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Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial
International Journal of Cardiology 170 (2013) 215–220
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial☆,☆☆ Maria Cecilia Bahit a,1, Renato D. Lopes b,⁎,1, Daniel M. Wojdyla b,1, Stefan H. Hohnloser c,1, John H. Alexander b,1, Basil S. Lewis d,1, Philip E. Aylward e,1, Freek W.A. Verheugt f,1, Matyas Keltai g,1, Rafael Diaz a,1, Michael Hanna h,1, Christopher B. Granger b,1, Lars Wallentin i,1 a
ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA c J.W. Goethe-University, Frankfurt, Germany d Lady Davis Carmel Medical Center, Haifa, Israel e Flinders Cardiovascular Center, Adelaide, Australia f Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands g Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary h Bristol-Myers Squibb, Princeton, NJ, USA i Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden b
a r t i c l e
i n f o
Article history: Received 2 May 2013 Received in revised form 24 September 2013 Accepted 19 October 2013 Available online 24 October 2013 Keywords: Coronary artery disease Atrial fibrillation Apixaban Warfarin
a b s t r a c t Background: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD. Methods and results: In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71–1.27, P for interaction = 0.12; HR 0.96, 95% CI 0.81–1.13, P for interaction = 0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD. Conclusions: In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with significant morbidity and mortality [1–5]. Patients with AF have reduced quality of life, a higher risk of developing heart failure, cognitive impairment, and approximately ☆ Funding sources: ARISTOTLE was supported by Bristol-Myers Squibb and Pfizer. ☆☆ Potential conflicts of interest: Please see Disclosures section. ⁎ Corresponding author at: Duke Clinical Research Institute, Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705, USA. Tel.: +1 919 668 8241; fax: +1 919 668 7056. E-mail address: [email protected] (R.D. Lopes). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.10.062
one-third have a history of coronary artery disease (CAD) [6]. The estimated prevalence of AF in a large international cohort is 12.5% in patients with CAD [7]. In addition, patients with both AF and CAD are at an increased risk for ischemic events and cardiovascular death [7]. Oral anticoagulation with warfarin, a vitamin K antagonist, is known to reduce stroke in patients with AF [8] and also to reduce stroke and mortality in patients with AF following myocardial infarction (MI) [9,10]. Recently, 3 pivotal trials have demonstrated benefits of the new oral anticoagulants dabigatran [11,12], rivaroxaban [13,14], and apixaban [15,16] compared with warfarin in patients with AF and an increased risk of stroke. A recent subgroup analysis of the RE-LY study showed that the beneficial effects of dabigatran over warfarin were similar in AF patients with and without prior CAD [17], although there
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was a higher rate of MI with dabigatran compared with warfarin in the trial [12]. In contrast, there was no difference in the rate of MI when comparing apixaban with warfarin in the ARISTOTLE trial or with aspirin in the AVERROES trial [18]. When comparing the 5 mg twice daily dose of apixaban with placebo in patients on antiplatelet agents after an acute coronary syndrome in the prematurely terminated APPRAISE-2 trial, there was no significant reduction in ischemic events [19]. This finding is in contrast to the reduction with low doses of rivaroxaban in the ATLAS-2 trial [20]. However, in both trials there was a 2–3 times increase in major bleeding when adding the factor Xa inhibitors to antiplatelet treatment in patients with CAD. Thus, the usefulness of novel oral anticoagulants in patients with AF and CAD needs further definition. In the ARISTOTLE [16] trial, 18,201 patients with AF and at least 1 additional risk factor for stroke were randomized to apixaban or doseadjusted warfarin. In the apixaban group there was a 21% relative reduction in the rate of the primary outcome (stroke or systemic embolism), 31% in major bleeding, and 11% in death from any cause. In this pre-specified subgroup analysis, we evaluated the treatment effects of apixaban compared with warfarin in patients with and without prior CAD. 2. Methods 2.1. Study population The design and results of the ARISTOTLE trial have been reported [15,16]. Briefly, 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban or dose-adjusted warfarin. The dose of apixaban (or matching placebo) was 5 mg twice daily or 2.5 mg twice daily for patients with 2 or more of the following factors: age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dL (133 μmol/L). Patients were enrolled in 39 countries between 2006 and 2010. The median duration of follow-up was 1.8 years. Patients taking concomitant aspirin (≤165 mg/day) were eligible, but patients taking dual antiplatelet therapy with aspirin plus clopidogrel were not. The ARISTOTLE trial complied with the Declaration of Helsinki. All patients enrolled provided written informed consent, and the trial was approved by the institutional review boards and ethics committees of participating sites. 2.2. Coronary artery disease CAD was defined as documented CAD, history of MI, and/or history of coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery) at randomization. Classification was used as recorded on the case report form (CRF), and no attempt to adjudicate these classifications was undertaken. Patients with missing data on the above-mentioned CRF check box were excluded.
an exploratory analysis to determine whether the treatment effect of apixaban versus warfarin in patients with CAD was consistent among patients taking and not taking aspirin at baseline, including the effect on MI. In all analyses, a P value b0.05 was considered statistically significant. All statistical analyses were performed with SAS software version 9.22 (SAS Institute, Inc., Cary, NC, USA).
3. Results 3.1. Baseline characteristics Of the 18,201 patients included in the ARISTOTLE study, excluding the 17 with missing data on CAD, 6639 (36.5%) had prior CAD. Of those, 2585 (38.9%) had prior MI, 1206 (18.2%) had prior CABG, and 1651 (24.9%) had prior PCI. Of patients with a history of PCI, 694 had a bare-metal stent and 388 received a drug-eluting stent. Baseline characteristics are shown in Table 1. Patients with prior CAD were more often male, and more commonly had prior peripheral arterial disease (PAD) and paroxysmal AF. Prior stroke, transient ischemic attack, or systemic embolism, and heart failure, reduced left ventricular ejection fraction (LVEF), diabetes, and hypertension were also more prevalent in patients with prior CAD. Accordingly, patients with prior CAD had higher CHADS2 scores, with a score of 3 or more in 36.7% compared with 26.5% in those without prior CAD. 3.2. Medications At baseline, patients with prior CAD were more likely to be on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and statins compared with patients with no CAD (Table 1). Aspirin use at randomization was 42.2% in patients with prior CAD compared with 24.5% in those without prior CAD. During the follow-up period and in the group of patients with prior CAD, study drug discontinuation rates, excluding discontinuation due to death, per 100 patient-years of follow-up were 14.4 for apixaban and 15.2 for warfarin (P = 0.32). For patients without prior CAD, the rates were 11.4 in the apixaban group and 13.1 in the warfarin group (P = 0.0008). In the warfarin group, the median time in the target range of the international normalized ratio was 65.2% in patients with prior CAD and 66.4% in patients without prior CAD (P = 0.0013). 3.3. Outcomes
2.3. Study outcomes The primary efficacy outcome was stroke or systemic embolism. The key secondary efficacy outcome was death from any cause. Additional outcomes were MI and coronary revascularization. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria [21]. A clinical event committee, whose members were not aware of study group assignments, adjudicated the primary and secondary efficacy and safety outcomes on the basis of pre-specified criteria. 2.4. Statistical analysis Baseline characteristics of patients with and without history of CAD are presented as medians with 25th and 75th percentiles for continuous variables and frequencies and percentages for categorical variables. Both groups are compared using Wilcoxon tests for continuous variables and chi-square tests for categorical variables. Events during followup are summarized as event rates per 100 patient-years of follow-up. Hazard ratios (HRs) along with 95% confidence intervals (CIs) comparing randomized treatments are derived from Cox regression models. The interaction between randomized treatment and CAD status was tested in a Cox model that included the main effects for treatment and CAD and their interaction. The probability of primary efficacy and safety endpoints are presented as Kaplan–Meier curves. The proportional hazard assumption was tested using methods based on cumulative sums of martingale residuals [22]. The proportional hazard assumption was valid for all the endpoints presented except for death from any cause in patients with prior CAD. Results for that endpoint represent an average HR and should be interpreted cautiously. Although it is recommended in the guidelines to avoid aspirin with warfarin for patients with AF and stable coronary disease, it is unknown whether novel oral anticoagulants alone are sufficient for patients with AF and chronic CAD. We performed
3.3.1. Prior CAD versus no CAD Compared with patients without a history of CAD, patients with prior CAD were more likely to die from any cause (4.30 vs. 3.39% per 100 patient-years, P b 0.0001) (Table 2). The rate of stroke or systemic embolism was similar (1.51 vs. 1.39% per 100 patient-years, P = 0.3666). In the prior CAD subgroup, the rate of MI was 3-fold higher than in patients without prior CAD (0.97 vs. 0.34% per 100 patientyears; P b 0.0001). Patients with and without prior CAD had similar rates of ISTH major bleeding (2.72 vs. 2.54% per 100 patient-years, respectively; P=0.3638). There were, however, numerically fewer intracranial hemorrhages in patients with prior CAD compared with patients without prior CAD. 3.3.2. Apixaban versus warfarin according to CAD status The absolute reductions in stroke or systemic embolism with apixaban were 0.48 per 100 patient-years in patients without prior CAD and 0.08 in patients with prior CAD. Treatment with apixaban was associated with a reduced rate of stroke or systemic embolism, death from any cause, and MI in both patients with prior CAD and those without prior CAD (P for interaction = 0.12, 0.28, and 0.45, respectively). Coronary revascularization including PCI and CABG during follow-up was 2- to 3-fold more common in patients with prior CAD. However, the treatment effect of apixaban on revascularization
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Table 1 Baseline characteristics according to CAD status.
Age, median (25th, 75th), years Female sex Region North America Latin America Europe Asia Pacific Systolic BP, median (25th, 75th), mm Hg Weight, median (25th, 75th), kg PAD, no. (%) Prior clinically relevant or spontaneous bleeding History of fall within previous year Bare-metal stent Drug-eluting stent Prior CABG Type of AF Paroxysmal Persistent or permanent Prior VKA use (N30 days) Qualifying risk factors Age ≥75 years Prior stroke, TIA, or systemic embolism HF or reduced LVEF Diabetes Hypertension requiring treatment CHADS2, mean (SD) CHADS2 score ≤1 2 ≥3 Medications at time of randomization ACE inhibitor or ARB Amiodarone Beta-blocker Aspirin Clopidogrel Digoxin Calcium blocker Statin Nonsteroidal antiinflammatory agent Gastric antacid drugs Renal function Normal (80 mL/min) Mild impairment (N50–80 mL/min) Moderate impairment (N30–50 mL/min) Severe impairment (≤30 mL/min)
No CAD (N = 11,545)
CAD (N = 6639)
P valuea
70 (62, 76) 4433 (38.4%)
70 (63, 76) 1976 (29.8%)
0.0035 b0.0001 b0.0001
2587 (22.4%) 2912 (25.2%) 3962 (34.3%) 2084 (18.1%) 130 (120, 140) 81 (68, 95) 329 (2.9%) 1861 (16.1%) 457 (4.4%) – – –
1887 (28.4%) 551 (8.3%) 3374 (50.8%) 827 (12.5%) 130 (120, 140) 84 (73, 97) 555 (8.4%) 1178 (17.7%) 296 (4.8%) 694 (10.5%) 388 (5.8%) 1206 (18.2%)
1587 (13.7%) 9958 (86.3%) 6748 (58.4%)
1197 (18.0%) 5439 (82.0%) 3644 (54.9%)
3641 (31.5%) 2114 (18.3%) 3280 (28.4%) 2602 (22.5%) 9912 (85.9%) 2.0 (1.1)
2032 (30.6%) 1420 (21.4%) 3166 (47.7%) 1941 (29.2%) 5991 (90.2%) 2.3 (1.2)
4475 (38.8%) 4009 (34.7%) 3061 (26.5%)
1701 (25.6%) 2502 (37.7%) 2436 (36.7%)
7747 (68.3%) 1221 (10.8%) 6782 (59.8%) 2826 (24.5%) 112 (1.0%) 3703 (32.6%) 3625 (32.0%) 3649 (32.2%) 1017 (9.0%) 2069 (18.2%)
5074 (77.5%) 826 (12.6%) 4689 (71.6%) 2801 (42.2%) 225 (3.4%) 2118 (32.3%) 1940 (29.6%) 3819 (58.3%) 503 (7.7%) 1279 (19.5%)
4856 (42.3%) 4710 (41.0%) 1760 (15.3%) 163 (1.4%)
2657 (40.1%) 2872 (43.4%) 983 (14.9%) 106 (1.6%)
0.0620 b0.0001 b0.0001 0.0047 0.2686 – – – b0.0001
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b.0001 b0.0001 b0.0001
b0.0001 0.0002 b0.0001 b0.0001 b0.0001 0.6858 0.0012 b0.0001 0.0030 0.0323 0.0078
Values presented as number (%), unless otherwise indicated. ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; HF, heart failure; LVEF, left ventricular ejection fraction; PAD, peripheral artery disease; SD, standard deviation; TIA, transient ischemic attack; VKA, vitamin K antagonist. a P value compares patients with CAD vs. patients without CAD.
was similar in patients with prior CAD and those without prior CAD (P for interaction = 0.47). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism (HR 0.95, 95% CI 0.71–1.27 vs. HR 0.70, 95% CI 0.56–0.89, P for interaction = 0.11) and death from any cause (HR 0.96, 95% CI 0.81–1.13 vs. HR
Table 2 Efficacy and safety outcomes according to CAD status. Endpoint
No prior CAD Events (rate)
Prior CAD Events (rate)
P value
Stroke/systemic embolism Stroke MI All-cause death ISTH major bleeding ICH
292 (1.39) 271 (1.29) 72 (0.34) 730 (3.39) 491 (2.54) 119 (0.61)
185 (1.51) 178 (1.45) 120 (0.97) 541 (4.30) 298 (2.72) 55 (0.49)
0.3666 0.2081 b0.0001 b0.0001 0.3638 0.2018
CAD indicates coronary artery disease; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction.
0.85, 95% CI 0.73–0.98, P for interaction=0.28). There was no significant interaction between the treatment effects and the presence or absence of prior CAD in any of the other efficacy endpoints (Fig. 1). Treatment with apixaban was associated with a reduced risk of ISTH major bleeding and intracranial bleeding, both in patients with and without prior CAD. Treatment effects were consistent in patients with and without prior CAD for ISTH major bleeding (P for interaction = 0.17) and intracranial hemorrhage (P for interaction = 0.59) (Fig. 1). 3.3.3. Assessment of randomized treatment effect with and without baseline aspirin The effect of apixaban compared with warfarin for reducing stroke or systemic embolism in patients with CAD was consistent irrespective of whether they were taking aspirin at baseline (3-way interaction [randomized treatment by aspirin at baseline by CAD status] P = 0.86). Of patients with a history of CAD who were not on aspirin at baseline, 25 of 1916 patients in the apixaban group and 35 of 1922 patients in the warfarin group had MI during follow-up. The effect of the relationship between apixaban and warfarin on the rate of MI in
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M.C. Bahit et al. / International Journal of Cardiology 170 (2013) 215–220 No CAD
Interaction P-Value
CAD
Apixaban
Warfarin
HR (95% CI)
Stroke or systemic embolism
1.15 (121) 1.47 (91)
1.63 (171) 1.55 (94)
0.704 (0.558, 0.889) 0.950 (0.712, 1.267)
0.11
Stroke
1.06 (112) 1.40 (87)
1.52 (159) 1.50 (91)
0.701 (0.550, 0.892) 0.937 (0.699, 1.258)
0.14
Death from any cause
3.11 (335) 4.21 (267)
3.68 (395) 4.40 (274)
0.847 (0.732, 0.979) 0.958 (0.809, 1.133)
0.28
MI
0.29 (31) 0.95 (59)
0.39 (41) 1.00 (61)
0.755 (0.473, 1.203) 0.947 (0.662, 1.354)
0.45
0.70 (74) 1.69 (104)
0.67 (71) 1.89 (114)
1.040 (0.751, 1.441) 0.890 (0.682, 1.161)
0.47
1.99 (194) 2.39 (133)
3.12 (297) 3.05 (165)
0.640 (0.534, 0.766) 0.784 (0.624, 0.985)
0.17
0.37 (37) 0.27 (15)
0.85 (82) 0.73 (40)
0.443 (0.301, 0.654) 0.364 (0.201, 0.659)
0.59
Efficacy endpoints:
Revascularization (PCI/CABG) Safety endpoints: ISTH major bleeding Intracranial bleeding
0.1
1
Favor Apixaban
10
Favor Warfarin
Fig. 1. Effect of apixaban vs. warfarin for safety and efficacy outcomes according to CAD status.
patients with CAD was consistent irrespective of baseline aspirin use (3-way interaction [randomized treatment by aspirin at baseline by CAD status] P = 0.86).
4. Discussion In this analysis of the ARISTOTLE study, patients with prior CAD had an increased risk of death and MI and higher aspirin use at baseline than those without prior CAD. The treatment effects of apixaban on stroke or systemic embolism, major bleeding, and death were consistent regardless of the presence of prior CAD. These results remained consistent after adjusting for baseline use of aspirin. Rates of MI were numerically lower in patients assigned to receive apixaban as compared with warfarin, regardless of whether patients had a history of CAD. Patients with AF and CAD are common in clinical practice, comprising approximately 30% of patients in AF registries [6,23] and trials [10], and AF is present in about 12.5% of patients in a registry of patients with CAD [7]. Patients with AF and prior CAD are at high risk for recurrent events and death. The increased risk of cardiovascular events in these patients has also been shown in the REACH registry [7], in which the presence of AF at baseline was associated with higher rates of adverse cardiovascular outcomes at 1-year follow-up after adjustment for other factors. AF is also an independent predictor of adverse events, including mortality, following ACS [9,10]. Warfarin has been shown to be effective in reducing the risk of stroke and other cardiovascular events in patients with AF [24]. Furthermore, in a meta-analysis that included 5938 patients after acute coronary syndromes, warfarin was demonstrated to provide a 44% relative reduction in the rate of MI and a 64% relative decrease in the rate of stroke compared with aspirin [8]. However, warfarin use is also associated with an increased risk of bleeding in both the AF and CAD populations. Another relevant issue is the underutilization of warfarin. Even though warfarin use has increased over time [25], only half of the potentially eligible high-risk patients with AF are being treated with warfarin [7,23,26]. It is noteworthy that in the current trial more patients in the CAD group stopped oral anticoagulation, which was more often seen in the warfarin than the apixaban group. An alternative oral anticoagulant with a better safety profile might be very useful in patients with acute coronary syndromes and AF.
Use of concomitant aspirin among patients with history of CAD was almost 2-fold higher than in patients without CAD in ARISTOTLE. Current guidelines discourage using concomitant antiplatelet therapy in patients with AF receiving warfarin with stable coronary disease [27–29]. In addition, in the open-label WOEST trial [30] that included 573 patients receiving oral anticoagulants and undergoing PCI, clopidogrel without aspirin (dual therapy) was associated with a significant reduction in bleeding and combined secondary endpoint of death, myocardial infarction, stroke, target-vessel revascularization, and stent thrombosis compared with triple therapy (aspirin plus clopidogrel plus oral anticoagulant). Caution should be taken when interpreting these results in light of the limitations of the study including the small sample size and the open-label design. Thus, the role of aspirin with oral anticoagulation, and with novel oral anticoagulants such as apixaban, deserves further evaluation [31]. Based on the current analyses, it appears that the benefits of apixaban are maintained among patients with or without CAD, irrespective of whether they are taking aspirin. The possible benefits of using these new oral anticoagulants in this high-risk patient population have recently been explored. A report from the RE-LY trial [17] has shown that, in patients with prior CAD or MI, the treatment effect of dabigatran over warfarin was consistent with the main trial results. There was no significant interaction between treatment effects and the presence or absence of a history of CAD or MI. However, a recent meta-analysis of randomized dabigatran studies has indicated a higher incidence of MI or acute coronary syndromes in patients treated with this thrombin inhibitor [32]. The results from the ATLAS ACS-2-TIMI-51 trial [33] showed that a low dose of rivaroxaban (2.5 mg twice daily) compared with placebo reduced the primary composite endpoint and the individual endpoint of MI in patients stabilized after STEMI. A recent meta-analysis of randomized trials with dabigatran indicated an increased risk of MI with dabigatran compared with various control treatments [32]. Differences in treatment effect on MI with new oral anticoagulants might be explained by differences in the mechanism of actions [34] or by the use of warfarin as comparator [35]. Lip and Lane [35] conducted a meta-analysis of the occurrence of MI in clinical trials of AF and compared warfarin with other anticoagulants. The authors suggested a protective effect of warfarin against MI; thus, dabigatran might not directly increase the risk of MI but rather may lack the beneficial effects that warfarin
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and aspirin have in preventing MI. In ARISTOTLE, there were nonsignificantly fewer MIs among patients on apixaban than warfarin. Moreover, among patients with prior coronary disease not on aspirin, the rate of MI was numerically lower with apixaban than with warfarin, suggesting that a strategy of avoiding aspirin for stable coronary disease patients on warfarin might also apply to such patients on apixaban. The current results demonstrating that apixaban resulted in lower rates of stroke or systemic embolism, lower all-cause mortality, and less major bleeding than warfarin, regardless of concomitant aspirin use and history of CAD, support its use in a broad population. These results are reinforced by the finding of similar rates of MI during treatment with apixaban versus aspirin in the AVERROES trial [18].
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Granger: Grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and The Medicines Company; consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-LaRoche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, and The Medicines Company; support for travel from the Medtronic Foundation and Merck. Wallentin: Grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck; consulting fees from Regado Biosciences, Portola, CSL Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, ScheringPlough, and Merck.
4.1. Limitations This paper has some limitations. First, we have limited data regarding the timing of CAD prior to patient inclusion in the study; thus, we cannot assess the treatment effect in chronic CAD versus more recently active CAD, including recent acute coronary syndromes. We did not analyze details regarding timing of concomitant aspirin therapy, which is the subject of a separate manuscript [29]. Even though the effect on coronary events was not the focus of the main trial, these events were adjudicated; however, there are relatively few events that limit the power to show differences. In addition, the interaction tests have low power, particularly the 3-way interactions. 5. Conclusion In conclusion, in patients with AF, apixaban as compared with warfarin reduces stroke or systemic embolism and death and causes less bleeding regardless of the presence of prior CAD. Given the common occurrence of both AF and CAD and the higher rates of cardiovascular events and death, the current results from ARISTOTLE indicate that apixaban may be a better treatment option than warfarin for these high-risk patients. Disclosures Bahit: Consulting fees/honoraria and research support from BristolMyers Squibb. Lopes: Grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo; consulting fees from Bristol-Myers Squibb. Wojdyla: None. Hohnloser: Consulting fees from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Cardiome, and Medtronic Vascular; lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and St. Jude Medical. Alexander: Grants from Merck/Schering-Plough and Regado Biosciences; consulting fees from Merck/Schering-Plough, AstraZeneca, Boehringer Ingelheim, Ortho-McNeil-Janssen, PolyMedix, Regado Biosciences, and Bayer. Lewis: Advisory board member for Bayer HealthCare. Aylward: Research support from AstraZeneca, Merck & Co, Eli Lilly, Bayer/Johnson & Johnson, Sanofi-Aventis, GlaxoSmithKline, and Daiichi Sankyo; consulting/advisory board fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Sanofi-Aventis, and Eli Lilly; and travel support from Bristol-Myers Squibb, AstraZeneca, and Boehringer Ingelheim. Verheugt: Lecture fees from Bayer and AstraZeneca; consulting fees from Bayer and Daiichi Sankyo. Keltai: Support for travel from Bristol-Myers Squibb and Pfizer as a member of the ARISTOTLE Steering Committee. Diaz: Consulting fees, honoraria, and research support from BristolMyers Squibb. Hanna: Employee of Bristol-Myers Squibb.
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[25] Baczek VL, Chen WT, Kluger J, Coleman CI. Predictors of warfarin use in atrial fibrillation in the United States: a systematic review and meta-analysis. BMC Fam Pract 2012;13:5. [26] Gladstone DJ, Bui E, Fang J, et al. Potentially preventable strokes in highrisk patients with atrial fibrillation who are not adequately anticoagulated. Stroke 2009;40:235–40. [27] Faxon DP, Eikelboom JW, Berger PB, et al. Consensus document: antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting. A NorthAmerican perspective. Thromb Haemost 2011;106:572–84. [28] You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141: e531S–75S. [29] Lip GY, Huber K, Andreotti F, et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost 2010;103:13–28.
[30] Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107–15. [31] Alexander JH, Lopes RD, McMurray JJV, et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in atrial fibrillation in patients taking concomitant aspirin. Poster presented at: 2012 American College of Cardiology Annual Scientific Session; March 25, 2012; Chicago, IL; 2012. [32] Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med 2012;172:397–402. [33] Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a STsegment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial. J Am Coll Cardiol 2013;61:1853–9. [34] Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood 2010;115:15–20. [35] Lip GY, Lane DA. Does warfarin for stroke thromboprophylaxis protect against MI in atrial fibrillation patients? Am J Med 2010;123:785–9.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Apixaban in patients with atrial fibrillation and prior coronary artery disease: Insights from the ARISTOTLE trial☆,☆☆ Maria Cecilia Bahit a,1, Renato D. Lopes b,⁎,1, Daniel M. Wojdyla b,1, Stefan H. Hohnloser c,1, John H. Alexander b,1, Basil S. Lewis d,1, Philip E. Aylward e,1, Freek W.A. Verheugt f,1, Matyas Keltai g,1, Rafael Diaz a,1, Michael Hanna h,1, Christopher B. Granger b,1, Lars Wallentin i,1 a
ECLA Estudios Cardiológicos Latinoamérica, Rosario, Argentina Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA c J.W. Goethe-University, Frankfurt, Germany d Lady Davis Carmel Medical Center, Haifa, Israel e Flinders Cardiovascular Center, Adelaide, Australia f Onze Lieve Vrouwe Gasthuis, Amsterdam, Netherlands g Hungarian Institute of Cardiology, Semmelweis University, Budapest, Hungary h Bristol-Myers Squibb, Princeton, NJ, USA i Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden b
a r t i c l e
i n f o
Article history: Received 2 May 2013 Received in revised form 24 September 2013 Accepted 19 October 2013 Available online 24 October 2013 Keywords: Coronary artery disease Atrial fibrillation Apixaban Warfarin
a b s t r a c t Background: A substantial portion of patients with atrial fibrillation (AF) also have coronary artery disease (CAD) and are at risk for coronary events. Warfarin is known to reduce these events, but increase the risk of bleeding. We assessed the effects of apixaban compared with warfarin in AF patients with and without prior CAD. Methods and results: In ARISTOTLE, 18,201 patients with AF were randomized to apixaban or warfarin. History of CAD was defined as documented CAD, prior myocardial infarction, and/or history of coronary revascularization. We analyzed baseline characteristics and clinical outcomes of patients with and without prior CAD and compared outcomes by randomized treatment using Cox models. A total of 6639 (36.5%) patients had prior CAD. These patients were more often male, more likely to have prior stroke, diabetes, and hypertension, and more often received aspirin at baseline (42.2% vs. 24.5%). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism and death from any cause (hazard ratio [HR] 0.95, 95% confidence interval [CI] 0.71–1.27, P for interaction = 0.12; HR 0.96, 95% CI 0.81–1.13, P for interaction = 0.28). Rates of myocardial infarction were numerically lower with apixaban than warfarin among patients with and without prior CAD. The effect of apixaban on reducing major bleeding and intracranial hemorrhage was consistent in patients with and without CAD. Conclusions: In patients with AF, apixaban more often prevented stroke or systemic embolism and death and caused less bleeding than warfarin, regardless of the presence of prior CAD. Given the common occurrence of AF and CAD and the higher rates of cardiovascular events and death, our results indicate that apixaban may be a better treatment option than warfarin for these high-risk patients. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Atrial fibrillation (AF) is the most common cardiac arrhythmia in clinical practice and is associated with significant morbidity and mortality [1–5]. Patients with AF have reduced quality of life, a higher risk of developing heart failure, cognitive impairment, and approximately ☆ Funding sources: ARISTOTLE was supported by Bristol-Myers Squibb and Pfizer. ☆☆ Potential conflicts of interest: Please see Disclosures section. ⁎ Corresponding author at: Duke Clinical Research Institute, Room 0311 Terrace Level, 2400 Pratt Street, Durham, NC 27705, USA. Tel.: +1 919 668 8241; fax: +1 919 668 7056. E-mail address: [email protected] (R.D. Lopes). 1 These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. 0167-5273/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2013.10.062
one-third have a history of coronary artery disease (CAD) [6]. The estimated prevalence of AF in a large international cohort is 12.5% in patients with CAD [7]. In addition, patients with both AF and CAD are at an increased risk for ischemic events and cardiovascular death [7]. Oral anticoagulation with warfarin, a vitamin K antagonist, is known to reduce stroke in patients with AF [8] and also to reduce stroke and mortality in patients with AF following myocardial infarction (MI) [9,10]. Recently, 3 pivotal trials have demonstrated benefits of the new oral anticoagulants dabigatran [11,12], rivaroxaban [13,14], and apixaban [15,16] compared with warfarin in patients with AF and an increased risk of stroke. A recent subgroup analysis of the RE-LY study showed that the beneficial effects of dabigatran over warfarin were similar in AF patients with and without prior CAD [17], although there
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was a higher rate of MI with dabigatran compared with warfarin in the trial [12]. In contrast, there was no difference in the rate of MI when comparing apixaban with warfarin in the ARISTOTLE trial or with aspirin in the AVERROES trial [18]. When comparing the 5 mg twice daily dose of apixaban with placebo in patients on antiplatelet agents after an acute coronary syndrome in the prematurely terminated APPRAISE-2 trial, there was no significant reduction in ischemic events [19]. This finding is in contrast to the reduction with low doses of rivaroxaban in the ATLAS-2 trial [20]. However, in both trials there was a 2–3 times increase in major bleeding when adding the factor Xa inhibitors to antiplatelet treatment in patients with CAD. Thus, the usefulness of novel oral anticoagulants in patients with AF and CAD needs further definition. In the ARISTOTLE [16] trial, 18,201 patients with AF and at least 1 additional risk factor for stroke were randomized to apixaban or doseadjusted warfarin. In the apixaban group there was a 21% relative reduction in the rate of the primary outcome (stroke or systemic embolism), 31% in major bleeding, and 11% in death from any cause. In this pre-specified subgroup analysis, we evaluated the treatment effects of apixaban compared with warfarin in patients with and without prior CAD. 2. Methods 2.1. Study population The design and results of the ARISTOTLE trial have been reported [15,16]. Briefly, 18,201 patients with AF or atrial flutter were randomly assigned to receive apixaban or dose-adjusted warfarin. The dose of apixaban (or matching placebo) was 5 mg twice daily or 2.5 mg twice daily for patients with 2 or more of the following factors: age ≥80 years, body weight ≤60 kg, and serum creatinine ≥1.5 mg/dL (133 μmol/L). Patients were enrolled in 39 countries between 2006 and 2010. The median duration of follow-up was 1.8 years. Patients taking concomitant aspirin (≤165 mg/day) were eligible, but patients taking dual antiplatelet therapy with aspirin plus clopidogrel were not. The ARISTOTLE trial complied with the Declaration of Helsinki. All patients enrolled provided written informed consent, and the trial was approved by the institutional review boards and ethics committees of participating sites. 2.2. Coronary artery disease CAD was defined as documented CAD, history of MI, and/or history of coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery) at randomization. Classification was used as recorded on the case report form (CRF), and no attempt to adjudicate these classifications was undertaken. Patients with missing data on the above-mentioned CRF check box were excluded.
an exploratory analysis to determine whether the treatment effect of apixaban versus warfarin in patients with CAD was consistent among patients taking and not taking aspirin at baseline, including the effect on MI. In all analyses, a P value b0.05 was considered statistically significant. All statistical analyses were performed with SAS software version 9.22 (SAS Institute, Inc., Cary, NC, USA).
3. Results 3.1. Baseline characteristics Of the 18,201 patients included in the ARISTOTLE study, excluding the 17 with missing data on CAD, 6639 (36.5%) had prior CAD. Of those, 2585 (38.9%) had prior MI, 1206 (18.2%) had prior CABG, and 1651 (24.9%) had prior PCI. Of patients with a history of PCI, 694 had a bare-metal stent and 388 received a drug-eluting stent. Baseline characteristics are shown in Table 1. Patients with prior CAD were more often male, and more commonly had prior peripheral arterial disease (PAD) and paroxysmal AF. Prior stroke, transient ischemic attack, or systemic embolism, and heart failure, reduced left ventricular ejection fraction (LVEF), diabetes, and hypertension were also more prevalent in patients with prior CAD. Accordingly, patients with prior CAD had higher CHADS2 scores, with a score of 3 or more in 36.7% compared with 26.5% in those without prior CAD. 3.2. Medications At baseline, patients with prior CAD were more likely to be on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and statins compared with patients with no CAD (Table 1). Aspirin use at randomization was 42.2% in patients with prior CAD compared with 24.5% in those without prior CAD. During the follow-up period and in the group of patients with prior CAD, study drug discontinuation rates, excluding discontinuation due to death, per 100 patient-years of follow-up were 14.4 for apixaban and 15.2 for warfarin (P = 0.32). For patients without prior CAD, the rates were 11.4 in the apixaban group and 13.1 in the warfarin group (P = 0.0008). In the warfarin group, the median time in the target range of the international normalized ratio was 65.2% in patients with prior CAD and 66.4% in patients without prior CAD (P = 0.0013). 3.3. Outcomes
2.3. Study outcomes The primary efficacy outcome was stroke or systemic embolism. The key secondary efficacy outcome was death from any cause. Additional outcomes were MI and coronary revascularization. The primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) criteria [21]. A clinical event committee, whose members were not aware of study group assignments, adjudicated the primary and secondary efficacy and safety outcomes on the basis of pre-specified criteria. 2.4. Statistical analysis Baseline characteristics of patients with and without history of CAD are presented as medians with 25th and 75th percentiles for continuous variables and frequencies and percentages for categorical variables. Both groups are compared using Wilcoxon tests for continuous variables and chi-square tests for categorical variables. Events during followup are summarized as event rates per 100 patient-years of follow-up. Hazard ratios (HRs) along with 95% confidence intervals (CIs) comparing randomized treatments are derived from Cox regression models. The interaction between randomized treatment and CAD status was tested in a Cox model that included the main effects for treatment and CAD and their interaction. The probability of primary efficacy and safety endpoints are presented as Kaplan–Meier curves. The proportional hazard assumption was tested using methods based on cumulative sums of martingale residuals [22]. The proportional hazard assumption was valid for all the endpoints presented except for death from any cause in patients with prior CAD. Results for that endpoint represent an average HR and should be interpreted cautiously. Although it is recommended in the guidelines to avoid aspirin with warfarin for patients with AF and stable coronary disease, it is unknown whether novel oral anticoagulants alone are sufficient for patients with AF and chronic CAD. We performed
3.3.1. Prior CAD versus no CAD Compared with patients without a history of CAD, patients with prior CAD were more likely to die from any cause (4.30 vs. 3.39% per 100 patient-years, P b 0.0001) (Table 2). The rate of stroke or systemic embolism was similar (1.51 vs. 1.39% per 100 patient-years, P = 0.3666). In the prior CAD subgroup, the rate of MI was 3-fold higher than in patients without prior CAD (0.97 vs. 0.34% per 100 patientyears; P b 0.0001). Patients with and without prior CAD had similar rates of ISTH major bleeding (2.72 vs. 2.54% per 100 patient-years, respectively; P=0.3638). There were, however, numerically fewer intracranial hemorrhages in patients with prior CAD compared with patients without prior CAD. 3.3.2. Apixaban versus warfarin according to CAD status The absolute reductions in stroke or systemic embolism with apixaban were 0.48 per 100 patient-years in patients without prior CAD and 0.08 in patients with prior CAD. Treatment with apixaban was associated with a reduced rate of stroke or systemic embolism, death from any cause, and MI in both patients with prior CAD and those without prior CAD (P for interaction = 0.12, 0.28, and 0.45, respectively). Coronary revascularization including PCI and CABG during follow-up was 2- to 3-fold more common in patients with prior CAD. However, the treatment effect of apixaban on revascularization
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Table 1 Baseline characteristics according to CAD status.
Age, median (25th, 75th), years Female sex Region North America Latin America Europe Asia Pacific Systolic BP, median (25th, 75th), mm Hg Weight, median (25th, 75th), kg PAD, no. (%) Prior clinically relevant or spontaneous bleeding History of fall within previous year Bare-metal stent Drug-eluting stent Prior CABG Type of AF Paroxysmal Persistent or permanent Prior VKA use (N30 days) Qualifying risk factors Age ≥75 years Prior stroke, TIA, or systemic embolism HF or reduced LVEF Diabetes Hypertension requiring treatment CHADS2, mean (SD) CHADS2 score ≤1 2 ≥3 Medications at time of randomization ACE inhibitor or ARB Amiodarone Beta-blocker Aspirin Clopidogrel Digoxin Calcium blocker Statin Nonsteroidal antiinflammatory agent Gastric antacid drugs Renal function Normal (80 mL/min) Mild impairment (N50–80 mL/min) Moderate impairment (N30–50 mL/min) Severe impairment (≤30 mL/min)
No CAD (N = 11,545)
CAD (N = 6639)
P valuea
70 (62, 76) 4433 (38.4%)
70 (63, 76) 1976 (29.8%)
0.0035 b0.0001 b0.0001
2587 (22.4%) 2912 (25.2%) 3962 (34.3%) 2084 (18.1%) 130 (120, 140) 81 (68, 95) 329 (2.9%) 1861 (16.1%) 457 (4.4%) – – –
1887 (28.4%) 551 (8.3%) 3374 (50.8%) 827 (12.5%) 130 (120, 140) 84 (73, 97) 555 (8.4%) 1178 (17.7%) 296 (4.8%) 694 (10.5%) 388 (5.8%) 1206 (18.2%)
1587 (13.7%) 9958 (86.3%) 6748 (58.4%)
1197 (18.0%) 5439 (82.0%) 3644 (54.9%)
3641 (31.5%) 2114 (18.3%) 3280 (28.4%) 2602 (22.5%) 9912 (85.9%) 2.0 (1.1)
2032 (30.6%) 1420 (21.4%) 3166 (47.7%) 1941 (29.2%) 5991 (90.2%) 2.3 (1.2)
4475 (38.8%) 4009 (34.7%) 3061 (26.5%)
1701 (25.6%) 2502 (37.7%) 2436 (36.7%)
7747 (68.3%) 1221 (10.8%) 6782 (59.8%) 2826 (24.5%) 112 (1.0%) 3703 (32.6%) 3625 (32.0%) 3649 (32.2%) 1017 (9.0%) 2069 (18.2%)
5074 (77.5%) 826 (12.6%) 4689 (71.6%) 2801 (42.2%) 225 (3.4%) 2118 (32.3%) 1940 (29.6%) 3819 (58.3%) 503 (7.7%) 1279 (19.5%)
4856 (42.3%) 4710 (41.0%) 1760 (15.3%) 163 (1.4%)
2657 (40.1%) 2872 (43.4%) 983 (14.9%) 106 (1.6%)
0.0620 b0.0001 b0.0001 0.0047 0.2686 – – – b0.0001
b0.0001 b0.0001 b0.0001 b0.0001 b0.0001 b.0001 b0.0001 b0.0001
b0.0001 0.0002 b0.0001 b0.0001 b0.0001 0.6858 0.0012 b0.0001 0.0030 0.0323 0.0078
Values presented as number (%), unless otherwise indicated. ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; BP, blood pressure; CAD, coronary artery disease; HF, heart failure; LVEF, left ventricular ejection fraction; PAD, peripheral artery disease; SD, standard deviation; TIA, transient ischemic attack; VKA, vitamin K antagonist. a P value compares patients with CAD vs. patients without CAD.
was similar in patients with prior CAD and those without prior CAD (P for interaction = 0.47). The effects of apixaban were similar among patients with and without prior CAD on reducing stroke or systemic embolism (HR 0.95, 95% CI 0.71–1.27 vs. HR 0.70, 95% CI 0.56–0.89, P for interaction = 0.11) and death from any cause (HR 0.96, 95% CI 0.81–1.13 vs. HR
Table 2 Efficacy and safety outcomes according to CAD status. Endpoint
No prior CAD Events (rate)
Prior CAD Events (rate)
P value
Stroke/systemic embolism Stroke MI All-cause death ISTH major bleeding ICH
292 (1.39) 271 (1.29) 72 (0.34) 730 (3.39) 491 (2.54) 119 (0.61)
185 (1.51) 178 (1.45) 120 (0.97) 541 (4.30) 298 (2.72) 55 (0.49)
0.3666 0.2081 b0.0001 b0.0001 0.3638 0.2018
CAD indicates coronary artery disease; ICH, intracranial hemorrhage; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction.
0.85, 95% CI 0.73–0.98, P for interaction=0.28). There was no significant interaction between the treatment effects and the presence or absence of prior CAD in any of the other efficacy endpoints (Fig. 1). Treatment with apixaban was associated with a reduced risk of ISTH major bleeding and intracranial bleeding, both in patients with and without prior CAD. Treatment effects were consistent in patients with and without prior CAD for ISTH major bleeding (P for interaction = 0.17) and intracranial hemorrhage (P for interaction = 0.59) (Fig. 1). 3.3.3. Assessment of randomized treatment effect with and without baseline aspirin The effect of apixaban compared with warfarin for reducing stroke or systemic embolism in patients with CAD was consistent irrespective of whether they were taking aspirin at baseline (3-way interaction [randomized treatment by aspirin at baseline by CAD status] P = 0.86). Of patients with a history of CAD who were not on aspirin at baseline, 25 of 1916 patients in the apixaban group and 35 of 1922 patients in the warfarin group had MI during follow-up. The effect of the relationship between apixaban and warfarin on the rate of MI in
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Interaction P-Value
CAD
Apixaban
Warfarin
HR (95% CI)
Stroke or systemic embolism
1.15 (121) 1.47 (91)
1.63 (171) 1.55 (94)
0.704 (0.558, 0.889) 0.950 (0.712, 1.267)
0.11
Stroke
1.06 (112) 1.40 (87)
1.52 (159) 1.50 (91)
0.701 (0.550, 0.892) 0.937 (0.699, 1.258)
0.14
Death from any cause
3.11 (335) 4.21 (267)
3.68 (395) 4.40 (274)
0.847 (0.732, 0.979) 0.958 (0.809, 1.133)
0.28
MI
0.29 (31) 0.95 (59)
0.39 (41) 1.00 (61)
0.755 (0.473, 1.203) 0.947 (0.662, 1.354)
0.45
0.70 (74) 1.69 (104)
0.67 (71) 1.89 (114)
1.040 (0.751, 1.441) 0.890 (0.682, 1.161)
0.47
1.99 (194) 2.39 (133)
3.12 (297) 3.05 (165)
0.640 (0.534, 0.766) 0.784 (0.624, 0.985)
0.17
0.37 (37) 0.27 (15)
0.85 (82) 0.73 (40)
0.443 (0.301, 0.654) 0.364 (0.201, 0.659)
0.59
Efficacy endpoints:
Revascularization (PCI/CABG) Safety endpoints: ISTH major bleeding Intracranial bleeding
0.1
1
Favor Apixaban
10
Favor Warfarin
Fig. 1. Effect of apixaban vs. warfarin for safety and efficacy outcomes according to CAD status.
patients with CAD was consistent irrespective of baseline aspirin use (3-way interaction [randomized treatment by aspirin at baseline by CAD status] P = 0.86).
4. Discussion In this analysis of the ARISTOTLE study, patients with prior CAD had an increased risk of death and MI and higher aspirin use at baseline than those without prior CAD. The treatment effects of apixaban on stroke or systemic embolism, major bleeding, and death were consistent regardless of the presence of prior CAD. These results remained consistent after adjusting for baseline use of aspirin. Rates of MI were numerically lower in patients assigned to receive apixaban as compared with warfarin, regardless of whether patients had a history of CAD. Patients with AF and CAD are common in clinical practice, comprising approximately 30% of patients in AF registries [6,23] and trials [10], and AF is present in about 12.5% of patients in a registry of patients with CAD [7]. Patients with AF and prior CAD are at high risk for recurrent events and death. The increased risk of cardiovascular events in these patients has also been shown in the REACH registry [7], in which the presence of AF at baseline was associated with higher rates of adverse cardiovascular outcomes at 1-year follow-up after adjustment for other factors. AF is also an independent predictor of adverse events, including mortality, following ACS [9,10]. Warfarin has been shown to be effective in reducing the risk of stroke and other cardiovascular events in patients with AF [24]. Furthermore, in a meta-analysis that included 5938 patients after acute coronary syndromes, warfarin was demonstrated to provide a 44% relative reduction in the rate of MI and a 64% relative decrease in the rate of stroke compared with aspirin [8]. However, warfarin use is also associated with an increased risk of bleeding in both the AF and CAD populations. Another relevant issue is the underutilization of warfarin. Even though warfarin use has increased over time [25], only half of the potentially eligible high-risk patients with AF are being treated with warfarin [7,23,26]. It is noteworthy that in the current trial more patients in the CAD group stopped oral anticoagulation, which was more often seen in the warfarin than the apixaban group. An alternative oral anticoagulant with a better safety profile might be very useful in patients with acute coronary syndromes and AF.
Use of concomitant aspirin among patients with history of CAD was almost 2-fold higher than in patients without CAD in ARISTOTLE. Current guidelines discourage using concomitant antiplatelet therapy in patients with AF receiving warfarin with stable coronary disease [27–29]. In addition, in the open-label WOEST trial [30] that included 573 patients receiving oral anticoagulants and undergoing PCI, clopidogrel without aspirin (dual therapy) was associated with a significant reduction in bleeding and combined secondary endpoint of death, myocardial infarction, stroke, target-vessel revascularization, and stent thrombosis compared with triple therapy (aspirin plus clopidogrel plus oral anticoagulant). Caution should be taken when interpreting these results in light of the limitations of the study including the small sample size and the open-label design. Thus, the role of aspirin with oral anticoagulation, and with novel oral anticoagulants such as apixaban, deserves further evaluation [31]. Based on the current analyses, it appears that the benefits of apixaban are maintained among patients with or without CAD, irrespective of whether they are taking aspirin. The possible benefits of using these new oral anticoagulants in this high-risk patient population have recently been explored. A report from the RE-LY trial [17] has shown that, in patients with prior CAD or MI, the treatment effect of dabigatran over warfarin was consistent with the main trial results. There was no significant interaction between treatment effects and the presence or absence of a history of CAD or MI. However, a recent meta-analysis of randomized dabigatran studies has indicated a higher incidence of MI or acute coronary syndromes in patients treated with this thrombin inhibitor [32]. The results from the ATLAS ACS-2-TIMI-51 trial [33] showed that a low dose of rivaroxaban (2.5 mg twice daily) compared with placebo reduced the primary composite endpoint and the individual endpoint of MI in patients stabilized after STEMI. A recent meta-analysis of randomized trials with dabigatran indicated an increased risk of MI with dabigatran compared with various control treatments [32]. Differences in treatment effect on MI with new oral anticoagulants might be explained by differences in the mechanism of actions [34] or by the use of warfarin as comparator [35]. Lip and Lane [35] conducted a meta-analysis of the occurrence of MI in clinical trials of AF and compared warfarin with other anticoagulants. The authors suggested a protective effect of warfarin against MI; thus, dabigatran might not directly increase the risk of MI but rather may lack the beneficial effects that warfarin
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and aspirin have in preventing MI. In ARISTOTLE, there were nonsignificantly fewer MIs among patients on apixaban than warfarin. Moreover, among patients with prior coronary disease not on aspirin, the rate of MI was numerically lower with apixaban than with warfarin, suggesting that a strategy of avoiding aspirin for stable coronary disease patients on warfarin might also apply to such patients on apixaban. The current results demonstrating that apixaban resulted in lower rates of stroke or systemic embolism, lower all-cause mortality, and less major bleeding than warfarin, regardless of concomitant aspirin use and history of CAD, support its use in a broad population. These results are reinforced by the finding of similar rates of MI during treatment with apixaban versus aspirin in the AVERROES trial [18].
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Granger: Grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck, Sanofi-Aventis, Astellas, and The Medicines Company; consulting fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-LaRoche, Novartis, Otsuka Pharmaceutical, Sanofi-Aventis, and The Medicines Company; support for travel from the Medtronic Foundation and Merck. Wallentin: Grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck; consulting fees from Regado Biosciences, Portola, CSL Behring, Athera Biotechnologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, ScheringPlough, and Merck.
4.1. Limitations This paper has some limitations. First, we have limited data regarding the timing of CAD prior to patient inclusion in the study; thus, we cannot assess the treatment effect in chronic CAD versus more recently active CAD, including recent acute coronary syndromes. We did not analyze details regarding timing of concomitant aspirin therapy, which is the subject of a separate manuscript [29]. Even though the effect on coronary events was not the focus of the main trial, these events were adjudicated; however, there are relatively few events that limit the power to show differences. In addition, the interaction tests have low power, particularly the 3-way interactions. 5. Conclusion In conclusion, in patients with AF, apixaban as compared with warfarin reduces stroke or systemic embolism and death and causes less bleeding regardless of the presence of prior CAD. Given the common occurrence of both AF and CAD and the higher rates of cardiovascular events and death, the current results from ARISTOTLE indicate that apixaban may be a better treatment option than warfarin for these high-risk patients. Disclosures Bahit: Consulting fees/honoraria and research support from BristolMyers Squibb. Lopes: Grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim, and Daiichi Sankyo; consulting fees from Bristol-Myers Squibb. Wojdyla: None. Hohnloser: Consulting fees from Sanofi-Aventis, St. Jude Medical, Boehringer Ingelheim, Cardiome, and Medtronic Vascular; lecture fees from Sanofi-Aventis, Bristol-Myers Squibb, Pfizer, Boehringer Ingelheim, and St. Jude Medical. Alexander: Grants from Merck/Schering-Plough and Regado Biosciences; consulting fees from Merck/Schering-Plough, AstraZeneca, Boehringer Ingelheim, Ortho-McNeil-Janssen, PolyMedix, Regado Biosciences, and Bayer. Lewis: Advisory board member for Bayer HealthCare. Aylward: Research support from AstraZeneca, Merck & Co, Eli Lilly, Bayer/Johnson & Johnson, Sanofi-Aventis, GlaxoSmithKline, and Daiichi Sankyo; consulting/advisory board fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Sanofi-Aventis, and Eli Lilly; and travel support from Bristol-Myers Squibb, AstraZeneca, and Boehringer Ingelheim. Verheugt: Lecture fees from Bayer and AstraZeneca; consulting fees from Bayer and Daiichi Sankyo. Keltai: Support for travel from Bristol-Myers Squibb and Pfizer as a member of the ARISTOTLE Steering Committee. Diaz: Consulting fees, honoraria, and research support from BristolMyers Squibb. Hanna: Employee of Bristol-Myers Squibb.
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