Unanswered Questions in Patients With Concurrent Atrial Fibrillation and Acute Coronary Syndrome Daniel S. Ice, MD*, Timothy A. Shapiro, MD, Eric M. Gnall, DO, and Peter R. Kowey, MD The best regimen for the long-term management of patients with atrial fibrillation who present with an acute coronary syndrome or require placement of a coronary stent remains unclear. Clinicians need to understand the risk of stroke, stent thrombosis, and major bleeding associated with treating these patients. Numerous studies and risk assessment schemes provide clinicians with an estimation of the risk of stroke, stent thrombosis, and major bleeding that may be associated with the use or avoidance of dual antiplatelet therapy with concurrent anticoagulation therapy (triple therapy). This review discusses the special antithrombotic needs in patients who have atrial fibrillation and either acute coronary syndrome or a requirement for percutaneous coronary intervention, including the published evidence for nonevitamin K oral anticoagulants, and the unanswered questions in this patient population. In conclusion, until the results of additional ongoing or planned randomized trials are known, clinicians must continue to rely on expert opinion and their own clinical judgment when treating these patients. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:888e896)
Not all thrombi are created equal. The composition and formation of thrombi in the venous system appears to be different to that in the arterial system.1 Consequently, fibrinrich venous thrombi are most effectively treated with anticoagulants,1e4 whereas antiplatelet agents have been the primary therapy for platelet-rich arterial thrombi.1,5e7 Clinical conditions leading to the potential for venous and arterial thrombi may exist simultaneously such as when patients with atrial fibrillation (AF) undergo percutaneous coronary intervention (PCI). This scenario is not uncommon as the prevalence of AF is 10% to 15% among patients with coronary artery disease and 5% to 7% among patients undergoing PCI.5,8e10 In such patients, the combination of oral anticoagulants with aspirin and a P2Y12 receptor antagonist (triple therapy) after coronary stent placement is, intuitively, the most effective antithrombotic regimen but also results in an increased risk of major bleeding,9,11,12 thus creating a management dilemma. Only 1 randomized prospective trial (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing [WOEST]) has evaluated this regimen,13 and most other data have been derived from single-center registries, small case-controlled series, or in a few cases, from post hoc analyses of prospective studies. The focus of this review will be to discuss the antithrombotic needs in patients who have AF and either acute coronary syndrome (ACS) or a requirement for PCI, including unanswered questions in these patient populations.
Division of Cardiovascular Diseases, Lankenau Medical Center and Lankenau Institute of Medical Research, Wynnewood, Jefferson Medical College, Philadelphia, Pennsylvania. Manuscript received July 30, 2013; revised manuscript received and accepted November 14, 2013. See page 893 for disclosure information. *Corresponding author: Tel: (484) 476-2682; fax: (484) 476-1658. E-mail address: [email protected] (D.S. Ice). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.11.046
Thrombosis in Atrial Fibrillation AF is associated with a significant risk of stroke and thromboembolism.14 Patients with nonvalvular AF not taking antithrombotic medications have an annual rate of ischemic stroke or thromboembolism of approximately 5% compared with 0.5% to 1% in age-matched controls without AF.5 AF-related strokes are cardioembolic, which are more disabling and have a higher early mortality rate than atherothrombotic strokes.15 Increased thromboembolic risk in patients with AF mainly stems from the activation of the coagulation cascade rather than from platelet activation,16 and this fact explains why anticoagulants that impact the coagulation cascade are more efficacious than antiplatelet agents in preventing thromboembolic events in patients with AF.2 The risk of thromboembolism is similar among patients with paroxysmal, persistent, or permanent AF and is increased by certain risk factors, notably Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2).5 Higher CHADS2 scores are associated with greater absolute benefit of oral anticoagulation with warfarin.17 Taking into consideration the presence of vascular disease, intermediate age (65e74), and female gender, the CHA2DS2-VASc score has been shown to be a better predictor of stroke risk, particularly in low-risk patients.18 Table 1 summarizes the rates of thromboembolism and death in patients not on oral anticoagulation according to the CHA2DS2-VASc score. Oral anticoagulant therapy is an effective means of stroke prophylaxis in patients with AF20; a meta-analysis showed that warfarin reduced stroke risk by 64% versus placebo and by 39% versus aspirin.21 Although the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial results suggested that aspirin and clopidogrel could be used in patients with AF unsuitable for vitamin K antagonist therapy,22 ACTIVE-W demonstrated www.ajconline.org
Review/Concurrent AF and ACS: Unanswered Questions Table 1 CHA2DS2-VASc and HAS-BLED scores and event rates CHA2DS2-VASc Score 0 1 2 3 4 5 6 7 8 9
HAS-BLED Event Rate*
Score
Event Rate†
0.78 2.01 3.71 5.92 9.27 15.26 19.74 21.50 22.38 23.64
0 1 2 3 4 5 6 7 8 9
1.13 1.02 1.88 3.74 8.7 12.5 — — — —
CHA2DS2-VASc ¼ Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior ischemic Stroke or transient ischemic attack þ Vascular disease, Age 65 to 75 years, female Sex; HAS-BLED ¼ Hypertension, Abnormal renal or liver function, Stroke, Bleeding history, Labile INR, Elderly, Drugs or alcohol. * Rate of hospital admission and death due to thromboembolism per 100 person-years at 1-year follow-up in 73,538 patients not on oral anticoagulation.18 † Rate of major bleeding per 100 person-years at 1-year follow-up in 3,456 patients of the Euro Heart Survey; 65% were on oral anticoagulation.19
clear superiority of warfarin compared with dual antiplatelet therapy in patients who were suitable.2 Thrombogenesis in ACS or After PCI Localized damage of the coronary artery endothelium is the underlying mechanism triggering thrombosis in ACS and typically stems from an underlying atherosclerotic plaque rupture exposing thrombogenic material in the plaque core to blood, triggering platelet aggregation and fibrin formation. This process results in the formation of a platelet-rich thrombus.5,23,24 Because of the role of platelet aggregation in this process, antiplatelet agents have become part of the primary treatment in ACS. In addition, antithrombin agents are also efficacious in the acute setting of myocardial infarction. Stent thrombosis, however, is largely platelet dependent and is significantly prevented by antiplatelet agents.25 PCI results in additional trauma to the vessel wall, initiating local prothrombotic activation. Stent implantation after angioplasty-induced dilation triggers further acute and chronic prothrombotic and proinflammatory reactions toward the stent.26 Drug-eluting stents inhibit restenosis and delay re-endothelialization; therefore, prothrombotic and proinflammatory activations can continue to occur and can lead to stent thrombosis even after 12 months.27,28 The incidence of stent thrombosis in the published data shows variation (Table 2) but is increased among patients with ACS and is greatest in the first month regardless of the type of stent used.32,34 The rate decreases to 65 years), Drug/alcohol concomitantly (HAS-BLED) schema to assess bleeding risk offers a valuable “net clinical benefit” assessment of using oral anticoagulation in patients with AF who are undergoing coronary stenting.61 Even in those with high bleeding risk (HAS-BLED score 3), oral anticoagulation therapy was associated with a lower mortality rate and fewer major adverse cardiac events at 1-year follow-up, with higher rates of major bleeding. Predictors of major bleeding were chronic renal failure and the use of drugeluting stents.61 As mentioned previously, the only prospective, randomized, controlled trial evaluating triple therapy has been the recently published WOEST trial,13 which was a multicenter study of patients receiving oral anticoagulants and undergoing PCI. Patients receiving clopidogrel alone (double therapy) were compared with those receiving clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI. In this study, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events, suggesting that the addition of aspirin provides no additional benefit in this setting while increasing the risk of bleeding. The study was not powered to detect differences in stent thrombosis occurrence. Of note, the study featured higher-than-expected bleeding rates in both arms of the study probably owing to the use of drug-eluting stents and femoral access in most cases and proton pump inhibitor use in only a minority of cases. As suggested by the WOEST trial, treatment of these patients with an oral anticoagulant and single antiplatelet therapy may represent a viable and possibly safer option with less risk of bleeding. Until the findings of this study are supported by additional trials, it remains unclear whether this oral anticoagulant plus clopidogrel regimen represents the most favorable option. It is also not known if this regimen provides the same benefits and risks when applied to a world population or if the novel oral anticoagulant agents can be used in this regimen. Currently, there are at least 3 ongoing trials (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE], Anticoagulation in Stent Intervention [MUSICA-2], and A Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention [PIONEER AF-PCI]) evaluating different strategies of antiplatelet agents and oral anticoagulants in patients with AF and stenting. These trials should help to clarify the best drug regimen and duration of therapy to minimize bleeding risk and ischemic events. Other trials may be necessary to clarify if there is a net benefit of triple therapy in patients with AF with recent ACS who do not receive stenting. Strategies for Assessing and Minimizing Bleeding Risk Bleeding risk in patients undergoing PCI can be estimated from clinical predictors, including advanced age, female gender, a history of bleeding, renal insufficiency, and use of
891
glycoprotein inhibitors.62 Using these risk factors, the risk score predicted major bleeding from 1% in the lowest risk patients to 40% in the highest risk patients. Other bleeding risk assessments take catheterization access site (femoral vs radial) into account because >85% of in-hospital major bleeding events are related to the access site.63 The use of triple therapy for patients with AF who are undergoing PCI has known anticipated bleeding risks, but strategies can be used to reduce the risk and can be tailored to the individual patient. Radial access is gaining popularity and quickly becoming the preferred vascular access site owing to its lower complication rates of major bleeding than femoral access, reducing major bleeding events by 73% and showing a trend toward reduced death, myocardial infarction, and stroke.64 In addition, the use of proton pump inhibitors can play a key role in this patient population because gastrointestinal bleeding events represent 20% to 30% of major bleeding events after PCI.65 Proton pump inhibitors not metabolized by cytochrome P450 2C19 and not interfering with clopidogrelmediated effects (e.g., pantoprazole) are preferred.35 Clopidogrel should be the P2Y12-receptor antagonist used in combination with aspirin and warfarin. Despite the association of prasugrel with fewer ischemic events, including stent thrombosis compared with clopidogrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel—Thrombolysis In Myocardial Infarction 38 trial,66 it was associated with an increased risk of major and minor bleedings without fewer ischemic events compared with clopidogrel in patients receiving triple therapy after drug-eluting stent implantation67 and should not be used as part of a triple therapy regimen. Ticagrelor is the P2Y12 antagonist recommended by the European Society of Cardiology for patients at moderate-to-high risk of ischemic events.48 However, although ticagrelor did not increase the risk of major bleeding compared with clopidogrel, it was associated with an increased risk of nonecoronary artery bypass grafterelated bleeding.68 In addition, ticagrelor has not been tested as part of a triple therapy regimen. For these reasons, its use with warfarin should not be recommended until its safety is demonstrated in a triple therapy regimen. Less than 25% of patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial received a stent but demonstrated benefit from receiving dual antiplatelet therapy.6 This suggests that patients with both ACS and AF who are not receiving PCI might also benefit from triple therapy, with a reduced risk of ischemic adverse events—at least in the acute setting. However, because patients on anticoagulation were excluded from the trial, it is unknown whether triple therapy provides a net clinical benefit after presentation with ACS without PCI in patients with AF. Owing to this uncertainty and with the known increased bleeding risk, treatment of these patients with oral anticoagulation and single antiplatelet therapy (aspirin or clopidogrel) may provide a safer regimen. Here, individual risk assessment is critical. NoneVitamin K Antagonist Oral Anticoagulants Dabigatran: Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and embolism in patients with AF. The Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) trial was a randomized study demonstrating that dabigatran 150 mg twice daily was superior
892
The American Journal of Cardiology (www.ajconline.org)
to warfarin in reducing stroke and systemic embolism but had similar rates of major bleeding, although it produced a significantly lower rate of intracranial bleeding.69 The rate of gastrointestinal bleeding was increased with the higher dose (150 mg), and there was a trend toward higher rates of myocardial infarction with both doses. Major bleeding was increased when aspirin was used with both doses of dabigatran in the RE-LY trial.70 However, a post hoc analysis of the RELY trial showed that the dabigatran 150 mg twice-daily dose produced similar major bleeding events compared with warfarin, even when an antiplatelet agent was added, whereas the dabigatran 110 mg twice-daily dose produced less major bleeding. When 2 antiplatelet agents were used, the lowest absolute risks were noted among patients in the dabigatran 110 mg twice-daily group.71 Rivaroxaban: Rivaroxaban, a highly selective, oral, direct factor Xa inhibitor, was studied in the large, multicenter, randomized Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.72 ROCKET AF trial included patients with nonvalvular AF at high risk of stroke (CHADS2 score of 2, mean score of 3.5) given rivaroxaban 20 mg/day (15 mg/day for creatinine clearance 30 to 49 ml/ min) or warfarin. Rivaroxaban was at least noninferior to warfarin in preventing stroke or systolic embolism and produced similar rates of major bleeding compared with warfarin, with significant reductions in the rates of intracranial hemorrhage and fatal bleeding but increased gastrointestinal bleeding. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2 TIMI 51) trial was conducted to evaluate low-dose (5 mg twice daily) and very low-dose (2.5 mg twice daily) rivaroxaban as an adjunctive therapy in patients with a recent ACS.73 Patients with previous gastrointestinal bleeding, previous ischemic stroke or transient ischemic attack, or poor renal function were excluded from the greater exposure arm. Rivaroxaban significantly reduced the primary end point of cardiovascular death, myocardial infarction, or stroke for both doses compared with placebo, with a >30% decrease in cardiovascular and all-cause deaths in the 2.5 mg twice-daily arm. There was also a 31% relative risk reduction for stent thrombosis. Data for the 2 doses of rivaroxaban combined showed increased major bleeding and intracranial hemorrhage, without significantly increasing fatal bleeding. The results of ATLAS ACS 2 TIMI 51 suggest that rivaroxaban, at the 2.5 mg twice-daily and 5 mg twice-daily doses, may improve ischemic events when added to dual antiplatelet therapy in patients with ACS. AF was an exclusion criterion, so ATLAS ACS 2 TIMI 51 does not provide an example of triple therapy use in patients with both ACS and AF. No data exist comparing rivaroxaban with warfarin in this setting. Owing to the intriguing mortality benefit, the 2012 European Society of Cardiology STEMI guidelines list rivaroxaban as a class IIb indication, in addition to aspirin and clopidogrel, for selected patients with low bleeding risk.47
Although the European Medicines Agency’s Committee for Medicinal Products for Human Use has recently recommended the approval of rivaroxaban for use in patients with ACS, the United States Food and Drug Administration is yet to approve it for this indication. Apixaban: Apixaban, another oral direct factor Xa inhibitor, was studied in the Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, comparing apixaban (5 or 2.5 mg twice daily for patients who met 2 of the following criteria: age 80 years, body weight 60 kg, or serum creatinine level of 1.5 mg/dl) with warfarin in patients with AF.74 Apixaban was superior to warfarin in the prevention of the primary outcome of stroke or systemic embolism. There was also significantly less major bleeding, hemorrhagic stroke, and intracranial bleeding with apixaban than warfarin. Apixaban was also associated with mortality benefit compared with warfarin. Producing fewer strokes and less bleeding than warfarin, the results of ARISTOTLE suggest that apixaban might serve as an alternative to warfarin in the setting of ACS. The phase 3 Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE 2) trial studied apixaban in patients with ACS and at least 2 additional risk factors for recurrent ischemic events.75 The trial was terminated early owing to an increase in major bleeding events with apixaban in the absence of a reduction in recurrent ischemic events. The increased bleeding reported with this agent in patients with ACS certainly raises concerns regarding its use in these patients. The newer oral anticoagulants have shown promise in reducing embolic and ischemic events in patients with AF and ACS, although they have not been adequately studied in patients with both conditions. Despite the survival benefit reported with rivaroxaban, a major concern exists with the three to fourfold excess in major and intracranial bleeding events with the addition of any dose of factor Xa inhibitors to dual antiplatelet therapy in ATLAS ACS 2 TIMI 51 and APPRAISE 2. This increased risk of bleeding occurred throughout the duration of treatment in both trials. Moreover, the net benefit of dabigatran compared with warfarin in the post hoc analysis of the RE-LY trial suggests that dabigatran may be a safer anticoagulant option when dual antiplatelet is necessary. Although the newer oral anticoagulants may be a viable and safe option, it is unclear whether they should be favored in patients with AF who are receiving PCI until more clinical data confirm them to be a safe option. Ultimately, the physician must consider the risks and benefits of the use of newer oral anticoagulants for these patients. Management Recommendations The following recommendations for patients with AF with ACS or requiring PCI are based on the opinion and practice of the authors, taking into consideration the best available data and review of the literature. 1. Low-dose (
Not all thrombi are created equal. The composition and formation of thrombi in the venous system appears to be different to that in the arterial system.1 Consequently, fibrinrich venous thrombi are most effectively treated with anticoagulants,1e4 whereas antiplatelet agents have been the primary therapy for platelet-rich arterial thrombi.1,5e7 Clinical conditions leading to the potential for venous and arterial thrombi may exist simultaneously such as when patients with atrial fibrillation (AF) undergo percutaneous coronary intervention (PCI). This scenario is not uncommon as the prevalence of AF is 10% to 15% among patients with coronary artery disease and 5% to 7% among patients undergoing PCI.5,8e10 In such patients, the combination of oral anticoagulants with aspirin and a P2Y12 receptor antagonist (triple therapy) after coronary stent placement is, intuitively, the most effective antithrombotic regimen but also results in an increased risk of major bleeding,9,11,12 thus creating a management dilemma. Only 1 randomized prospective trial (What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing [WOEST]) has evaluated this regimen,13 and most other data have been derived from single-center registries, small case-controlled series, or in a few cases, from post hoc analyses of prospective studies. The focus of this review will be to discuss the antithrombotic needs in patients who have AF and either acute coronary syndrome (ACS) or a requirement for PCI, including unanswered questions in these patient populations.
Division of Cardiovascular Diseases, Lankenau Medical Center and Lankenau Institute of Medical Research, Wynnewood, Jefferson Medical College, Philadelphia, Pennsylvania. Manuscript received July 30, 2013; revised manuscript received and accepted November 14, 2013. See page 893 for disclosure information. *Corresponding author: Tel: (484) 476-2682; fax: (484) 476-1658. E-mail address: [email protected] (D.S. Ice). 0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.11.046
Thrombosis in Atrial Fibrillation AF is associated with a significant risk of stroke and thromboembolism.14 Patients with nonvalvular AF not taking antithrombotic medications have an annual rate of ischemic stroke or thromboembolism of approximately 5% compared with 0.5% to 1% in age-matched controls without AF.5 AF-related strokes are cardioembolic, which are more disabling and have a higher early mortality rate than atherothrombotic strokes.15 Increased thromboembolic risk in patients with AF mainly stems from the activation of the coagulation cascade rather than from platelet activation,16 and this fact explains why anticoagulants that impact the coagulation cascade are more efficacious than antiplatelet agents in preventing thromboembolic events in patients with AF.2 The risk of thromboembolism is similar among patients with paroxysmal, persistent, or permanent AF and is increased by certain risk factors, notably Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS2).5 Higher CHADS2 scores are associated with greater absolute benefit of oral anticoagulation with warfarin.17 Taking into consideration the presence of vascular disease, intermediate age (65e74), and female gender, the CHA2DS2-VASc score has been shown to be a better predictor of stroke risk, particularly in low-risk patients.18 Table 1 summarizes the rates of thromboembolism and death in patients not on oral anticoagulation according to the CHA2DS2-VASc score. Oral anticoagulant therapy is an effective means of stroke prophylaxis in patients with AF20; a meta-analysis showed that warfarin reduced stroke risk by 64% versus placebo and by 39% versus aspirin.21 Although the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial results suggested that aspirin and clopidogrel could be used in patients with AF unsuitable for vitamin K antagonist therapy,22 ACTIVE-W demonstrated www.ajconline.org
Review/Concurrent AF and ACS: Unanswered Questions Table 1 CHA2DS2-VASc and HAS-BLED scores and event rates CHA2DS2-VASc Score 0 1 2 3 4 5 6 7 8 9
HAS-BLED Event Rate*
Score
Event Rate†
0.78 2.01 3.71 5.92 9.27 15.26 19.74 21.50 22.38 23.64
0 1 2 3 4 5 6 7 8 9
1.13 1.02 1.88 3.74 8.7 12.5 — — — —
CHA2DS2-VASc ¼ Congestive heart failure, Hypertension, Age 75 years, Diabetes mellitus, prior ischemic Stroke or transient ischemic attack þ Vascular disease, Age 65 to 75 years, female Sex; HAS-BLED ¼ Hypertension, Abnormal renal or liver function, Stroke, Bleeding history, Labile INR, Elderly, Drugs or alcohol. * Rate of hospital admission and death due to thromboembolism per 100 person-years at 1-year follow-up in 73,538 patients not on oral anticoagulation.18 † Rate of major bleeding per 100 person-years at 1-year follow-up in 3,456 patients of the Euro Heart Survey; 65% were on oral anticoagulation.19
clear superiority of warfarin compared with dual antiplatelet therapy in patients who were suitable.2 Thrombogenesis in ACS or After PCI Localized damage of the coronary artery endothelium is the underlying mechanism triggering thrombosis in ACS and typically stems from an underlying atherosclerotic plaque rupture exposing thrombogenic material in the plaque core to blood, triggering platelet aggregation and fibrin formation. This process results in the formation of a platelet-rich thrombus.5,23,24 Because of the role of platelet aggregation in this process, antiplatelet agents have become part of the primary treatment in ACS. In addition, antithrombin agents are also efficacious in the acute setting of myocardial infarction. Stent thrombosis, however, is largely platelet dependent and is significantly prevented by antiplatelet agents.25 PCI results in additional trauma to the vessel wall, initiating local prothrombotic activation. Stent implantation after angioplasty-induced dilation triggers further acute and chronic prothrombotic and proinflammatory reactions toward the stent.26 Drug-eluting stents inhibit restenosis and delay re-endothelialization; therefore, prothrombotic and proinflammatory activations can continue to occur and can lead to stent thrombosis even after 12 months.27,28 The incidence of stent thrombosis in the published data shows variation (Table 2) but is increased among patients with ACS and is greatest in the first month regardless of the type of stent used.32,34 The rate decreases to 65 years), Drug/alcohol concomitantly (HAS-BLED) schema to assess bleeding risk offers a valuable “net clinical benefit” assessment of using oral anticoagulation in patients with AF who are undergoing coronary stenting.61 Even in those with high bleeding risk (HAS-BLED score 3), oral anticoagulation therapy was associated with a lower mortality rate and fewer major adverse cardiac events at 1-year follow-up, with higher rates of major bleeding. Predictors of major bleeding were chronic renal failure and the use of drugeluting stents.61 As mentioned previously, the only prospective, randomized, controlled trial evaluating triple therapy has been the recently published WOEST trial,13 which was a multicenter study of patients receiving oral anticoagulants and undergoing PCI. Patients receiving clopidogrel alone (double therapy) were compared with those receiving clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI. In this study, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events, suggesting that the addition of aspirin provides no additional benefit in this setting while increasing the risk of bleeding. The study was not powered to detect differences in stent thrombosis occurrence. Of note, the study featured higher-than-expected bleeding rates in both arms of the study probably owing to the use of drug-eluting stents and femoral access in most cases and proton pump inhibitor use in only a minority of cases. As suggested by the WOEST trial, treatment of these patients with an oral anticoagulant and single antiplatelet therapy may represent a viable and possibly safer option with less risk of bleeding. Until the findings of this study are supported by additional trials, it remains unclear whether this oral anticoagulant plus clopidogrel regimen represents the most favorable option. It is also not known if this regimen provides the same benefits and risks when applied to a world population or if the novel oral anticoagulant agents can be used in this regimen. Currently, there are at least 3 ongoing trials (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE], Anticoagulation in Stent Intervention [MUSICA-2], and A Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention [PIONEER AF-PCI]) evaluating different strategies of antiplatelet agents and oral anticoagulants in patients with AF and stenting. These trials should help to clarify the best drug regimen and duration of therapy to minimize bleeding risk and ischemic events. Other trials may be necessary to clarify if there is a net benefit of triple therapy in patients with AF with recent ACS who do not receive stenting. Strategies for Assessing and Minimizing Bleeding Risk Bleeding risk in patients undergoing PCI can be estimated from clinical predictors, including advanced age, female gender, a history of bleeding, renal insufficiency, and use of
891
glycoprotein inhibitors.62 Using these risk factors, the risk score predicted major bleeding from 1% in the lowest risk patients to 40% in the highest risk patients. Other bleeding risk assessments take catheterization access site (femoral vs radial) into account because >85% of in-hospital major bleeding events are related to the access site.63 The use of triple therapy for patients with AF who are undergoing PCI has known anticipated bleeding risks, but strategies can be used to reduce the risk and can be tailored to the individual patient. Radial access is gaining popularity and quickly becoming the preferred vascular access site owing to its lower complication rates of major bleeding than femoral access, reducing major bleeding events by 73% and showing a trend toward reduced death, myocardial infarction, and stroke.64 In addition, the use of proton pump inhibitors can play a key role in this patient population because gastrointestinal bleeding events represent 20% to 30% of major bleeding events after PCI.65 Proton pump inhibitors not metabolized by cytochrome P450 2C19 and not interfering with clopidogrelmediated effects (e.g., pantoprazole) are preferred.35 Clopidogrel should be the P2Y12-receptor antagonist used in combination with aspirin and warfarin. Despite the association of prasugrel with fewer ischemic events, including stent thrombosis compared with clopidogrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel—Thrombolysis In Myocardial Infarction 38 trial,66 it was associated with an increased risk of major and minor bleedings without fewer ischemic events compared with clopidogrel in patients receiving triple therapy after drug-eluting stent implantation67 and should not be used as part of a triple therapy regimen. Ticagrelor is the P2Y12 antagonist recommended by the European Society of Cardiology for patients at moderate-to-high risk of ischemic events.48 However, although ticagrelor did not increase the risk of major bleeding compared with clopidogrel, it was associated with an increased risk of nonecoronary artery bypass grafterelated bleeding.68 In addition, ticagrelor has not been tested as part of a triple therapy regimen. For these reasons, its use with warfarin should not be recommended until its safety is demonstrated in a triple therapy regimen. Less than 25% of patients in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial received a stent but demonstrated benefit from receiving dual antiplatelet therapy.6 This suggests that patients with both ACS and AF who are not receiving PCI might also benefit from triple therapy, with a reduced risk of ischemic adverse events—at least in the acute setting. However, because patients on anticoagulation were excluded from the trial, it is unknown whether triple therapy provides a net clinical benefit after presentation with ACS without PCI in patients with AF. Owing to this uncertainty and with the known increased bleeding risk, treatment of these patients with oral anticoagulation and single antiplatelet therapy (aspirin or clopidogrel) may provide a safer regimen. Here, individual risk assessment is critical. NoneVitamin K Antagonist Oral Anticoagulants Dabigatran: Dabigatran is an oral direct thrombin inhibitor approved for the prevention of stroke and embolism in patients with AF. The Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) trial was a randomized study demonstrating that dabigatran 150 mg twice daily was superior
892
The American Journal of Cardiology (www.ajconline.org)
to warfarin in reducing stroke and systemic embolism but had similar rates of major bleeding, although it produced a significantly lower rate of intracranial bleeding.69 The rate of gastrointestinal bleeding was increased with the higher dose (150 mg), and there was a trend toward higher rates of myocardial infarction with both doses. Major bleeding was increased when aspirin was used with both doses of dabigatran in the RE-LY trial.70 However, a post hoc analysis of the RELY trial showed that the dabigatran 150 mg twice-daily dose produced similar major bleeding events compared with warfarin, even when an antiplatelet agent was added, whereas the dabigatran 110 mg twice-daily dose produced less major bleeding. When 2 antiplatelet agents were used, the lowest absolute risks were noted among patients in the dabigatran 110 mg twice-daily group.71 Rivaroxaban: Rivaroxaban, a highly selective, oral, direct factor Xa inhibitor, was studied in the large, multicenter, randomized Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.72 ROCKET AF trial included patients with nonvalvular AF at high risk of stroke (CHADS2 score of 2, mean score of 3.5) given rivaroxaban 20 mg/day (15 mg/day for creatinine clearance 30 to 49 ml/ min) or warfarin. Rivaroxaban was at least noninferior to warfarin in preventing stroke or systolic embolism and produced similar rates of major bleeding compared with warfarin, with significant reductions in the rates of intracranial hemorrhage and fatal bleeding but increased gastrointestinal bleeding. The Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51 (ATLAS ACS 2 TIMI 51) trial was conducted to evaluate low-dose (5 mg twice daily) and very low-dose (2.5 mg twice daily) rivaroxaban as an adjunctive therapy in patients with a recent ACS.73 Patients with previous gastrointestinal bleeding, previous ischemic stroke or transient ischemic attack, or poor renal function were excluded from the greater exposure arm. Rivaroxaban significantly reduced the primary end point of cardiovascular death, myocardial infarction, or stroke for both doses compared with placebo, with a >30% decrease in cardiovascular and all-cause deaths in the 2.5 mg twice-daily arm. There was also a 31% relative risk reduction for stent thrombosis. Data for the 2 doses of rivaroxaban combined showed increased major bleeding and intracranial hemorrhage, without significantly increasing fatal bleeding. The results of ATLAS ACS 2 TIMI 51 suggest that rivaroxaban, at the 2.5 mg twice-daily and 5 mg twice-daily doses, may improve ischemic events when added to dual antiplatelet therapy in patients with ACS. AF was an exclusion criterion, so ATLAS ACS 2 TIMI 51 does not provide an example of triple therapy use in patients with both ACS and AF. No data exist comparing rivaroxaban with warfarin in this setting. Owing to the intriguing mortality benefit, the 2012 European Society of Cardiology STEMI guidelines list rivaroxaban as a class IIb indication, in addition to aspirin and clopidogrel, for selected patients with low bleeding risk.47
Although the European Medicines Agency’s Committee for Medicinal Products for Human Use has recently recommended the approval of rivaroxaban for use in patients with ACS, the United States Food and Drug Administration is yet to approve it for this indication. Apixaban: Apixaban, another oral direct factor Xa inhibitor, was studied in the Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, comparing apixaban (5 or 2.5 mg twice daily for patients who met 2 of the following criteria: age 80 years, body weight 60 kg, or serum creatinine level of 1.5 mg/dl) with warfarin in patients with AF.74 Apixaban was superior to warfarin in the prevention of the primary outcome of stroke or systemic embolism. There was also significantly less major bleeding, hemorrhagic stroke, and intracranial bleeding with apixaban than warfarin. Apixaban was also associated with mortality benefit compared with warfarin. Producing fewer strokes and less bleeding than warfarin, the results of ARISTOTLE suggest that apixaban might serve as an alternative to warfarin in the setting of ACS. The phase 3 Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE 2) trial studied apixaban in patients with ACS and at least 2 additional risk factors for recurrent ischemic events.75 The trial was terminated early owing to an increase in major bleeding events with apixaban in the absence of a reduction in recurrent ischemic events. The increased bleeding reported with this agent in patients with ACS certainly raises concerns regarding its use in these patients. The newer oral anticoagulants have shown promise in reducing embolic and ischemic events in patients with AF and ACS, although they have not been adequately studied in patients with both conditions. Despite the survival benefit reported with rivaroxaban, a major concern exists with the three to fourfold excess in major and intracranial bleeding events with the addition of any dose of factor Xa inhibitors to dual antiplatelet therapy in ATLAS ACS 2 TIMI 51 and APPRAISE 2. This increased risk of bleeding occurred throughout the duration of treatment in both trials. Moreover, the net benefit of dabigatran compared with warfarin in the post hoc analysis of the RE-LY trial suggests that dabigatran may be a safer anticoagulant option when dual antiplatelet is necessary. Although the newer oral anticoagulants may be a viable and safe option, it is unclear whether they should be favored in patients with AF who are receiving PCI until more clinical data confirm them to be a safe option. Ultimately, the physician must consider the risks and benefits of the use of newer oral anticoagulants for these patients. Management Recommendations The following recommendations for patients with AF with ACS or requiring PCI are based on the opinion and practice of the authors, taking into consideration the best available data and review of the literature. 1. Low-dose (
