involving patients with acute VTE who were initially given parenteral 1
Henry Ford Hospital, Detroit, MI, USA
Corresponding Author: Jona Lekura, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, MI 48202, USA. Email: [email protected]
Downloaded from aop.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on March 7, 2015
2
Annals of Pharmacotherapy
anticoagulation therapy for least 5 days with or without VKA, and the true or sham INR was recorded as 2 or higher on 2 consecutive days.4 Afterward, patients were randomized through a “double dummy phase” into the dabigatran arm (n = 1274), which was administered at a dose of 150 mg twice daily, or the warfarin arm (n = 1265), which was dose adjusted to achieve an INR of 2 to 3 for 6 months. The primary efficacy outcome was the occurrence of recurrent symptomatic VTE or death that was related to a VTE. The safety end points included bleeding events, acute coronary syndromes (ACSs), other adverse events, and results of liver function tests. The study involved a cohort of predominantly white male patients with an average age of 55 years. Creatinine clearance (CrCl) was >50 mL/min in >90% of the participants. The majority of the patients received lowmolecular-weight heparin (LMWH) as a parenteral agent, and the time in therapeutic range (TTR) in the warfarin arm was 60%. As illustrated in Table 1, among patients included in the intention-to-treat analysis, dabigatran was noninferior in the prevention of recurrent VTE or death. There was 1 death in each treatment arm. There was no statistical difference between groups; however, in the warfarin arm, there were numerically higher bleeding events into critical organs. Statistical differences were observed when major bleeding was combined with clinically relevant nonmajor bleeding events as well as any bleeding event. The dabigatran arm had numerically higher GI bleeding events, whereas the warfarin arm had higher urogenital and nasal bleeding events. These findings appear to support the use of dabigatran for the secondary prevention of VTE; however, as mentioned by the authors, the data cannot be applied to a patient population that differs from the one in RECOVER. In addition to the lack of a single drug approach, opponents of dabigatran use may cite the exclusion of patients at high risk of bleeding or on antiplatelet therapy as a drawback to the study design. In a similar manner, the investigators conducted RECOVER II to investigate the effect of extended dabigatran use in the treatment and secondary prevention of VTE after 3 months of conventional therapy.5 Patients were randomized to the dabigatran 150 mg twice-a-day arm (n = 1279) or to the warfarin arm (n = 1289), and similar inclusion and exclusion criteria were applied. Dabigatran was administered after 2 consecutive therapeutic INRs and a 5-day long duration of the parenteral agent in the “single dummy phase.” The “double-dummy phase,” where the study drugs were given to participants, lasted for 6 months from randomization. The primary efficacy outcome was a comparison of the time to first occurrence of the composite end point of symptomatic VTE or death associated with VTE in the 6 months after randomization. The safety outcomes included major bleeding, major or clinically relevant nonmajor bleeding,
and any bleeding. The RECOVER II cohort had more patients with Asian heritage and fewer patients with previous VTE than the RECOVER cohort. Similar to RECOVER, about 25% of the patients had a malignancy, and roughly 10% of patients were receiving acetylsalicylic acid. In RECOVER II, the majority of patients received LMWH as a parenteral agent, and TTR in the warfarin arm was 57%. Noninferiority was met, with fewer recurrent DVTs or PEs in patients treated with dabigatran compared with patients treated with warfarin. Although there was no difference in mortality rates and no difference in the rate of serious adverse events, the number of major bleeding events and any bleeding event was higher in the warfarin arm. Two additional studies were conducted to evaluate the efficacy and safety of dabigatran during long-term prophylaxis after VTE, an active-control study (RE-MEDY) and a placebo-control study (RE-SONATE).6 Both studies had a randomized, double-blind design but enrolled patients who had completed at least 3 months of treatment for VTE. In RE-MEDY, patients were assigned in a 1:1 ratio to receive active dabigatran 150 mg twice a day and a warfarin-like placebo or active warfarin and a dabigatran-like placebo. In RE-SONATE, patients were assigned in a 1:1 ratio to receive dabigatran 150 mg twice a day or a matching placebo. Both studies shared a similar primary efficacy outcome, which was recurrent symptomatic and objectively verified VTE or death associated with VTE. Safety outcomes included major bleeding and clinically relevant nonmajor bleeding. RE-MEDY was designed to evaluate whether dabigatran was noninferior to warfarin in preventing recurrent VTE or death related to VTE, whereas RE-SONATE was designed to evaluate whether dabigatran was superior to placebo for preventing recurrent VTE. In RE-MEDY, 2866 patients underwent randomization, and 1353 patients underwent randomization in RE-SONATE. TTR in RE-MEDY was 65%. In both trials, patients were on average 55-year-old men. The average weight was 85 kg, and estimated CrCl was >100 mL/min. In both studies, the number of patients with coronary artery disease, diabetes mellitus, and hypertension was higher in the dabigatran arms. In RE-MEDY, dabigatran had similar rates of recurrent or fatal VTE compared with warfarin and lower rates of major or clinically relevant bleeding events. There were more ACS events in the dabigatran group (n = 13) than in those taking warfarin (n = 3) during active treatment. In RE-SONATE, dabigatran had a 92% reduction in rates of recurrent or fatal VTE compared with placebo, and the active group was 3 times more likely to experience major or clinically relevant bleeding events. There were similar rates of ACS (n = 1) in each treatment arm. The investigators recognized the fact that prescribers have to assess the risk of ACS versus fewer rates of bleeding when deciding if dabigatran is an option for VTE treatment or prophylaxis.
Downloaded from aop.sagepub.com at HOWARD UNIV UNDERGRAD LIBRARY on March 7, 2015
3
Lekura Table 1. Summary of Dabigatran Studies.
Number of patients Methodology Comparator
Time in therapeutic range Inclusion criteria
Exclusion criteria
Primary outcome
Duration of followup Efficacy results Recurrent VTE or fatal VTE
Safety results Major bleeding
Major or clinically relevant bleeding event
RECOVER
RECOVER-2
2539 Double-blind, double-dummy, randomized trial Parenteral agent, then dabigatran 150 mg twice daily vs parenteral agenta + warfarin 60%
2568 Double-blind, double-dummy, randomized trial Parenteral agent, then dabigatran 150 mg twice daily vs parenterala agent + warfarin 57%
2856 Randomized, double-blind, noninferiority trial Dabigatran 150 mg twice a day vs parenterala agent + warfarin
1343 Randomized, double-blind, superiority trial Dabigatran 150 mg twice a day vs placebo
65.3%
n/a
>18 Years old, acute, symptomatic, objectively verified proximal DVT or PE
>18 Years old, acute, symptomatic, objectively verified proximal DVT or PE
>18 Years old, objective >18 Years old, objective diagnosis of DVT or PE, diagnosis of DVT or PE, already treated with already treated with an anticoagulant or an anticoagulant or RECOVER and RECOVER II RECOVER and RECOVER II participants participants Symptomatic DVT or 3× ULN, CrCl 2× ULN, an endocarditis, active bleeding estimated CrCl 14 days, PE with hemodynamic days, PE with hemodynamic instability or requiring instability or requiring thrombolytic therapy, thrombolytic therapy, another indication for another indication for warfarin therapy, recent warfarin therapy, recent unstable CVD, a high risk unstable CVD, a high risk of bleeding, liver disease of bleeding, liver disease with an aminotransferase with an aminotransferase level that was >2× ULN, level that was >3× ULN, an estimated CrCl 165 mg daily, >2.5 mg/dL, elevated treatment with potent inhibitor LFTs, contraindications of CYP450-3A4, hemoglobin 80%. TTR was 63.5%. In the intention-to-treat population, which included all patients who underwent randomization and received at least 1 dose of the study drug, edoxaban was noninferior to warfarin with respect to the primary efficacy outcome, regardless of administered dose. Edoxaban, regardless of administered dose, was superior in reducing clinically relevant bleeding when compared with warfarin. The types of bleeding that were most notably reduced with edoxaban in this study were intracranial and retroperitoneal bleeding. The authors concluded that edoxaban administered once daily after initial treatment with heparin was noninferior to parenteral VKA therapy and caused significantly less bleeding in a broad spectrum of patients with VTE. Although the primary safety outcome met statistical significance for superiority, the driving factor seems to have been the clinically relevant nonmajor bleeding.
Special Considerations These studies shed light on the efficacy and safety of TSACs and support their role as a new alternative for the treatment of acute VTE. However, it is important to highlight a few important concepts. Unlike the EINSTEIN and AMPLIFY programs, the studies that investigated dabigatran and edoxaban utilized parenteral agents before the initiation of TSACs. From a practicality standpoint, the necessity of a parenteral agent for at least 5 days as suggested by the study design might be considered inconvenient from a cost perspective and from the need to have patients learn and accept self-injections. Other significant differences between the studies include the variable TTR as well as inclusion and exclusion criteria. Doses of dabigatran, rivaroxaban, and apixaban in these studies were different from the ones in the atrial fibrillation study. Patients with CrCl
