REVIEWS
OF
THERAPEUTICS
Role of Novel and Emerging Oral Anticoagulants for Secondary Prevention of Acute Coronary Syndromes Valerie S. Ganetsky,* Diane E. Hadley, and Tyan F. Thomas Department of Pharmacy Practice, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania
Dual antiplatelet therapy has become a mainstay of long-term management of patients after an acute coronary syndrome (ACS). Mortality for these patients remains high despite current evidence-based treatment strategies. The coagulation cascade plays a role in the pathophysiology of ACS, and trials with warfarin in combination with dual antiplatelet therapy have found decreased rates of ischemic events at the expense of increased bleeding risk. Novel oral anticoagulants (NOACs) in the direct factor Xa (FXa) inhibitor and direct thrombin inhibitor (DTI) categories have been evaluated in combination with standard post-ACS therapy. Rivaroxaban, a FXa inhibitor, reduced the rates of ischemic events but increased major bleeding rates. Apixaban did not decrease the rates of ischemic events and also increased major bleeding rates. Other FXa inhibitors have not been studied in the long-term management of ACS (e.g., otamixaban), are not currently being studied in ongoing phase III trials (e.g., TAK-442), or have been discontinued by the manufacturer (e.g., darexaban). The DTI dabigatran had a 2- to 4-fold increased risk of major bleeding with unclear benefit for reducing ischemic events. The factor IXa inhibitor pegnivacogin is an RNA-based aptamer that has been studied in patients undergoing cardiac catheterization but has not been studied for long-term post-ACS management. The European Society of Cardiology Working Group on Thrombosis recommends the use of newer antiplatelet agents over addition of NOACs. Additional guidelines are available to guide management in patients requiring triple antithrombotic therapy but do not provide definitive recommendations on NOACs. Many questions remain about the place of NOACs for long-term post-ACS management. Recent trials have evaluated double versus triple antithrombotic therapy to balance efficacy and bleeding risk, but they did not include NOACs. It also remains unclear if NOACs hold a place in post-ACS therapy in the era of more potent antiplatelet agents such as prasugrel and ticagrelor. KEY WORDS acute coronary syndrome, anticoagulation, oral anticoagulant, novel oral anticoagulant, oral direct thrombin inhibitor, oral direct factor Xa inhibitor. (Pharmacotherapy 2014;34(6):590–604) doi: 10.1002/phar.1375
Dual antiplatelet therapy (DAPT) with aspirin and adenosine diphosphate receptor P2Y12 inhibitors have become the cornerstone of antithrombotic therapy for patients after an acute coronary syndrome (ACS).1 Several landmark trials have established the benefit of P2Y12 *Address for correspondence: Valerie S. Ganetsky, Philadelphia College of Pharmacy, University of the Sciences, 600 S. 43rd Street, Philadelphia, PA 19104; e-mail: [email protected]. Ó 2013 Pharmacotherapy Publications, Inc.
inhibitors such as clopidogrel, prasugrel, and ticagrelor in combination with low-dose aspirin in decreasing ischemic events.2–4 Despite the advancements in the management of patients with ACS, including the standard use of statins, b-blockers, angiotensin-converting enzyme inhibitors, and antiplatelet agents, mortality remains high for several years after an event. The Global Registry of Acute Coronary Events (GRACE) registry, conducted in the United Kingdom and Belgium, found that mortality for all types of ACS was ~20% at 5 years of follow-up,
NOVEL AND EMERGING ORAL ANTICOAGULANTS FOR ACS Ganetsky et al signaling the existence of room for improvement for secondary prevention interventions.5 The coagulation cascade has been shown to play a role in ACS. Thrombin plays an important role in activation of the coagulation cascade as well as platelet activation and aggregation. After an ACS, patients have been shown to generate thrombin, both in the acute setting and for over a year after an event.6 A meta-analysis of 14 randomized controlled trials comparing the combination of aspirin and warfarin versus aspirin alone found a ~25% relative risk reduction in the rate of all-cause death, nonfatal myocardial infarction (MI), or stroke in the 10 studies with international normalized ratio (INR) targets between 2.0 and 3.0.7 Another meta-analysis that only included studies with a target INR greater than 2.0 found approximate relative risk reductions of 40% and 50% in rates of MI and ischemic stroke, respectively, with no statistically significant difference in mortality.8 These benefits were at the expense of 2- to 3-fold higher rates of minor and major bleeding. Additionally, the combination of DAPT with warfarin was associated with a higher bleeding risk. A nationwide registry in Denmark of ~40,000 patients with acute MI found a yearly incidence of bleeding of 2.6% for aspirin, 4.6% for clopidogrel, 3.7% for DAPT, 4.3% for vitamin K antagonists (VKAs), 5.1% for aspirin plus VKA, 12.3% for clopidogrel plus VKA, and 12.0% for triple antithrombotic therapy.9 A meta-analysis of triple antithrombotic therapy after stent placement found a 2-fold higher incidence of major bleeding events in the first 6 months of follow-up with triple antithrombotic therapy versus DAPT.10 Management of patients receiving VKAs is challenging due to the complex pharmacokinetic (PK) and pharmacodynamic (PD) properties as well as their narrow therapeutic index. Additional limitations include slow onset and offset of action, frequent laboratory and clinical monitoring, and multiple drug and dietary interac-
591
tions.11 In an attempt to overcome these limitations, novel oral anticoagulants (NOACs) with alternative coagulation cascade targets have been developed. Several of these agents have already been approved by the U.S. Food and Drug Administration (FDA) and are being used for patients with atrial fibrillation.12–14 However, their use as an adjunct to antiplatelet therapy to reduce thrombotic complications while balancing bleeding risks in patients after an ACS is less clear. In this review, we focus on NOACs in the direct thrombin inhibitor (DTI) and direct factor Xa (FXa) inhibitor classes for stable ACS patients. The FDA has approved three NOACs: one DTI and two direct FXa inhibitors. Table 1 shows their FDA-approved indications.12–14 DTIs such as dabigatran inhibit thrombin directly without the need for a cofactor, which differentiates them from indirect coagulation inhibitors like the heparins.15 FXa inhibitors, such as rivaroxaban and apixaban, directly inhibit FXa. This mechanism is in contrast to synthetic pentasaccharides such as fondaparinux that indirectly inhibit FXa through antithrombin.16 Methodology Literature Search A literature search was performed to identify clinical trials that evaluated the safety and efficacy of NOACs in patients after an ACS. The PubMed database was searched for English-language clinical trials published between January 2000 and January 2013, using the search terms acute coronary syndrome, anticoagulation, direct thrombin inhibitor, and factor Xa inhibitor. Approximately 300 trials were identified, and trials that evaluated NOACs for ACS indications were included. Trials that included agents other than NOACs, evaluated drug-drug interactions with NOACs, evaluated PK-PD parameters, and evaluated reversal agents for NOACs were
Table 1. FDA-Approved Indications for the NOACs12–14 Drug Dabigatran
FDA-approved indications
Nonvalvular atrial fibrillation (no history of heart valve disorder, such as prosthetic valve, or hemodynamically relevant valve disease) Apixaban Nonvalvular atrial fibrillation (no history of moderate or severe mitral stenosis, prosthetic heart valve) Rivaroxaban Nonvalvular atrial fibrillation (no history of hemodynamically significant mitral valve stenosis or prosthetic heart valve) Treatment and reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism Prophylaxis of deep vein thrombosis following hip or knee replacement surgery FDA = U.S. Food and Drug Administration.
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excluded. Additionally, references used in the identified articles, review articles, and metaanalyses were screened for inclusion. The ClinicalTrials.gov database was used to determine the investigation status for select agents. Bleeding End Points and Definitions Because bleeding is the most frequently encountered adverse event associated with anticoagulant agents, it is important to have a clear understanding of the bleeding-related end points reported in these investigations. Although study
investigators used similar terminology describing bleeding-related end points such as “major bleeding” or “clinically relevant nonmajor bleeding,” the criteria they used to categorize a bleeding event as “major” or “clinically relevant nonmajor” differed. Table 2 describes the primary bleeding-related end points and criteria used to categorize bleeding events in the clinical trials summarized in this review.17, 19, 26, 27, 37 To allow for cross-study comparison of bleeding rates, most of the studies reported bleeding rates using Thrombolysis in Myocardial Infarction Study Group (TIMI) criteria.
Table 2. Bleeding Definitions in Select Long-Term Post-ACS Trials of NOACs Investigation APPRAISE
26
Anticoagulant Apixaban
APPRAISE-227
Apixaban
ATLAS ACS–TIMI 46 Trial17
Rivaroxaban
ATLAS ACS 2–TIMI 51 Trial19 RE-DEEM37
Rivaroxaban Dabigatran
Primary bleedingrelated outcome
Definition of primary bleeding-related outcome
Combination of major Occurrence of major bleeding (in accordance with ISTH-defined criteriaa) and clinically significant nonmajor and clinically significant nonmajor bleeding bleeding (defined as bleeding requiring medical or surgical intervention) Major bleeding Occurrence of major bleeding in accordance with TIMI-defined major bleeding criteriab Clinically significant bleeding
Occurrence of clinically significant bleeding (composite of TIMI-major bleeding, TIMI-minor bleeding, or bleeding requiring medical attentionb) Major bleeding not Occurrence of bleeding, in accordance related to CABG with TIMI-major bleeding criteria not meeting criteria for being CABG relatedb Combination of major Occurrence of major bleeding (in accordance with ISTH-defined criteriaa) and clinically and clinically significant minor bleeding relevant minor (defined as a bleeding event that did not bleeding meet the criteria for a major bleeding event but required medical intervention [e.g., hospital admission, medical or surgical treatment, or a change in antithrombotic therapy])
Were bleeding rates reported using other bleeding criteria? Yes; TIMI-defined bleeding rates were also reportedb Yes; ISTH-defineda and GUSTO-definedc bleeding rates were also reported No
No Yes TIMI-majorb and GUSTO-defined severec bleeding rates reported
APPRAISE (Apixaban for Prevention of Acute Ischemic and Safety Events); ATLAS ACS-TIMI (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction); ATLAS ACSTIMI (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction); CABG = coronary artery bypass grafting; GUSTO = Global Use of Strategies to Open Occluded Arteries; ISTH = International Society of Thrombosis and Hemostasis; RE-DEEM = Dabigatran vs Placebo in Patients with Acute Coronary Syndromes on Dual Antiplatelet Therapy: A Randomized, Double-blind, Phase II Trial; TIMI = Thrombolysis in Myocardial Infarction. a ISTH bleeding criteria are as follows: major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical anatomical area or organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with intracompartmental syndrome), and/or bleeding causing at least a 2-g/dl reduction in hemoglobin or requiring at least 2 units of whole blood or red blood cells. b TIMI bleeding criteria are as follows: major bleeding: intracranial bleeding; or clinically overt bleeding event associated with at least a 5-g/dl reduction in hemoglobin or at least a 15% absolute reduction in hematocrit; minor bleeding: clinically overt bleeding event that is associated with at least a 3- but less than a 5-g/dl reduction in baseline hemoglobin; bleeding requiring medical attention: any bleeding event (not meeting criteria for major or minor bleeding) requiring medical or surgical treatment, or laboratory evaluation; clinically significant bleeding: combination of major, minor, and bleeding requiring medical attention; major bleeding related to CABG: fatal bleeding event; or perioperative intracranial bleeding; or reoperation after sternotomy incision closure for the purpose of controlling bleeding; or more than a 5-unit transfusion of whole blood or packed red blood cells within 48 hours after CABG; or chest tube output greater than 2 L within a 24-hour period. c GUSTO bleeding criteria are as follows: severe bleeding: intracerebral bleeding; or bleeding resulting in hemodynamic compromise; moderate bleeding: bleeding event requiring blood transfusion but not causing hemodynamic compromise; minor bleeding: bleeding event not meeting severe or moderate criteria.
NOVEL AND EMERGING ORAL ANTICOAGULANTS FOR ACS Ganetsky et al Overview of Trials of Novel and Emerging Oral Anticoagulants Table 3 includes an overview of clinical trials for select NOACs: rivaroxaban, apixaban, and dabigatran.17, 19, 26, 27, 37 Oral Direct Factor Xa Inhibitors Rivaroxaban Rivaroxaban added to antiplatelet therapy (DAPT or aspirin monotherapy) in patients after ACS was investigated in the phase II Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS–TIMI) 46 and the phase III ATLAS ACS 2–TIMI 51 trials.17, 19 The ATLAS ACS–TIMI 46 trial was a phase II trial evaluating rivaroxaban in addition to DAPT or aspirin monotherapy in patients after an ACS.17 The trial included 3491 patients within 7 days of hospitalization for an ACS. The trial evaluated placebo versus rivaroxaban 5, 10, 15, or 20 mg/day, given once/day or in two divided doses, in combination with either aspirin 75–100 mg/day (stratum 1) or aspirin plus thienopyridine (stratum 2). Patients in stratum 1, on average, were older and more likely to have had an MI prior to study enrollment, whereas patients in stratum 2 were more likely to have had an ST-segment elevation myocardial infarction (STEMI) as their index event and to have undergone percutaneous coronary interventions (PCIs) prior to study enrollment. Rivaroxaban use was associated with a nonsignificant reduction in the primary composite efficacy end point of death, MI, stroke, or severe ischemia requiring revascularization versus placebo across both strata (5.6% vs 7.0%; hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.60–1.05, p=0.10), with no significant differences noted between once/day and twice/day dosing regimens. A reduction in the primary efficacy end point was found in stratum 1 versus placebo (HR 0.53, 95% CI 0.33–0.84) but not in stratum 2 versus placebo (HR 0.99, 95% CI 0.60–1.42); however, this finding should be taken into context with the previously mentioned differences in baseline characteristics. The trial was not designed to assess differences in outcomes between stratum 1 and stratum 2. Rivaroxaban significantly reduced the rate of the secondary end point (death, MI, or stroke) compared with
593
placebo in the overall study population (3.9% vs 5.5%; HR 0.69, 95% CI 0.50–0.96, p=0.027). The primary safety end point (minor and major TIMI bleeding or bleeding requiring medical attention) occurred more frequently in the rivaroxaban once/day dosing groups versus placebo in a dose-dependent manner: HR 2.21 (95% CI 1.25–3.91) for 5 mg, HR 3.35 (95% CI 2.31– 4.87) for 10 mg, HR 3.60 (95% CI 2.32–5.58) for 15 mg, and HR 5.06 (95% CI 3.45–7.42) for 20 mg once/day (p1 mm ST-segment deviation, or TIMI score ≥ 3
Inclusion criteria Stratum 1: rivaroxaban 5, 10, or 20 mg/day (given once/ day or in two divided doses) vs placebo + aspirin 75–100 mg/day Stratum 2: rivaroxaban 5, 10, 15, or 20 mg/day (given once/day or in two divided doses) vs placebo + aspirin 75–100 mg/ day + thienopyridine Duration: 6 months
Treatment regimen and duration
Table 3. Overview of Clinical Trials for Select NOACs for ACS
Efficacy: Death, MI, stroke, or severe recurrent ischemia requiring revascularization Rivaroxaban (both strata) vs placebo: 5.6% vs 7.0% (HR 0.79, 95% CI 0.60–1.05, p=0.10) Stratum 1 vs placebo 0.53 (95% CI 0.33–0.84) Stratum 2 vs placebo: 0.99 (95% CI 0.69–1.42); p for interaction=0.034 Safety: Clinically significant bleeding (TIMI major and minor bleeding or bleeding requiring medical attention) All doses given once/day vs placebo: 5 mg: HR 2.21 (95% CI 1.25–3.91); 10 mg: HR 3.35 (95% CI 2.31–4.87); 15 mg: HR 3.60 (95% CI 2.32–5.58); 20 mg: HR 5.06 (95% CI 3.45–7.42), p
OF
THERAPEUTICS
Role of Novel and Emerging Oral Anticoagulants for Secondary Prevention of Acute Coronary Syndromes Valerie S. Ganetsky,* Diane E. Hadley, and Tyan F. Thomas Department of Pharmacy Practice, Philadelphia College of Pharmacy, University of the Sciences, Philadelphia, Pennsylvania
Dual antiplatelet therapy has become a mainstay of long-term management of patients after an acute coronary syndrome (ACS). Mortality for these patients remains high despite current evidence-based treatment strategies. The coagulation cascade plays a role in the pathophysiology of ACS, and trials with warfarin in combination with dual antiplatelet therapy have found decreased rates of ischemic events at the expense of increased bleeding risk. Novel oral anticoagulants (NOACs) in the direct factor Xa (FXa) inhibitor and direct thrombin inhibitor (DTI) categories have been evaluated in combination with standard post-ACS therapy. Rivaroxaban, a FXa inhibitor, reduced the rates of ischemic events but increased major bleeding rates. Apixaban did not decrease the rates of ischemic events and also increased major bleeding rates. Other FXa inhibitors have not been studied in the long-term management of ACS (e.g., otamixaban), are not currently being studied in ongoing phase III trials (e.g., TAK-442), or have been discontinued by the manufacturer (e.g., darexaban). The DTI dabigatran had a 2- to 4-fold increased risk of major bleeding with unclear benefit for reducing ischemic events. The factor IXa inhibitor pegnivacogin is an RNA-based aptamer that has been studied in patients undergoing cardiac catheterization but has not been studied for long-term post-ACS management. The European Society of Cardiology Working Group on Thrombosis recommends the use of newer antiplatelet agents over addition of NOACs. Additional guidelines are available to guide management in patients requiring triple antithrombotic therapy but do not provide definitive recommendations on NOACs. Many questions remain about the place of NOACs for long-term post-ACS management. Recent trials have evaluated double versus triple antithrombotic therapy to balance efficacy and bleeding risk, but they did not include NOACs. It also remains unclear if NOACs hold a place in post-ACS therapy in the era of more potent antiplatelet agents such as prasugrel and ticagrelor. KEY WORDS acute coronary syndrome, anticoagulation, oral anticoagulant, novel oral anticoagulant, oral direct thrombin inhibitor, oral direct factor Xa inhibitor. (Pharmacotherapy 2014;34(6):590–604) doi: 10.1002/phar.1375
Dual antiplatelet therapy (DAPT) with aspirin and adenosine diphosphate receptor P2Y12 inhibitors have become the cornerstone of antithrombotic therapy for patients after an acute coronary syndrome (ACS).1 Several landmark trials have established the benefit of P2Y12 *Address for correspondence: Valerie S. Ganetsky, Philadelphia College of Pharmacy, University of the Sciences, 600 S. 43rd Street, Philadelphia, PA 19104; e-mail: [email protected]. Ó 2013 Pharmacotherapy Publications, Inc.
inhibitors such as clopidogrel, prasugrel, and ticagrelor in combination with low-dose aspirin in decreasing ischemic events.2–4 Despite the advancements in the management of patients with ACS, including the standard use of statins, b-blockers, angiotensin-converting enzyme inhibitors, and antiplatelet agents, mortality remains high for several years after an event. The Global Registry of Acute Coronary Events (GRACE) registry, conducted in the United Kingdom and Belgium, found that mortality for all types of ACS was ~20% at 5 years of follow-up,
NOVEL AND EMERGING ORAL ANTICOAGULANTS FOR ACS Ganetsky et al signaling the existence of room for improvement for secondary prevention interventions.5 The coagulation cascade has been shown to play a role in ACS. Thrombin plays an important role in activation of the coagulation cascade as well as platelet activation and aggregation. After an ACS, patients have been shown to generate thrombin, both in the acute setting and for over a year after an event.6 A meta-analysis of 14 randomized controlled trials comparing the combination of aspirin and warfarin versus aspirin alone found a ~25% relative risk reduction in the rate of all-cause death, nonfatal myocardial infarction (MI), or stroke in the 10 studies with international normalized ratio (INR) targets between 2.0 and 3.0.7 Another meta-analysis that only included studies with a target INR greater than 2.0 found approximate relative risk reductions of 40% and 50% in rates of MI and ischemic stroke, respectively, with no statistically significant difference in mortality.8 These benefits were at the expense of 2- to 3-fold higher rates of minor and major bleeding. Additionally, the combination of DAPT with warfarin was associated with a higher bleeding risk. A nationwide registry in Denmark of ~40,000 patients with acute MI found a yearly incidence of bleeding of 2.6% for aspirin, 4.6% for clopidogrel, 3.7% for DAPT, 4.3% for vitamin K antagonists (VKAs), 5.1% for aspirin plus VKA, 12.3% for clopidogrel plus VKA, and 12.0% for triple antithrombotic therapy.9 A meta-analysis of triple antithrombotic therapy after stent placement found a 2-fold higher incidence of major bleeding events in the first 6 months of follow-up with triple antithrombotic therapy versus DAPT.10 Management of patients receiving VKAs is challenging due to the complex pharmacokinetic (PK) and pharmacodynamic (PD) properties as well as their narrow therapeutic index. Additional limitations include slow onset and offset of action, frequent laboratory and clinical monitoring, and multiple drug and dietary interac-
591
tions.11 In an attempt to overcome these limitations, novel oral anticoagulants (NOACs) with alternative coagulation cascade targets have been developed. Several of these agents have already been approved by the U.S. Food and Drug Administration (FDA) and are being used for patients with atrial fibrillation.12–14 However, their use as an adjunct to antiplatelet therapy to reduce thrombotic complications while balancing bleeding risks in patients after an ACS is less clear. In this review, we focus on NOACs in the direct thrombin inhibitor (DTI) and direct factor Xa (FXa) inhibitor classes for stable ACS patients. The FDA has approved three NOACs: one DTI and two direct FXa inhibitors. Table 1 shows their FDA-approved indications.12–14 DTIs such as dabigatran inhibit thrombin directly without the need for a cofactor, which differentiates them from indirect coagulation inhibitors like the heparins.15 FXa inhibitors, such as rivaroxaban and apixaban, directly inhibit FXa. This mechanism is in contrast to synthetic pentasaccharides such as fondaparinux that indirectly inhibit FXa through antithrombin.16 Methodology Literature Search A literature search was performed to identify clinical trials that evaluated the safety and efficacy of NOACs in patients after an ACS. The PubMed database was searched for English-language clinical trials published between January 2000 and January 2013, using the search terms acute coronary syndrome, anticoagulation, direct thrombin inhibitor, and factor Xa inhibitor. Approximately 300 trials were identified, and trials that evaluated NOACs for ACS indications were included. Trials that included agents other than NOACs, evaluated drug-drug interactions with NOACs, evaluated PK-PD parameters, and evaluated reversal agents for NOACs were
Table 1. FDA-Approved Indications for the NOACs12–14 Drug Dabigatran
FDA-approved indications
Nonvalvular atrial fibrillation (no history of heart valve disorder, such as prosthetic valve, or hemodynamically relevant valve disease) Apixaban Nonvalvular atrial fibrillation (no history of moderate or severe mitral stenosis, prosthetic heart valve) Rivaroxaban Nonvalvular atrial fibrillation (no history of hemodynamically significant mitral valve stenosis or prosthetic heart valve) Treatment and reduction in risk of recurrence of deep vein thrombosis and pulmonary embolism Prophylaxis of deep vein thrombosis following hip or knee replacement surgery FDA = U.S. Food and Drug Administration.
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PHARMACOTHERAPY Volume 34, Number 6, 2014
excluded. Additionally, references used in the identified articles, review articles, and metaanalyses were screened for inclusion. The ClinicalTrials.gov database was used to determine the investigation status for select agents. Bleeding End Points and Definitions Because bleeding is the most frequently encountered adverse event associated with anticoagulant agents, it is important to have a clear understanding of the bleeding-related end points reported in these investigations. Although study
investigators used similar terminology describing bleeding-related end points such as “major bleeding” or “clinically relevant nonmajor bleeding,” the criteria they used to categorize a bleeding event as “major” or “clinically relevant nonmajor” differed. Table 2 describes the primary bleeding-related end points and criteria used to categorize bleeding events in the clinical trials summarized in this review.17, 19, 26, 27, 37 To allow for cross-study comparison of bleeding rates, most of the studies reported bleeding rates using Thrombolysis in Myocardial Infarction Study Group (TIMI) criteria.
Table 2. Bleeding Definitions in Select Long-Term Post-ACS Trials of NOACs Investigation APPRAISE
26
Anticoagulant Apixaban
APPRAISE-227
Apixaban
ATLAS ACS–TIMI 46 Trial17
Rivaroxaban
ATLAS ACS 2–TIMI 51 Trial19 RE-DEEM37
Rivaroxaban Dabigatran
Primary bleedingrelated outcome
Definition of primary bleeding-related outcome
Combination of major Occurrence of major bleeding (in accordance with ISTH-defined criteriaa) and clinically significant nonmajor and clinically significant nonmajor bleeding bleeding (defined as bleeding requiring medical or surgical intervention) Major bleeding Occurrence of major bleeding in accordance with TIMI-defined major bleeding criteriab Clinically significant bleeding
Occurrence of clinically significant bleeding (composite of TIMI-major bleeding, TIMI-minor bleeding, or bleeding requiring medical attentionb) Major bleeding not Occurrence of bleeding, in accordance related to CABG with TIMI-major bleeding criteria not meeting criteria for being CABG relatedb Combination of major Occurrence of major bleeding (in accordance with ISTH-defined criteriaa) and clinically and clinically significant minor bleeding relevant minor (defined as a bleeding event that did not bleeding meet the criteria for a major bleeding event but required medical intervention [e.g., hospital admission, medical or surgical treatment, or a change in antithrombotic therapy])
Were bleeding rates reported using other bleeding criteria? Yes; TIMI-defined bleeding rates were also reportedb Yes; ISTH-defineda and GUSTO-definedc bleeding rates were also reported No
No Yes TIMI-majorb and GUSTO-defined severec bleeding rates reported
APPRAISE (Apixaban for Prevention of Acute Ischemic and Safety Events); ATLAS ACS-TIMI (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction); ATLAS ACSTIMI (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction); CABG = coronary artery bypass grafting; GUSTO = Global Use of Strategies to Open Occluded Arteries; ISTH = International Society of Thrombosis and Hemostasis; RE-DEEM = Dabigatran vs Placebo in Patients with Acute Coronary Syndromes on Dual Antiplatelet Therapy: A Randomized, Double-blind, Phase II Trial; TIMI = Thrombolysis in Myocardial Infarction. a ISTH bleeding criteria are as follows: major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical anatomical area or organ (e.g., intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, intramuscular with intracompartmental syndrome), and/or bleeding causing at least a 2-g/dl reduction in hemoglobin or requiring at least 2 units of whole blood or red blood cells. b TIMI bleeding criteria are as follows: major bleeding: intracranial bleeding; or clinically overt bleeding event associated with at least a 5-g/dl reduction in hemoglobin or at least a 15% absolute reduction in hematocrit; minor bleeding: clinically overt bleeding event that is associated with at least a 3- but less than a 5-g/dl reduction in baseline hemoglobin; bleeding requiring medical attention: any bleeding event (not meeting criteria for major or minor bleeding) requiring medical or surgical treatment, or laboratory evaluation; clinically significant bleeding: combination of major, minor, and bleeding requiring medical attention; major bleeding related to CABG: fatal bleeding event; or perioperative intracranial bleeding; or reoperation after sternotomy incision closure for the purpose of controlling bleeding; or more than a 5-unit transfusion of whole blood or packed red blood cells within 48 hours after CABG; or chest tube output greater than 2 L within a 24-hour period. c GUSTO bleeding criteria are as follows: severe bleeding: intracerebral bleeding; or bleeding resulting in hemodynamic compromise; moderate bleeding: bleeding event requiring blood transfusion but not causing hemodynamic compromise; minor bleeding: bleeding event not meeting severe or moderate criteria.
NOVEL AND EMERGING ORAL ANTICOAGULANTS FOR ACS Ganetsky et al Overview of Trials of Novel and Emerging Oral Anticoagulants Table 3 includes an overview of clinical trials for select NOACs: rivaroxaban, apixaban, and dabigatran.17, 19, 26, 27, 37 Oral Direct Factor Xa Inhibitors Rivaroxaban Rivaroxaban added to antiplatelet therapy (DAPT or aspirin monotherapy) in patients after ACS was investigated in the phase II Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction (ATLAS ACS–TIMI) 46 and the phase III ATLAS ACS 2–TIMI 51 trials.17, 19 The ATLAS ACS–TIMI 46 trial was a phase II trial evaluating rivaroxaban in addition to DAPT or aspirin monotherapy in patients after an ACS.17 The trial included 3491 patients within 7 days of hospitalization for an ACS. The trial evaluated placebo versus rivaroxaban 5, 10, 15, or 20 mg/day, given once/day or in two divided doses, in combination with either aspirin 75–100 mg/day (stratum 1) or aspirin plus thienopyridine (stratum 2). Patients in stratum 1, on average, were older and more likely to have had an MI prior to study enrollment, whereas patients in stratum 2 were more likely to have had an ST-segment elevation myocardial infarction (STEMI) as their index event and to have undergone percutaneous coronary interventions (PCIs) prior to study enrollment. Rivaroxaban use was associated with a nonsignificant reduction in the primary composite efficacy end point of death, MI, stroke, or severe ischemia requiring revascularization versus placebo across both strata (5.6% vs 7.0%; hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.60–1.05, p=0.10), with no significant differences noted between once/day and twice/day dosing regimens. A reduction in the primary efficacy end point was found in stratum 1 versus placebo (HR 0.53, 95% CI 0.33–0.84) but not in stratum 2 versus placebo (HR 0.99, 95% CI 0.60–1.42); however, this finding should be taken into context with the previously mentioned differences in baseline characteristics. The trial was not designed to assess differences in outcomes between stratum 1 and stratum 2. Rivaroxaban significantly reduced the rate of the secondary end point (death, MI, or stroke) compared with
593
placebo in the overall study population (3.9% vs 5.5%; HR 0.69, 95% CI 0.50–0.96, p=0.027). The primary safety end point (minor and major TIMI bleeding or bleeding requiring medical attention) occurred more frequently in the rivaroxaban once/day dosing groups versus placebo in a dose-dependent manner: HR 2.21 (95% CI 1.25–3.91) for 5 mg, HR 3.35 (95% CI 2.31– 4.87) for 10 mg, HR 3.60 (95% CI 2.32–5.58) for 15 mg, and HR 5.06 (95% CI 3.45–7.42) for 20 mg once/day (p1 mm ST-segment deviation, or TIMI score ≥ 3
Inclusion criteria Stratum 1: rivaroxaban 5, 10, or 20 mg/day (given once/ day or in two divided doses) vs placebo + aspirin 75–100 mg/day Stratum 2: rivaroxaban 5, 10, 15, or 20 mg/day (given once/day or in two divided doses) vs placebo + aspirin 75–100 mg/ day + thienopyridine Duration: 6 months
Treatment regimen and duration
Table 3. Overview of Clinical Trials for Select NOACs for ACS
Efficacy: Death, MI, stroke, or severe recurrent ischemia requiring revascularization Rivaroxaban (both strata) vs placebo: 5.6% vs 7.0% (HR 0.79, 95% CI 0.60–1.05, p=0.10) Stratum 1 vs placebo 0.53 (95% CI 0.33–0.84) Stratum 2 vs placebo: 0.99 (95% CI 0.69–1.42); p for interaction=0.034 Safety: Clinically significant bleeding (TIMI major and minor bleeding or bleeding requiring medical attention) All doses given once/day vs placebo: 5 mg: HR 2.21 (95% CI 1.25–3.91); 10 mg: HR 3.35 (95% CI 2.31–4.87); 15 mg: HR 3.60 (95% CI 2.32–5.58); 20 mg: HR 5.06 (95% CI 3.45–7.42), p
