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Antithrombotics in atrial fibrillation and coronary disease Expert Rev. Cardiovasc. Ther. 12(8), 977–986 (2014)
Poonam Velagapudi1, Mohit K Turagam*1, Harsh Agrawal1, Mayank Mittal1, Abraham G Kocheril2 and Kul Aggarwal1 1 Department of Cardiovascular Medicine, University of Missouri–Columbia, School of Medicine, Columbia, MO, USA 2 Christie Clinic and University of Illinois College of Medicine at Urbana-Champaign, IL, USA *Author for correspondence: Tel.: +1 608 262 2434 [email protected]
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Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and approximately 18–45% of AF patients have concomitant coronary artery disease (CAD). Several studies have demonstrated that oral anticoagulation is the mainstay of therapy for stroke prevention in AF. Similarly, antiplatelet therapy including aspirin and P2Y12 inhibitor is recommended in the management of acute coronary syndrome and stable CAD. Despite the high prevalence of CAD with AF, practice guidelines are scarce on the appropriate antithrombotic regimen due to lack of large-scale randomized clinical trials. The use of direct thrombin and factor Xa inhibitors for stroke prevention in AF has also complicated the possible combinations of antithrombotic therapies. This review aims to discuss the available evidence regarding aspirin as an antithrombotic strategy, the role of novel anticoagulants and the specific clinical situations where aspirin may be beneficial in patients with AF and CAD. KEYWORDS: antithrombotic • aspirin • atrial fibrillation • coronary artery disease • novel anticoagulants • warfarin
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia affecting 3 million individuals in the USA, especially the elderly [1]. Similarly, coronary artery disease (CAD) is extremely prevalent in the USA and is estimated to occur in 18–45% of patients with concomitant AF, due to similar risk factors [2,3]. Currently, oral anticoagulation with warfarin or one of the novel agents including dabigatran, rivaroxaban and apixaban is recommended in AF patients with a CHA2DS2-VASc score (C: congestive heart failure; H: hypertension; A: age with 2 points for >75 years and 1 point for 65–74 years; D: diabetes; S2: history of stroke or transient ischemic attack (TIA); V: vascular disease which includes previous myocardial infarction [MI], peripheral arterial disease or aortic plaque; Sc: sex category with 1 point for female) of 2 or greater; this recommendation is based on large-scale clinical trials [4–7]. Aspirin, which was earlier recommended in low-risk stroke patients with AF, has been sidelined by the 2012 European Society of Cardiology (ESC)-AF guidelines with the emergence of novel anticoagulants [8]. However, the 2014 American College of Cardiology (ACC)/ American Heart Association (AHA)/Heart Rhythm Society guidelines prefer the use of oral
10.1586/14779072.2014.937427
anticoagulation in AF patients with CHA2DS2VASc score of 1 and aspirin as an alternative therapy to oral anticoagulation [9]. Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is recommended in individuals with acute coronary syndrome (ACS) and post stent implantation (PCI) for the prevention of stent thrombosis, MI and cardiovascular death [10–13]. However, the appropriate antithrombotic regimen in stable CAD and ACS in the presence of AF is unclear due to the lack of randomized clinical trials (RCTs). The use of direct thrombin and factor Xa inhibitors for stroke prevention in AF has also complicated the possible combinations of antithrombotic therapies, as recent studies have demonstrated an increased bleeding risk when these agents are used in the setting of ACS [14–18]. This article aims to discuss the available evidence regarding aspirin as an antithrombotic strategy, the role of novel anticoagulants and the specific clinical situations where aspirin may be beneficial in patients with AF and CAD. Current guidelines on antithrombotics in AF & ACS
The recommendations provided by various organizations with regard to this topic are
2014 Informa UK Ltd
ISSN 1477-9072
977
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Velagapudi, Turagam, Agrawal, Mittal, Kocheril & Aggarwal
Atrial fibrillation and coronary disease
CHA2DS2-VASc ≥1
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Stable CAD
ACS + PCI
Medically managed ACS
Bare metal Drug eluting
Warfarin (INR 2–3) Warfarin (INR 2 –3) + aspirin + clopidogrel for 6–12 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Warfarin (INR 2–3) + clopidogrel + aspirin at least 6 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Warfarin (INR 2–3) + clopidogrel + aspirin at least 1–3 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Figure 1. Antithrombotic treatment for atrial fibrillation and coronary artery disease based on CHA2DS2-VASc score. † Prasugrel and Ticagrelor – not indicated in the management for Atrial fibrillation + Acute coronary syndrome. ACS: Acute coronary syndrome; CAD: Coronary artery disease; INR: International normalized ratio; PCI: Post stent implantation.
based on expert consensus and not based on high-level clinical evidence (FIGURE 1). According to the 2012 ESC-AF guidelines, treatment with oral anticoagulation is recommended (class IA) for patients with CHA2DS2-VASc score of 2 or greater. Oral anticoagulation is also recommended with warfarin or one of the novel agents for patients with CHA2DS2-VASc score of 1 (class IIA). For individuals with CHA2DS2-VASc score of 0, the recommendation is not to prescribe any antithrombotic therapy (class IB) [8]. The 2014 ACC/AHA/Heart Rhythm Society AF guidelines recommend oral anticoagulation for CHA2DS2-VASc of 2 or greater (class IA with warfarin and class IB with the novel anticoagulants), no treatment/aspirin/ oral anticoagulation based on the clinical risk profile for CHA2DS2-VASc score of 1 (class IIB, level of evidence C) and no antithrombotic treatment for CHA2DS2-VASc score of 0 (class IIA, level of evidence B) [9]. Unlike a validated thrombosis risk stratification tool in AF, like the CHA2DS2-VASc score; there is no risk score to predict thrombosis in patients with CAD and the recommendation is to stratify patients based on clinical risk factors [19,20], creating a discrepancy and variability about estimating the risk of thrombosis in CAD. Unlike AF, aspirin is the mainstay of antithrombotic therapy in patients with CAD or ACS. In the absence of contraindications, aspirin is recommended indefinitely for secondary prevention of recurrent vascular events, MI and cardiovascular death in patients with ischemic heart disease [10,19,20]. The 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12], 978
2011 ACC/AHA focused update on AF [21] and the 2010 ESC-AF guidelines [22] recommend against the use of low-dose aspirin and use only warfarin with an international normalized ratio (INR) goal of 2–3 in patients with moderate–high risk of stroke and stable ischemic heart disease (12 months without ischemic events). However, the 2011 ACC/AHA guidelines on secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease [13] recommend the addition of low-dose aspirin to warfarin in patients with moderate–high risk of stroke in AF and concomitant stable ischemic heart disease. In individuals undergoing PCI, stent thrombosis is a major complication with an estimated annual incidence of 1–2% in both drug-eluting stents (DES) and bare metal stents (BMS) and can cause death in 10–20% and MI in 30–70% [23,24]. The greatest risk is reported in the first month and decreases significantly beyond 1 year [24,25]. The premature discontinuation of DAPT increases the risk of stent thrombosis by 5–36% [25]. Studies have also demonstrated a significant increased bleeding risk with the addition of multiple antithrombotic medications, creating controversy among various practice guidelines on what may be the appropriate antithrombotic therapy balancing the risk of bleeding and thrombosis [26–28]. The 2012 ACC/AHA guidelines for the management of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI) [10] recommend triple antithrombotic therapy (TAT) including aspirin, warfarin and a P2Y12 inhibitor for at least 12 months, irrespective of the type of stent implanted Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
in individuals requiring long-term anticoagulation after PCI. The 2014 ACC/AHA/Heart Rhythm Society AF guidelines [8] recommend that it may be reasonable to use clopidogrel with oral anticoagulation without aspirin for patients with CHA2DS2-VASc score of 2 and above undergoing coronary revascularization. The 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12] recommends treatment with TAT for 1 month after a BMS and for 3–6 months after a DES, after which the recommendation is to continue warfarin (INR 2–3) and a single antiplatelet agent for at least 12 months. There is similar controversy regarding appropriate anithrombotics in medically managed ACS patients not undergoing PCI. The 2012 ACC/AHA guidelines [10] for the management of unstable angina and NSTEMI recommend TAT for at least 1 year; while the 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12] recommends treating with warfarin (INR 2–3) and a single antiplatelet agent only. Mechanism of thrombosis in AF & ACS
The exact mechanism of thrombosis in AF and ACS remains unclear, but studies have demonstrated several overlapping pathways [29,30]. The clot associated with coronary thrombosis is predominantly a ‘white’ thrombus consisting of platelets entrapped in fibrin [29], while the clot associated with AF is typically a ‘red’ thrombus consisting of red blood cells and fibrin [30]. This explains the modest benefit of antiplatelet agents (aspirin, clopidogrel) in reducing the risk of stroke in AF and the reason for combining antithrombotics with antiplatelet therapy in patients with both AF and ACS in various clinical scenarios. This section briefly highlights the mechanism of thrombosis in AF and ACS. Activation of the coagulation cascade plays a major role in AF-related clot formation. Several studies have demonstrated abnormal levels of plasma fibrinogen, platelet factor 4, tissue plasminogen activator, von Willebrand factor, plasminogen activator inhibitor, thromboglobulin and soluble thrombomodulin complexes in AF [31–34]. Furthermore, anticoagulation with warfarin rather than antiplatelets has shown to decrease the concentration of some of these prothrombotic indices, which also explains the importance of coagulation cascade activation in thrombus formation in AF [35–38]. Structural endothelial changes [39], inflammation (abnormal C-reactive protein, IL-6) [40], growth factors (VEGF, angiopoietin) [41,42], extracellular matrix turnover (abnormal matrix metalloproteinase and tissue inhibitor matrix metalloproteinase) [43], nitric oxide [44] and activation of rennin–angiotensin system [45] are all implicated in the mechanism of thrombosis in AF. Platelets play a major role in thrombosis associated with ACS, when compared to the coagulation factors [46]. Endothelial injury from the rupture of an atherosclerotic plaque results in platelet activation and increased expression of cytokines, chemokines and growth factors and triggering of the coagulation system by the production of tissue factors by aggregating informahealthcare.com
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macrophages results in thrombin generation which further amplifies platelet activation [46]. Inflammation plays a major role in coronary thrombosis with the release of thromboxanes, leukotrienes and activated circulating leukocytes [47]. Abnormal levels of plasminogen activator inhibitor-1 have been reported in patients with ACS and CAD, which inhibit tissue plasminogen activator and urokinase-like activators, which further contributes to thrombosis [48]. Similar to AF, abnormal levels of plasma fibrinogen, von Willebrand factor and IL-6 have been reported in ACS [30,49]. Drug-based clinical trials in ACS further support this understanding of the platelet activation pathways [49]. This explains the lack of effectiveness of aspirin in AF and how combination therapy with aspirin and clopidogrel is superior to aspirin alone due to targeting multiple sites of platelet activation pathway. Novel anticoagulants in CAD
Recently, four novel anticoagulants have shown excellent efficacy and safety for stroke prevention in AF in RCTs [6–8,50]. Additionally, the safety and efficacy of two new anticoagulants, darexaban and letaxaban, have been studied in phase II trials [51,52]. Dabigatran is a direct thrombin inhibitor, while rivaroxaban, apixaban, edoxaban, darexaban and letaxaban are factor Xa inhibitors. In this section, we briefly discuss the current clinical evidence and future directions regarding the use of these novel anticoagulants in CAD (TABLE 1). RE-DEEM (dabigatran vs placebo in patients with ACS on DAPT) [15] was a Phase II, double-blind placebo RCT including 1861 patients after STEMI and NSTEMI randomized to four doses of twice-daily dabigatran (50, 75, 110 and 150 mg) in addition to standard therapy with DAPT versus placebo. Exactly 99.2% of patients were on DAPT treatment. The study reported a dose-dependent increase in bleeding risk with dabigatran and no significant clinical benefit in the prevention of MI or recurrent ischemia. The reported risk of MI with dabigatran has been conflicting. The RE-LY trial [6] reported the rate of MI to be 0.53% per year with warfarin, 0.72% per year in the 110-mg group of dabigatran and 0.74% per year in the 150-mg group of dabigatran. Further analysis in the RE-LY trial [53] reported a statistically insignificant increase in MI in both doses of dabigatran when compared to warfarin. There was no significant increase in other myocardial ischemic events like unstable angina, cardiac arrest, composite MI and cardiovascular death between dabigatran and warfarin. However, two recent metaanalyses have shown a small increase in the risk of ACS with dabigatran [54,55]. Uchino et al. [54] included 30,514 patients reporting ACS with dabigatran. Dabigatran was associated with a 0.27% absolute increase in the risk of ACS. Another recent meta-analysis [55] including 11 trials and 39,300 patients reported an increased risk of MI with the entire class of direct thrombin inhibitors when compared to warfarin. However, a recent Danish registry [56] reported lower MI with both doses of dabigatran compared to warfarin in ‘everyday clinical practice.’ Several hypotheses have been suggested for this increased risk of MI with dabigatran, but none was validated. Further 979
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Table 1. Summary of novel anticoagulants in acute coronary syndrome. Study (year)
Trial name
Type of trial
Number of subjects
Drugs studied
Bleeding outcomes
Ref.
Oldgren et al. (2011)
RE-DEEM
Double-blind, placebo-controlled, Phase II study
1861
Dabigatran + DAPT vs DAPT + placebo
Dabigatran was associated with a dose-dependent increase in major and clinically significant minor bleeding
[15]
Mega et al. (2009)
ATLAS ACS-TIMI 46
Double-blind, placebo-controlled, Phase II study
3491
Rivaroxaban + DAPT vs DAPT + placebo vs rivaroxaban + aspirin vs aspirin + placebo
Rivaroxaban was associated with a dose-dependent increase in bleeding
[16]
Mega et al. (2012)
ATLAS ACS-TIMI 51
Double-blind, placebo-controlled trial, Phase III
15,526
Rivaroxaban + DAPT vs DAPT + placebo
Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage
[17]
Alexander et al. (2009)
APPRAISE
Double-blind, placebo-controlled, Phase II study
1715
Apixaban + DAPT vs DAPT + placebo
Apixaban was associated with a dose-dependent increase in bleeding
[18]
Alexander et al. (2011)
APPRAISE-2
Randomized, double-blind, placebo-controlled
7392
Apixaban + DAPT vs DAPT + placebo
Apixaban increased the risk of major bleeding
[19]
ACS: Acute coronary syndrome; APPRAISE: Apixaban for Prevention of Acute Ischemic 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; DAPT: Dual Antiplatelet Therapy.
randomized trials are required before dabigatran can be safely recommended in patients with AF and ACS. Two clinical trials studied the effect of rivaroxaban in ACS. The 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 trial [16] was a Phase II double-blind RCT including 3491 patients with ACS. The study reported rivaroxaban to be associated with a dose-dependent significant increased risk of bleeding when compared to placebo (in addition to DAPT) without significant reduction in ischemic outcomes [43]. ATLAS ACS-2 TIMI 51 trial [17], a phase III RCT including 15,526 patients with ACS, studied rivaroxaban (2.5 and 5 mg daily) in addition to standard therapy with DAPT. The study reported significant reduction in ischemic outcomes including death and MI with rivaroxaban in addition to standard DAPT in both 2.5 mg and 5 mg doses with an increased risk of bleeding, especially intracranial bleed. Stent thrombosis was reduced significantly with 2.5 mg rivaroxaban in addition to DAPT and non-significantly in the 5-mg group. Rivaroxaban at a dose of 2.5 mg twice daily was associated with overall reduction in mortality when compared to placebo. This 2.5 mg twice-daily dose in ATLAS ACS-2 TIMI 51 trial was significantly lower than the dose used for stroke prevention in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF) trial [7]. However, no significant reduction in ischemic outcomes was reported in patients with a prior history of MI in the ROCKET-AF trial at a higher dose (10 mg daily). 980
Apixaban in ACS was studied in two trials: Apixaban for Prevention of Acute Ischemic Events (APPRAISE) and APPRAISE-2 [18,19]. APPRAISE [18] was a Phase II, doubleblind RCT including 1715 ACS patients. Apixaban (in addition to DAPT) was reported to cause a dose-dependent increased risk of bleeding and significantly reduced the ischemic outcomes when compared to placebo. APPRAISE-2 [19] was a Phase III trial that included 7392 ACS patients in which 5 mg of apixaban given twice daily (in addition to DAPT) significantly increased the risk of bleeding, especially intracranial and fatal bleeding, without reducing the ischemic outcomes when compared to placebo. Darexaban [51], a novel factor Xa inhibitor, was studied in the RUBY-1 trial, a Phase II, double-blind RCT which included 1279 patients with STEMI or NSTEMI. The study reported that darexaban was associated with a dose-related increased risk of bleeding with no significant reduction in major ischemic events when used in combination with DAPT in ACS. Another factor Xa inhibitor, letaxaban, was studied in AXIOM-ACS [52], a phase II RCT including 2753 patients with ACS. The study reported that in addition to DAPT, letaxaban was associated with a dose-dependent increased bleeding risk with no significant risk of major bleeding or reduction in ischemic events. A recent meta-analysis [57] including 31,286 patients from seven RCTs reported highly significant increase in major bleeding events and a lack of clinical benefit with the use of both factor Xa inhibitors and direct thrombin inhibitors in addition to DAPT when compared to placebo in ACS. Another metaanalysis [58] reported similar increased bleeding risk (hazard Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
ratio [HR]: 1.79; 95% confidence intervals [CI]: 1.54–2.09) and a reduction in the incidence of major ischemic events (HR: 0.7; 95% CI: 0.59–0.84) on combining aspirin with an oral anticoagulant. Further, the addition of an oral anticoagulant to DAPT doubled the risk of bleeding (HR: 2.34; 95% CI: 2.06–2.66) with a modest decrease observed in major ischemic outcomes (HR: 0.87; 95% CI: 0.80–0.95). Finally, these novel agents have been shown to have a marginal role in CAD, barring rivaroxaban which has obtained a class IIB recommendation in ESC guidelines in STEMI patients receiving aspirin and clopidogrel. Role of aspirin in AF
Studies have demonstrated that aspirin may have a modest benefit in stroke prevention compared with anticoagulation with warfarin or one of the novel agents in AF. The 2014 ACC/AHA AF guidelines suggest that it may be reasonable to use aspirin for stroke prevention in CHA2DS2-VASc score of 1 [9]. However, the European guidelines do not routinely recommend aspirin for stroke prevention in AF [10] and this recommendation is based on recent large-scale RCTs involving new anticoagulants. The AVERROES trial [59], which included patients with AF not suitable for warfarin, reported that aspirin may have similar bleeding risk as the novel anticoagulant apixaban (1.2 vs 1.4% per year; HR: 1.13; 95% CI: 0.74–1.75; p = 0.57) and a significantly lower efficacy (3.7 vs 1.6% per year) in stroke prevention. Further analysis of the AVERROES trial [60] reported similar anatomic sites and predictors of bleeding in both aspirin and apixaban. A meta-analysis by Hart et al. [61] reported that aspirin was significantly ineffective in reducing stroke when compared to warfarin (64 vs 22%) and the adjusted-dose warfarin was more efficacious than antiplatelet therapy based on the analysis of 12 trials and 12,963 patients. In the analysis confined to the aspirin-only trials, stroke risk was reduced by only 19% (95% CI: 1–35%) when compared with placebo and these results were largely driven by positive results from the Stroke Prevention in Atrial Fibrillation Study [62], which reported an overall significant reduction in stroke risk of 42% with aspirin versus placebo (3.6%/year; 95% CI: 9–63%). Another meta-analysis by Aguilar et al. [63] reported that aspirin significantly reduced the combination of stroke, MI and cardiovascular death with no increase in bleeding, but did not significantly reduce the risk of all strokes or ischemic strokes in patients with non-valvular AF and no previous history of stroke or TIA. Studies involving combination therapy of aspirin with warfarin and clopidogrel report modest improvement in stroke prevention with a significantly increased risk of bleeding [64–66]. In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A trial [64], aspirin–clopidogrel therapy was compared with aspirin monotherapy in patients with AF who were unsuitable for warfarin. The study reported that the risk of stroke and/or systemic embolism was reduced to 2.4% per year with aspirin and clopidogrel versus apirin alone with a 57% increased risk of major informahealthcare.com
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bleeding. In the ACTIVE-W trial [65], the risk of stroke and/ or systemic embolism with aspirin–clopidogrel combination was significantly higher (5.6 vs 3.93% per year) when compared with warfarin with a significant risk of major bleeding (2.42 and 2.21% per year). Furthermore, the combination of aspirin and warfarin increased the risk of bleeding (3.9% per year vs 2.3%; p < 0.01) with no reduction in stroke, MI or systemic embolism (0.6%/year vs 1%) in AF [66]. Management of AF & ACS
AF may be stratified into low (CHA2DS2-VASc score 0), moderate (CHA2DS2-VASc = 1) and high risk (CHA2DS2-VASc ‡2) of stroke or systemic embolism based on the CHA2DS2VASc score. In the presence of concomitant vascular disease (previous MI, peripheral arterial disease or aortic plaque), the individual is at moderate risk for stroke based on a CHA2DS2VASc score of 1. This section will discuss antithrombotic treatment recommendations based on the CHA2DS2-VASc score in the management of patients with both AF and CAD. AF with low risk of thromboembolism
Patients with AF in the presence of CAD or peripheral vascular disease are never truly at low risk for thromboembolism (CHA2DS2-VASc of 1). AF with moderate–high risk of thromboembolism Chronic stable CAD
AF with chronic stable CAD (free from ischemic events for 6–12 months) may be stratified as being at moderate risk for stroke (CHA2DS2-VASc ‡1). Oral anticoagulation remains the cornerstone therapy in this group of patients due to an estimated stroke risk of >1.3% per year. However, data on addition of low-dose aspirin over anticoagulation are scarce due to lack of evidence. Warfarin (INR >2) has also proven to be more efficacious and relatively safe for the prevention of stroke, thromboembolism and coronary events in this group of patients [61,67,68]. The use of dabigatran in patients with AF and stable CAD remains controversial due to the lack of strong evidence, while studies involving factor Xa inhibitors have shown that they reduce coronary events and overall mortality [69,70]. No RCT has compared warfarin with a direct thrombin inhibitor (dabigatran) or a factor Xa inhibitor (rivaroxaban, apixaban) for prevention of coronary events. A recent study including 8700 patients with AF and stable CAD (defined as 12 months from ACS) reported significant increase in bleeding risk with the addition of antiplatelet agent to warfarin; the bleeding risk reported was higher with clopidogrel than aspirin, with no significant reduction in ischemic or embolic events [71]. It can be concluded that in patients with AF (CHA2DS2VASc score 1) and stable CAD, warfarin with an INR 2–3 is safe and effective in prevention of both cardiovascular and cerebrovascular events. Based on recent meta-analysis, factor Xa inhibitors (rivaroxaban and apixaban) may be a reasonable alternative as they cause a reduction in overall mortality. However, the addition of aspirin increases the bleeding risk without 981
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causing significant reduction in coronary events or stroke. The evidence regarding the use of dabigatran in this group is scare and conflicting and further studies are required before the drug can be safely used in this group of patients.
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Medically managed ACS
The evidence regarding antithrombotic therapy in individuals with AF (CHA2DS2-VASc of 1) presenting with ACS but not undergoing PCI is also unclear with several conflicting recommendations by major organizations [10–12]. Treatment with DAPT including clopidogrel and aspirin for a year following ACS reduced death and further coronary events and this combination was superior when compared to combination therapy with warfarin and aspirin [72–75]. More recently, DAPT, including prasugrel and aspirin, did not significantly lower ischemic events when compared to clopidogrel and aspirin in patients with ACS not undergoing PCI [76]. However, DAPT therapy with ticagrelor and aspirin was reported to significantly reduce the vascular events, MI or stroke, with no major increase in bleeding when compared to standard DAPT therapy with clopidogrel and aspirin, regardless of invasive or non-invasive strategy [77]. However, there are no RCTs on the combination of these newer antiplatelet agents (prasugrel and ticagrelor) with oral anticoagulants. In patients with AF (CHA2DS2-VaSc = 1), presenting with ACS and not undergoing PCI, treatment with DAPT including clopidogrel and aspirin for 1 year followed by lifelong therapy with either aspirin or clopidogrel is required for the prevention of ischemic events, MI and cardiovascular mortality, while anticoagulation with warfarin is recommended for the prevention of stroke and systemic thromboembolism. The ACTIVE-W trial [65] showed that DAPT (aspirin and clopidogrel) was inferior to warfarin in stroke prevention and increased the bleeding risk in AF. Newer anticoagulant trials in ACS have not been favorable. Dabigatran, apixaban, darexaban and letaxaban have been shown to increase the risk of bleeding without significant reduction of coronary events in patients with ACS treated with DAPT [15,18,19]. Low-dose rivaroxaban (2.5 and 5 mg twice daily) was shown to significantly prevent ischemic outcomes, MI and overall mortality, when used in combination with DAPT [17]. However, this drug was associated with increased risk of bleeding, especially intracranial bleeding. It can be safely concluded that in patients with AF (CHA2DS2-VaSc = 1) and medically managed ACS, it may be reasonable to treat with TAT consisting of warfarin, aspirin and clopidogrel for at least 1 year. Continuing DAPT with aspirin and clopidogrel beyond 1 year significantly increases the risk of bleeding [78]. It may be reasonable to drop one antiplatelet agent when the bleeding risk is high after a few months of TAT. Combination of prasugrel and ticagrelor with warfarin is not recommended due to lack of RCTs and the increased bleeding risk. Similarly, due to increased bleeding risk and lack of ischemic benefit in CAD, the newer anticoagulants dabigatran, rivaroxaban and apixaban are not recommended to be used in combination with DAPT in this group of patients. 982
ACS patients undergoing PCI
The optimal management of AF patients with a CHA2DS2VaSc = 1 on chronic anticoagulation and undergoing PCI (elective or emergent) is based on expert consensus and not supported by RCTs. The intensity of antithrombotic treatment and duration are largely based on the type of stent used, with the goal being to prevent stent thrombosis. Based on clinical trials, the duration of DAPT with aspirin and a second antiplatelet agent such as P2Y12 inhibitors is at least 1 month for BMS and 3–6 months for DES, with P2Y12 inhibitor being the cornerstone of this therapy [78,79]. However, a subgroup analysis from the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study trial reported that long-term DAPT (24 months) may be beneficial in patients treated for in-stent restenosis [80]. A recent study including 377 patients undergoing PCI with DES and requiring TAT reported that prasugrel increased the risk of bleeding with no difference in ischemic outcomes when compared to clopidogrel [80]. BMS is typically recommended in the setting of AF and the concomitant need for anticoagulation is due to the reduced duration of TAT and the subsequent risk of increased bleeding when compared to dual antithrombotic therapy [9,10,12,13]. A recent open-label randomized controlled trial including 573 patients undergoing PCI and taking oral anticoagulants reported that clopidogrel without aspirin may be used with no increase in thrombotic events and with a significant reduction in bleeding risk. The study included 65% of subjects with DES and 30–35% with BMS [27]. However, the trial was underpowered to estimate the ischemic events reliably and provides insufficient evidence to suggest dual antithrombotic therapy rather than TAT after PCI. Dabigatran, rivaroxaban and apixaban are not recommended in AF patients undergoing PCI. Expert commentary & five-year view
Due to increasing geriatric population in the USA, there is an increase in the prevalence of patients having multiple cardiovascular diseases and compelling indications for the use of combination of antiplatelet agents and anticoagulants. Our literature review has suggested that there is no clear data on the combination usage of aspirin–anticoagulants for the routine cardiovascular benefit or even in chronic stable CAD in any age group and, even more so, in the geriatric population. The only exception to this rule is patients with mechanical heart valves. However, the usage may be reasonable in other settings including acute ACS and PCI where the risk of coronary thrombosis may be high. There are several areas which need further studies, including the role of TAT, both in patients undergoing an interventional procedure and in medically managed patients with CAD and AF. It is important to note that all studies done so far included patients 75 years of age who carry the greatest risk of bleeding and stroke. Currently, the novel anticoagulants are not Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
recommended in the setting of CAD, ACS and PCI. It is unclear how best to manage patients currently being treated with one of the novel oral anticoagulants for AF who may later develop ACS or MI. It is also unclear if warfarin can be switched to one of these novel agents after a year of standard therapy following ACS and PCI. Larger antithrombotic trials, especially including newer anticoagulants with remote ACS, are underway and would be very useful. In summary, stacking up of antithrombotics increases the risk of bleeding. Physicians should be cautious while recommending aspirin along with routine anticoagulation in patients in the absence of a compelling indication due to lack of clear-cut evidence. The need for clinical trials to determine the safety and
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efficacy of such combinations remains paramount and is essential for informed decision-making in the management of these challenging patients, especially in an era of new anticoagulants. Financial and competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia affecting 3 million individuals in the USA. Similarly, coronary artery disease (CAD) is estimated to occur in 18–45% of patients with concomitant AF. • Unlike the CHA2DS2-VASc score for AF, there is no validated risk score to predict future thrombosis in CAD. • Patients with AF in the presence of CAD or peripheral vascular disease are never truly at low risk for systemic thromboembolism including stroke (at least a CHA2DS2-VASc of 1). • Clinical risk assessment of thrombosis and bleeding is recommended in every AF patient with CAD and acute coronary syndrome (ACS). • The appropriate antithrombotic regimen in stable CAD and ACS in the presence of AF is unclear and based on best practice standards due to a lack of randomized clinical trials. • Studies involving the role of novel anticoagulants, with the exception of rivaroxaban, in ACS have found them to be unfavorable with increased bleeding risk and they are not recommended. • Triple antithrombotic therapy may be used in AF patients with high risk of coronary thrombosis in the setting of ACS or stent placement. • Physicians should be cautious while recommending aspirin along with routine anticoagulation in the absence of a compelling indication due to lack of clear-cut evidence, especially in patients with AF and stable CAD. • The need for clinical trials to determine the safety and efficacy of such combination antithrombotics remains paramount and is essential for informed decision-making in the management of these challenging patients.
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Antithrombotics in atrial fibrillation and coronary disease Expert Rev. Cardiovasc. Ther. 12(8), 977–986 (2014)
Poonam Velagapudi1, Mohit K Turagam*1, Harsh Agrawal1, Mayank Mittal1, Abraham G Kocheril2 and Kul Aggarwal1 1 Department of Cardiovascular Medicine, University of Missouri–Columbia, School of Medicine, Columbia, MO, USA 2 Christie Clinic and University of Illinois College of Medicine at Urbana-Champaign, IL, USA *Author for correspondence: Tel.: +1 608 262 2434 [email protected]
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Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and approximately 18–45% of AF patients have concomitant coronary artery disease (CAD). Several studies have demonstrated that oral anticoagulation is the mainstay of therapy for stroke prevention in AF. Similarly, antiplatelet therapy including aspirin and P2Y12 inhibitor is recommended in the management of acute coronary syndrome and stable CAD. Despite the high prevalence of CAD with AF, practice guidelines are scarce on the appropriate antithrombotic regimen due to lack of large-scale randomized clinical trials. The use of direct thrombin and factor Xa inhibitors for stroke prevention in AF has also complicated the possible combinations of antithrombotic therapies. This review aims to discuss the available evidence regarding aspirin as an antithrombotic strategy, the role of novel anticoagulants and the specific clinical situations where aspirin may be beneficial in patients with AF and CAD. KEYWORDS: antithrombotic • aspirin • atrial fibrillation • coronary artery disease • novel anticoagulants • warfarin
Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia affecting 3 million individuals in the USA, especially the elderly [1]. Similarly, coronary artery disease (CAD) is extremely prevalent in the USA and is estimated to occur in 18–45% of patients with concomitant AF, due to similar risk factors [2,3]. Currently, oral anticoagulation with warfarin or one of the novel agents including dabigatran, rivaroxaban and apixaban is recommended in AF patients with a CHA2DS2-VASc score (C: congestive heart failure; H: hypertension; A: age with 2 points for >75 years and 1 point for 65–74 years; D: diabetes; S2: history of stroke or transient ischemic attack (TIA); V: vascular disease which includes previous myocardial infarction [MI], peripheral arterial disease or aortic plaque; Sc: sex category with 1 point for female) of 2 or greater; this recommendation is based on large-scale clinical trials [4–7]. Aspirin, which was earlier recommended in low-risk stroke patients with AF, has been sidelined by the 2012 European Society of Cardiology (ESC)-AF guidelines with the emergence of novel anticoagulants [8]. However, the 2014 American College of Cardiology (ACC)/ American Heart Association (AHA)/Heart Rhythm Society guidelines prefer the use of oral
10.1586/14779072.2014.937427
anticoagulation in AF patients with CHA2DS2VASc score of 1 and aspirin as an alternative therapy to oral anticoagulation [9]. Dual antiplatelet therapy (DAPT) consisting of aspirin and a P2Y12 inhibitor is recommended in individuals with acute coronary syndrome (ACS) and post stent implantation (PCI) for the prevention of stent thrombosis, MI and cardiovascular death [10–13]. However, the appropriate antithrombotic regimen in stable CAD and ACS in the presence of AF is unclear due to the lack of randomized clinical trials (RCTs). The use of direct thrombin and factor Xa inhibitors for stroke prevention in AF has also complicated the possible combinations of antithrombotic therapies, as recent studies have demonstrated an increased bleeding risk when these agents are used in the setting of ACS [14–18]. This article aims to discuss the available evidence regarding aspirin as an antithrombotic strategy, the role of novel anticoagulants and the specific clinical situations where aspirin may be beneficial in patients with AF and CAD. Current guidelines on antithrombotics in AF & ACS
The recommendations provided by various organizations with regard to this topic are
2014 Informa UK Ltd
ISSN 1477-9072
977
Review
Velagapudi, Turagam, Agrawal, Mittal, Kocheril & Aggarwal
Atrial fibrillation and coronary disease
CHA2DS2-VASc ≥1
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Stable CAD
ACS + PCI
Medically managed ACS
Bare metal Drug eluting
Warfarin (INR 2–3) Warfarin (INR 2 –3) + aspirin + clopidogrel for 6–12 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Warfarin (INR 2–3) + clopidogrel + aspirin at least 6 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Warfarin (INR 2–3) + clopidogrel + aspirin at least 1–3 months
Warfarin (INR 2–3) ± single antiplatelet agent for long term
Figure 1. Antithrombotic treatment for atrial fibrillation and coronary artery disease based on CHA2DS2-VASc score. † Prasugrel and Ticagrelor – not indicated in the management for Atrial fibrillation + Acute coronary syndrome. ACS: Acute coronary syndrome; CAD: Coronary artery disease; INR: International normalized ratio; PCI: Post stent implantation.
based on expert consensus and not based on high-level clinical evidence (FIGURE 1). According to the 2012 ESC-AF guidelines, treatment with oral anticoagulation is recommended (class IA) for patients with CHA2DS2-VASc score of 2 or greater. Oral anticoagulation is also recommended with warfarin or one of the novel agents for patients with CHA2DS2-VASc score of 1 (class IIA). For individuals with CHA2DS2-VASc score of 0, the recommendation is not to prescribe any antithrombotic therapy (class IB) [8]. The 2014 ACC/AHA/Heart Rhythm Society AF guidelines recommend oral anticoagulation for CHA2DS2-VASc of 2 or greater (class IA with warfarin and class IB with the novel anticoagulants), no treatment/aspirin/ oral anticoagulation based on the clinical risk profile for CHA2DS2-VASc score of 1 (class IIB, level of evidence C) and no antithrombotic treatment for CHA2DS2-VASc score of 0 (class IIA, level of evidence B) [9]. Unlike a validated thrombosis risk stratification tool in AF, like the CHA2DS2-VASc score; there is no risk score to predict thrombosis in patients with CAD and the recommendation is to stratify patients based on clinical risk factors [19,20], creating a discrepancy and variability about estimating the risk of thrombosis in CAD. Unlike AF, aspirin is the mainstay of antithrombotic therapy in patients with CAD or ACS. In the absence of contraindications, aspirin is recommended indefinitely for secondary prevention of recurrent vascular events, MI and cardiovascular death in patients with ischemic heart disease [10,19,20]. The 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12], 978
2011 ACC/AHA focused update on AF [21] and the 2010 ESC-AF guidelines [22] recommend against the use of low-dose aspirin and use only warfarin with an international normalized ratio (INR) goal of 2–3 in patients with moderate–high risk of stroke and stable ischemic heart disease (12 months without ischemic events). However, the 2011 ACC/AHA guidelines on secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease [13] recommend the addition of low-dose aspirin to warfarin in patients with moderate–high risk of stroke in AF and concomitant stable ischemic heart disease. In individuals undergoing PCI, stent thrombosis is a major complication with an estimated annual incidence of 1–2% in both drug-eluting stents (DES) and bare metal stents (BMS) and can cause death in 10–20% and MI in 30–70% [23,24]. The greatest risk is reported in the first month and decreases significantly beyond 1 year [24,25]. The premature discontinuation of DAPT increases the risk of stent thrombosis by 5–36% [25]. Studies have also demonstrated a significant increased bleeding risk with the addition of multiple antithrombotic medications, creating controversy among various practice guidelines on what may be the appropriate antithrombotic therapy balancing the risk of bleeding and thrombosis [26–28]. The 2012 ACC/AHA guidelines for the management of unstable angina and non-ST segment elevation myocardial infarction (NSTEMI) [10] recommend triple antithrombotic therapy (TAT) including aspirin, warfarin and a P2Y12 inhibitor for at least 12 months, irrespective of the type of stent implanted Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
in individuals requiring long-term anticoagulation after PCI. The 2014 ACC/AHA/Heart Rhythm Society AF guidelines [8] recommend that it may be reasonable to use clopidogrel with oral anticoagulation without aspirin for patients with CHA2DS2-VASc score of 2 and above undergoing coronary revascularization. The 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12] recommends treatment with TAT for 1 month after a BMS and for 3–6 months after a DES, after which the recommendation is to continue warfarin (INR 2–3) and a single antiplatelet agent for at least 12 months. There is similar controversy regarding appropriate anithrombotics in medically managed ACS patients not undergoing PCI. The 2012 ACC/AHA guidelines [10] for the management of unstable angina and NSTEMI recommend TAT for at least 1 year; while the 2012 American College of Chest Physicians Consensus Conference on Antithrombotic and Thrombolytic Therapy [12] recommends treating with warfarin (INR 2–3) and a single antiplatelet agent only. Mechanism of thrombosis in AF & ACS
The exact mechanism of thrombosis in AF and ACS remains unclear, but studies have demonstrated several overlapping pathways [29,30]. The clot associated with coronary thrombosis is predominantly a ‘white’ thrombus consisting of platelets entrapped in fibrin [29], while the clot associated with AF is typically a ‘red’ thrombus consisting of red blood cells and fibrin [30]. This explains the modest benefit of antiplatelet agents (aspirin, clopidogrel) in reducing the risk of stroke in AF and the reason for combining antithrombotics with antiplatelet therapy in patients with both AF and ACS in various clinical scenarios. This section briefly highlights the mechanism of thrombosis in AF and ACS. Activation of the coagulation cascade plays a major role in AF-related clot formation. Several studies have demonstrated abnormal levels of plasma fibrinogen, platelet factor 4, tissue plasminogen activator, von Willebrand factor, plasminogen activator inhibitor, thromboglobulin and soluble thrombomodulin complexes in AF [31–34]. Furthermore, anticoagulation with warfarin rather than antiplatelets has shown to decrease the concentration of some of these prothrombotic indices, which also explains the importance of coagulation cascade activation in thrombus formation in AF [35–38]. Structural endothelial changes [39], inflammation (abnormal C-reactive protein, IL-6) [40], growth factors (VEGF, angiopoietin) [41,42], extracellular matrix turnover (abnormal matrix metalloproteinase and tissue inhibitor matrix metalloproteinase) [43], nitric oxide [44] and activation of rennin–angiotensin system [45] are all implicated in the mechanism of thrombosis in AF. Platelets play a major role in thrombosis associated with ACS, when compared to the coagulation factors [46]. Endothelial injury from the rupture of an atherosclerotic plaque results in platelet activation and increased expression of cytokines, chemokines and growth factors and triggering of the coagulation system by the production of tissue factors by aggregating informahealthcare.com
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macrophages results in thrombin generation which further amplifies platelet activation [46]. Inflammation plays a major role in coronary thrombosis with the release of thromboxanes, leukotrienes and activated circulating leukocytes [47]. Abnormal levels of plasminogen activator inhibitor-1 have been reported in patients with ACS and CAD, which inhibit tissue plasminogen activator and urokinase-like activators, which further contributes to thrombosis [48]. Similar to AF, abnormal levels of plasma fibrinogen, von Willebrand factor and IL-6 have been reported in ACS [30,49]. Drug-based clinical trials in ACS further support this understanding of the platelet activation pathways [49]. This explains the lack of effectiveness of aspirin in AF and how combination therapy with aspirin and clopidogrel is superior to aspirin alone due to targeting multiple sites of platelet activation pathway. Novel anticoagulants in CAD
Recently, four novel anticoagulants have shown excellent efficacy and safety for stroke prevention in AF in RCTs [6–8,50]. Additionally, the safety and efficacy of two new anticoagulants, darexaban and letaxaban, have been studied in phase II trials [51,52]. Dabigatran is a direct thrombin inhibitor, while rivaroxaban, apixaban, edoxaban, darexaban and letaxaban are factor Xa inhibitors. In this section, we briefly discuss the current clinical evidence and future directions regarding the use of these novel anticoagulants in CAD (TABLE 1). RE-DEEM (dabigatran vs placebo in patients with ACS on DAPT) [15] was a Phase II, double-blind placebo RCT including 1861 patients after STEMI and NSTEMI randomized to four doses of twice-daily dabigatran (50, 75, 110 and 150 mg) in addition to standard therapy with DAPT versus placebo. Exactly 99.2% of patients were on DAPT treatment. The study reported a dose-dependent increase in bleeding risk with dabigatran and no significant clinical benefit in the prevention of MI or recurrent ischemia. The reported risk of MI with dabigatran has been conflicting. The RE-LY trial [6] reported the rate of MI to be 0.53% per year with warfarin, 0.72% per year in the 110-mg group of dabigatran and 0.74% per year in the 150-mg group of dabigatran. Further analysis in the RE-LY trial [53] reported a statistically insignificant increase in MI in both doses of dabigatran when compared to warfarin. There was no significant increase in other myocardial ischemic events like unstable angina, cardiac arrest, composite MI and cardiovascular death between dabigatran and warfarin. However, two recent metaanalyses have shown a small increase in the risk of ACS with dabigatran [54,55]. Uchino et al. [54] included 30,514 patients reporting ACS with dabigatran. Dabigatran was associated with a 0.27% absolute increase in the risk of ACS. Another recent meta-analysis [55] including 11 trials and 39,300 patients reported an increased risk of MI with the entire class of direct thrombin inhibitors when compared to warfarin. However, a recent Danish registry [56] reported lower MI with both doses of dabigatran compared to warfarin in ‘everyday clinical practice.’ Several hypotheses have been suggested for this increased risk of MI with dabigatran, but none was validated. Further 979
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Table 1. Summary of novel anticoagulants in acute coronary syndrome. Study (year)
Trial name
Type of trial
Number of subjects
Drugs studied
Bleeding outcomes
Ref.
Oldgren et al. (2011)
RE-DEEM
Double-blind, placebo-controlled, Phase II study
1861
Dabigatran + DAPT vs DAPT + placebo
Dabigatran was associated with a dose-dependent increase in major and clinically significant minor bleeding
[15]
Mega et al. (2009)
ATLAS ACS-TIMI 46
Double-blind, placebo-controlled, Phase II study
3491
Rivaroxaban + DAPT vs DAPT + placebo vs rivaroxaban + aspirin vs aspirin + placebo
Rivaroxaban was associated with a dose-dependent increase in bleeding
[16]
Mega et al. (2012)
ATLAS ACS-TIMI 51
Double-blind, placebo-controlled trial, Phase III
15,526
Rivaroxaban + DAPT vs DAPT + placebo
Rivaroxaban increased the risk of major bleeding and intracranial hemorrhage
[17]
Alexander et al. (2009)
APPRAISE
Double-blind, placebo-controlled, Phase II study
1715
Apixaban + DAPT vs DAPT + placebo
Apixaban was associated with a dose-dependent increase in bleeding
[18]
Alexander et al. (2011)
APPRAISE-2
Randomized, double-blind, placebo-controlled
7392
Apixaban + DAPT vs DAPT + placebo
Apixaban increased the risk of major bleeding
[19]
ACS: Acute coronary syndrome; APPRAISE: Apixaban for Prevention of Acute Ischemic 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; DAPT: Dual Antiplatelet Therapy.
randomized trials are required before dabigatran can be safely recommended in patients with AF and ACS. Two clinical trials studied the effect of rivaroxaban in ACS. The 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 trial [16] was a Phase II double-blind RCT including 3491 patients with ACS. The study reported rivaroxaban to be associated with a dose-dependent significant increased risk of bleeding when compared to placebo (in addition to DAPT) without significant reduction in ischemic outcomes [43]. ATLAS ACS-2 TIMI 51 trial [17], a phase III RCT including 15,526 patients with ACS, studied rivaroxaban (2.5 and 5 mg daily) in addition to standard therapy with DAPT. The study reported significant reduction in ischemic outcomes including death and MI with rivaroxaban in addition to standard DAPT in both 2.5 mg and 5 mg doses with an increased risk of bleeding, especially intracranial bleed. Stent thrombosis was reduced significantly with 2.5 mg rivaroxaban in addition to DAPT and non-significantly in the 5-mg group. Rivaroxaban at a dose of 2.5 mg twice daily was associated with overall reduction in mortality when compared to placebo. This 2.5 mg twice-daily dose in ATLAS ACS-2 TIMI 51 trial was significantly lower than the dose used for stroke prevention in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKETAF) trial [7]. However, no significant reduction in ischemic outcomes was reported in patients with a prior history of MI in the ROCKET-AF trial at a higher dose (10 mg daily). 980
Apixaban in ACS was studied in two trials: Apixaban for Prevention of Acute Ischemic Events (APPRAISE) and APPRAISE-2 [18,19]. APPRAISE [18] was a Phase II, doubleblind RCT including 1715 ACS patients. Apixaban (in addition to DAPT) was reported to cause a dose-dependent increased risk of bleeding and significantly reduced the ischemic outcomes when compared to placebo. APPRAISE-2 [19] was a Phase III trial that included 7392 ACS patients in which 5 mg of apixaban given twice daily (in addition to DAPT) significantly increased the risk of bleeding, especially intracranial and fatal bleeding, without reducing the ischemic outcomes when compared to placebo. Darexaban [51], a novel factor Xa inhibitor, was studied in the RUBY-1 trial, a Phase II, double-blind RCT which included 1279 patients with STEMI or NSTEMI. The study reported that darexaban was associated with a dose-related increased risk of bleeding with no significant reduction in major ischemic events when used in combination with DAPT in ACS. Another factor Xa inhibitor, letaxaban, was studied in AXIOM-ACS [52], a phase II RCT including 2753 patients with ACS. The study reported that in addition to DAPT, letaxaban was associated with a dose-dependent increased bleeding risk with no significant risk of major bleeding or reduction in ischemic events. A recent meta-analysis [57] including 31,286 patients from seven RCTs reported highly significant increase in major bleeding events and a lack of clinical benefit with the use of both factor Xa inhibitors and direct thrombin inhibitors in addition to DAPT when compared to placebo in ACS. Another metaanalysis [58] reported similar increased bleeding risk (hazard Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
ratio [HR]: 1.79; 95% confidence intervals [CI]: 1.54–2.09) and a reduction in the incidence of major ischemic events (HR: 0.7; 95% CI: 0.59–0.84) on combining aspirin with an oral anticoagulant. Further, the addition of an oral anticoagulant to DAPT doubled the risk of bleeding (HR: 2.34; 95% CI: 2.06–2.66) with a modest decrease observed in major ischemic outcomes (HR: 0.87; 95% CI: 0.80–0.95). Finally, these novel agents have been shown to have a marginal role in CAD, barring rivaroxaban which has obtained a class IIB recommendation in ESC guidelines in STEMI patients receiving aspirin and clopidogrel. Role of aspirin in AF
Studies have demonstrated that aspirin may have a modest benefit in stroke prevention compared with anticoagulation with warfarin or one of the novel agents in AF. The 2014 ACC/AHA AF guidelines suggest that it may be reasonable to use aspirin for stroke prevention in CHA2DS2-VASc score of 1 [9]. However, the European guidelines do not routinely recommend aspirin for stroke prevention in AF [10] and this recommendation is based on recent large-scale RCTs involving new anticoagulants. The AVERROES trial [59], which included patients with AF not suitable for warfarin, reported that aspirin may have similar bleeding risk as the novel anticoagulant apixaban (1.2 vs 1.4% per year; HR: 1.13; 95% CI: 0.74–1.75; p = 0.57) and a significantly lower efficacy (3.7 vs 1.6% per year) in stroke prevention. Further analysis of the AVERROES trial [60] reported similar anatomic sites and predictors of bleeding in both aspirin and apixaban. A meta-analysis by Hart et al. [61] reported that aspirin was significantly ineffective in reducing stroke when compared to warfarin (64 vs 22%) and the adjusted-dose warfarin was more efficacious than antiplatelet therapy based on the analysis of 12 trials and 12,963 patients. In the analysis confined to the aspirin-only trials, stroke risk was reduced by only 19% (95% CI: 1–35%) when compared with placebo and these results were largely driven by positive results from the Stroke Prevention in Atrial Fibrillation Study [62], which reported an overall significant reduction in stroke risk of 42% with aspirin versus placebo (3.6%/year; 95% CI: 9–63%). Another meta-analysis by Aguilar et al. [63] reported that aspirin significantly reduced the combination of stroke, MI and cardiovascular death with no increase in bleeding, but did not significantly reduce the risk of all strokes or ischemic strokes in patients with non-valvular AF and no previous history of stroke or TIA. Studies involving combination therapy of aspirin with warfarin and clopidogrel report modest improvement in stroke prevention with a significantly increased risk of bleeding [64–66]. In the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) A trial [64], aspirin–clopidogrel therapy was compared with aspirin monotherapy in patients with AF who were unsuitable for warfarin. The study reported that the risk of stroke and/or systemic embolism was reduced to 2.4% per year with aspirin and clopidogrel versus apirin alone with a 57% increased risk of major informahealthcare.com
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bleeding. In the ACTIVE-W trial [65], the risk of stroke and/ or systemic embolism with aspirin–clopidogrel combination was significantly higher (5.6 vs 3.93% per year) when compared with warfarin with a significant risk of major bleeding (2.42 and 2.21% per year). Furthermore, the combination of aspirin and warfarin increased the risk of bleeding (3.9% per year vs 2.3%; p < 0.01) with no reduction in stroke, MI or systemic embolism (0.6%/year vs 1%) in AF [66]. Management of AF & ACS
AF may be stratified into low (CHA2DS2-VASc score 0), moderate (CHA2DS2-VASc = 1) and high risk (CHA2DS2-VASc ‡2) of stroke or systemic embolism based on the CHA2DS2VASc score. In the presence of concomitant vascular disease (previous MI, peripheral arterial disease or aortic plaque), the individual is at moderate risk for stroke based on a CHA2DS2VASc score of 1. This section will discuss antithrombotic treatment recommendations based on the CHA2DS2-VASc score in the management of patients with both AF and CAD. AF with low risk of thromboembolism
Patients with AF in the presence of CAD or peripheral vascular disease are never truly at low risk for thromboembolism (CHA2DS2-VASc of 1). AF with moderate–high risk of thromboembolism Chronic stable CAD
AF with chronic stable CAD (free from ischemic events for 6–12 months) may be stratified as being at moderate risk for stroke (CHA2DS2-VASc ‡1). Oral anticoagulation remains the cornerstone therapy in this group of patients due to an estimated stroke risk of >1.3% per year. However, data on addition of low-dose aspirin over anticoagulation are scarce due to lack of evidence. Warfarin (INR >2) has also proven to be more efficacious and relatively safe for the prevention of stroke, thromboembolism and coronary events in this group of patients [61,67,68]. The use of dabigatran in patients with AF and stable CAD remains controversial due to the lack of strong evidence, while studies involving factor Xa inhibitors have shown that they reduce coronary events and overall mortality [69,70]. No RCT has compared warfarin with a direct thrombin inhibitor (dabigatran) or a factor Xa inhibitor (rivaroxaban, apixaban) for prevention of coronary events. A recent study including 8700 patients with AF and stable CAD (defined as 12 months from ACS) reported significant increase in bleeding risk with the addition of antiplatelet agent to warfarin; the bleeding risk reported was higher with clopidogrel than aspirin, with no significant reduction in ischemic or embolic events [71]. It can be concluded that in patients with AF (CHA2DS2VASc score 1) and stable CAD, warfarin with an INR 2–3 is safe and effective in prevention of both cardiovascular and cerebrovascular events. Based on recent meta-analysis, factor Xa inhibitors (rivaroxaban and apixaban) may be a reasonable alternative as they cause a reduction in overall mortality. However, the addition of aspirin increases the bleeding risk without 981
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causing significant reduction in coronary events or stroke. The evidence regarding the use of dabigatran in this group is scare and conflicting and further studies are required before the drug can be safely used in this group of patients.
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Medically managed ACS
The evidence regarding antithrombotic therapy in individuals with AF (CHA2DS2-VASc of 1) presenting with ACS but not undergoing PCI is also unclear with several conflicting recommendations by major organizations [10–12]. Treatment with DAPT including clopidogrel and aspirin for a year following ACS reduced death and further coronary events and this combination was superior when compared to combination therapy with warfarin and aspirin [72–75]. More recently, DAPT, including prasugrel and aspirin, did not significantly lower ischemic events when compared to clopidogrel and aspirin in patients with ACS not undergoing PCI [76]. However, DAPT therapy with ticagrelor and aspirin was reported to significantly reduce the vascular events, MI or stroke, with no major increase in bleeding when compared to standard DAPT therapy with clopidogrel and aspirin, regardless of invasive or non-invasive strategy [77]. However, there are no RCTs on the combination of these newer antiplatelet agents (prasugrel and ticagrelor) with oral anticoagulants. In patients with AF (CHA2DS2-VaSc = 1), presenting with ACS and not undergoing PCI, treatment with DAPT including clopidogrel and aspirin for 1 year followed by lifelong therapy with either aspirin or clopidogrel is required for the prevention of ischemic events, MI and cardiovascular mortality, while anticoagulation with warfarin is recommended for the prevention of stroke and systemic thromboembolism. The ACTIVE-W trial [65] showed that DAPT (aspirin and clopidogrel) was inferior to warfarin in stroke prevention and increased the bleeding risk in AF. Newer anticoagulant trials in ACS have not been favorable. Dabigatran, apixaban, darexaban and letaxaban have been shown to increase the risk of bleeding without significant reduction of coronary events in patients with ACS treated with DAPT [15,18,19]. Low-dose rivaroxaban (2.5 and 5 mg twice daily) was shown to significantly prevent ischemic outcomes, MI and overall mortality, when used in combination with DAPT [17]. However, this drug was associated with increased risk of bleeding, especially intracranial bleeding. It can be safely concluded that in patients with AF (CHA2DS2-VaSc = 1) and medically managed ACS, it may be reasonable to treat with TAT consisting of warfarin, aspirin and clopidogrel for at least 1 year. Continuing DAPT with aspirin and clopidogrel beyond 1 year significantly increases the risk of bleeding [78]. It may be reasonable to drop one antiplatelet agent when the bleeding risk is high after a few months of TAT. Combination of prasugrel and ticagrelor with warfarin is not recommended due to lack of RCTs and the increased bleeding risk. Similarly, due to increased bleeding risk and lack of ischemic benefit in CAD, the newer anticoagulants dabigatran, rivaroxaban and apixaban are not recommended to be used in combination with DAPT in this group of patients. 982
ACS patients undergoing PCI
The optimal management of AF patients with a CHA2DS2VaSc = 1 on chronic anticoagulation and undergoing PCI (elective or emergent) is based on expert consensus and not supported by RCTs. The intensity of antithrombotic treatment and duration are largely based on the type of stent used, with the goal being to prevent stent thrombosis. Based on clinical trials, the duration of DAPT with aspirin and a second antiplatelet agent such as P2Y12 inhibitors is at least 1 month for BMS and 3–6 months for DES, with P2Y12 inhibitor being the cornerstone of this therapy [78,79]. However, a subgroup analysis from the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study trial reported that long-term DAPT (24 months) may be beneficial in patients treated for in-stent restenosis [80]. A recent study including 377 patients undergoing PCI with DES and requiring TAT reported that prasugrel increased the risk of bleeding with no difference in ischemic outcomes when compared to clopidogrel [80]. BMS is typically recommended in the setting of AF and the concomitant need for anticoagulation is due to the reduced duration of TAT and the subsequent risk of increased bleeding when compared to dual antithrombotic therapy [9,10,12,13]. A recent open-label randomized controlled trial including 573 patients undergoing PCI and taking oral anticoagulants reported that clopidogrel without aspirin may be used with no increase in thrombotic events and with a significant reduction in bleeding risk. The study included 65% of subjects with DES and 30–35% with BMS [27]. However, the trial was underpowered to estimate the ischemic events reliably and provides insufficient evidence to suggest dual antithrombotic therapy rather than TAT after PCI. Dabigatran, rivaroxaban and apixaban are not recommended in AF patients undergoing PCI. Expert commentary & five-year view
Due to increasing geriatric population in the USA, there is an increase in the prevalence of patients having multiple cardiovascular diseases and compelling indications for the use of combination of antiplatelet agents and anticoagulants. Our literature review has suggested that there is no clear data on the combination usage of aspirin–anticoagulants for the routine cardiovascular benefit or even in chronic stable CAD in any age group and, even more so, in the geriatric population. The only exception to this rule is patients with mechanical heart valves. However, the usage may be reasonable in other settings including acute ACS and PCI where the risk of coronary thrombosis may be high. There are several areas which need further studies, including the role of TAT, both in patients undergoing an interventional procedure and in medically managed patients with CAD and AF. It is important to note that all studies done so far included patients 75 years of age who carry the greatest risk of bleeding and stroke. Currently, the novel anticoagulants are not Expert Rev. Cardiovasc. Ther. 12(8), (2014)
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Antithrombotics in AF-CAD
recommended in the setting of CAD, ACS and PCI. It is unclear how best to manage patients currently being treated with one of the novel oral anticoagulants for AF who may later develop ACS or MI. It is also unclear if warfarin can be switched to one of these novel agents after a year of standard therapy following ACS and PCI. Larger antithrombotic trials, especially including newer anticoagulants with remote ACS, are underway and would be very useful. In summary, stacking up of antithrombotics increases the risk of bleeding. Physicians should be cautious while recommending aspirin along with routine anticoagulation in patients in the absence of a compelling indication due to lack of clear-cut evidence. The need for clinical trials to determine the safety and
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efficacy of such combinations remains paramount and is essential for informed decision-making in the management of these challenging patients, especially in an era of new anticoagulants. Financial and competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia affecting 3 million individuals in the USA. Similarly, coronary artery disease (CAD) is estimated to occur in 18–45% of patients with concomitant AF. • Unlike the CHA2DS2-VASc score for AF, there is no validated risk score to predict future thrombosis in CAD. • Patients with AF in the presence of CAD or peripheral vascular disease are never truly at low risk for systemic thromboembolism including stroke (at least a CHA2DS2-VASc of 1). • Clinical risk assessment of thrombosis and bleeding is recommended in every AF patient with CAD and acute coronary syndrome (ACS). • The appropriate antithrombotic regimen in stable CAD and ACS in the presence of AF is unclear and based on best practice standards due to a lack of randomized clinical trials. • Studies involving the role of novel anticoagulants, with the exception of rivaroxaban, in ACS have found them to be unfavorable with increased bleeding risk and they are not recommended. • Triple antithrombotic therapy may be used in AF patients with high risk of coronary thrombosis in the setting of ACS or stent placement. • Physicians should be cautious while recommending aspirin along with routine anticoagulation in the absence of a compelling indication due to lack of clear-cut evidence, especially in patients with AF and stable CAD. • The need for clinical trials to determine the safety and efficacy of such combination antithrombotics remains paramount and is essential for informed decision-making in the management of these challenging patients.
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