- Email: [email protected]
Systemic, noncerebral, arterial embolism in 21,105 patients with atrial fibrillation randomized to edoxaban or warfarin: Results from the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 trial
Systemic, noncerebral, arterial embolism in 21,105 patients with atrial fibrillation randomized to edoxaban or warfarin: Results from the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 trial Bram J. Geller, MD, a Robert P. Giugliano, MD, SM, b Eugene Braunwald, MD, b Sabina A. Murphy, MPH, b James J. Hanyok, PharmD, c Jianqing Jin, PhD, c Michele Mercuri, MD, PhD, c Elliott M. Antman, MD, b and Christian T. Ruff, MD, MPH b Philadelphia, PA, Boston, MA, and Edison, NJ
Background Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non–vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking. Methods and results We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarincontrolled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01). Conclusion Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin. (Am Heart J 2015;170:669-74.) Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, afflicting 2.2 million Americans. 1-4 Vitamin K antagonists (VKA), such as warfarin, have been shown to reduce the risk of stroke by 60% to 70% compared with placebo. 5 Several new or non–VKA oral anticoagulants (NOACs) that directly inhibit thrombin or
activated factor Xa have been identified to be at least as effective as and safer than warfarin in preventing stroke and systemic embolic events (SEEs) in patients with AF. 6-13 Although there has been substantial investigation characterizing the types and severity of strokes in these trials as well as the comparative efficacy and safety of
From the aUniversity of Pennsylvania Health System, Philadelphia, PA, bBrigham and Women's Hospital and Harvard Medical School, Boston, MA, and cDaiichi-Sankyo Pharma Development, Edison, NJ. Conflict of interest: In addition to study support provided by Daiichi Sankyo Pharma Division for conducting the ENGAGE AF-TIMI 48 trial, the TIMI Study Group has received research grant support from Abbott, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, BG Medicine,
AstraZeneca, Merck & Co, and GlaxoSmithKline. He also reports serving as an unpaid consultant
BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Eli Lilly and Co, GlaxoSmithKline, Johnson & Johnson, Merck and Co, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. Dr Geller, none to report. Dr Giugliano, reports receiving consulting fees from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Pfizer, Portola, and Sanofi; and grant support to his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Braunwald, reports receiving consulting fees from The Medicines Company; lecture fees from
and grant support through his institution from Daiichi Sankyo, Astra Zeneca, Eisai, and Intarcia. Submitted April 3, 2015; accepted June 21, 2015. Reprint requests: Christian T. Ruff, MD, MPH, TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Ave, First Floor, Boston, MA 02115. E-mail: [email protected] 0002-8703 © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2015.06.020
Menarini and Medscape; and grant support through his institution from Daiichi Sankyo,
for Merck and Novartis and providing uncompensated lectures for Merck & Co. Ms Murphy, reports receiving grant support through her institution from Daiichi Sankyo. Dr Hanyok, employed at Daiichi Sankyo. Dr Jin, employed at Daiichi Sankyo. Dr Mercuri, employed at Daiichi Sankyo. Dr Antman, reports receiving grant support through his institution from Daiichi Sankyo. Dr Ruff, reports receiving consulting fees from Bayer, Daiichi Sankyo, Portola, and Boehringer Ingelheim
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Table I. Comparison of clinical characteristics in patients with systemic embolism versus stroke versus neither (first event only) Characteristic Age, y, median (25th,75th) Male sex, n (%) Region, n (%) North American Latin American Western Europe Eastern Europe Asia, Japan, and South Africa Type of AF, n (%) Paroxysmal Persistent Permanent CHA2DS2-VASc risk factors, n (%) Congestive heart failure Hypertension Age ≥75 y Diabetes mellitus Prior stroke or transient ischemic attack Vascular disease Age 65-74 years CHA2DS2-VASc score (mean) History of PAD (%) Current smoker Dose reduction at randomization, n (%) Creatinine clearance ≤50 mL/min Weight ≤60 kg Use of verapamil or quinidine VKA naive, n (%) Medication at time of randomization, n (%) Aspirin Thienopyridine Amiodarone Digoxin or digitalis preparation
Systemic embolism (n = 60)
Stroke (n = 956)
Neither (n = 20,089)
78 (71, 82) 32 (53.3)
74 (67, 79) 548 (57.3)
72 (64, 77) 12,485 (62.1)
10 11 10 18 11
(16.7) (18.3) (16.7) (30.0) (18.3)
181 124 140 324 187
(18.9) (13.0) (14.6) (33.9) (19.6)
4490 2526 3086 6802 3185
210 (22.0) 225 (23.5) 521 (54.5)
5150 (25.6) 4632 (23.1) 10,301 (51.3)
36 (60.0) 57 (95) 38 (63.3) 19 (31.7) 21 (35.0) 23 (38.3) 15 (25.0) 4.9 ± 1.3 9 (15.0) 5 (8.3) 29 (48.3) 25 (41.7) 14 (23.3) 0 (0.0) 12 (20.0)
530 (55.4) 876 (91.6) 459 (48.0) 310 (32.4) 414 (43.3) 378 (39.5) 316 (33.1) 4.8 ± 1.4 27 (2.8) 77 (8.1) 340 (35.6) 258 (27.0) 141 (14.7) 45 (4.7) 409 (42.8)
11,558 (57.5) 18,821 (93.7) 7977 (39.7) 7295 (36.3) 5538 (27.6) 7445 (37.1) 6803 (33.9) 4.3 ± 1.4 805 (4.0) 1470 (7.3) 4987 (24.8) 3791 (18.9) 1928 (9.6) 716 (3.6) 8242 (41.0)
16 0 4 24
297 32 91 293
(31.1) (3.3) (9.5) (30.6)
5867 455 2397 6010
P (stroke vs SEE)
b.001 .004 .04
.005 .55 .77
.001
.02
.41 .04 b.001 .04 b.001 .30 b.001 b.001 b.001 .67 b.001 b.001 b.001 .06 .002
.49 .36 .02 .90 .21 .85 .07 .38 b.001 .94 .05 .01 .07 .09 b.001
.42 .05 .04 .21
.47 .15 .46 .13
(22.4) (12.6) (15.4) (33.9) (15.9)
6 (10.0) 11 (18.3) 43 (71.7)
(26.7) (0.0) (6.7) (40.0)
3-way P
(29.2) (2.3) (11.9) (29.9)
Abbreviations: CHA2DS2-VASc, Congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, stroke/transient ischemic attack (2 points), vascular disease, age 65 to 74 years, sex category; PAD, peripheral arterial disease. This table includes participants with SEE as a first event and therefore does not include all participants with SEEs.
NOACs compared with warfarin in reducing stroke, there are limited data characterizing the risk and clinical consequences of SEE, which comprise 5% to 10% of all arterial thromboembolic events. 6-10,14-18 The aim of this study was to investigate the incidence, risk factors, location, and severity of SEE in the ENGAGE AF-TIMI 48 trial as well as assess the relative efficacy and safety of edoxaban and the NOACs as a class in preventing them.
Methods Study design The ENGAGE AF-TIMI 48 design and primary results have been reported previously. 9,19 The study was a multicenter, randomized, double-blind, double-dummy trial comparing 2 once-daily regimens of edoxaban (higher and lower dose regimens) with warfarin. A total of 21,105 were enrolled and followed up for a median of 2.8 years. Eligible patients were ≥21 years of age with AF documented on an electrical tracing within 12 months, a congestive heart failure, hypertension, age
≥75 years, diabetes mellitus, stroke/transient ischemic attach (2 points) risk score ≥2, and anticoagulation planned for the duration of the trial.
Outcomes The primary efficacy end point was the time to the first SEE, a component of the composite end point in the ENGAGE AF-TIMI 48 trial of stroke (ischemic or hemorrhagic) or SEE. An SEE was defined as an abrupt episode of arterial insufficiency associated with either clinical or radiographic evidence of arterial occlusion that occurred in the absence of other likely mechanisms that included atherosclerosis or instrumentation. Arterial embolic events to the central nervous system (including the eye), coronary, and pulmonary arterial circulation were classified as stroke/transient ischemic attack, myocardial infarction, and pulmonary embolism, respectively, rather than SEE. In patients with atherosclerotic peripheral vascular disease, the diagnosis of a systemic embolism to the lower extremities required arteriographic evidence of abrupt arterial occlusion. 19 An independent
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Figure 1
Abdominal/ mesenteric 10%
Renal 4%
Other 1%
Upper Extremity 15%
Outcomes were then pooled and compared with a fixed-effects model. 21 We assessed the appropriateness of pooling data across studies with the use of the Cochran Q statistics and I 2 test for heterogeneity. 22 A 2-sided P value b.05 was considered statistically significant. Statistical analyses were performed using Stata (version 12.1; Stata, College Station, TX). The ENGAGE AF-TIMI 48 trial was funded by Daiichi Sankyo Pharma Development. The TIMI Study Group had access to all the data, performed all analyses, and had final responsibility for the decision to submit for publication.
Results Lower Extremity 70%
Location of SEEs (includes multiple events).
clinical end point events committee, blinded to the study drug assignment, adjudicated all end points.
Statistical analysis All analyses were performed on the intention-to-treat population from randomization until the end of the treatment period. Descriptive statistics of baseline characteristics were given as numbers and percentages, medians with 25th and 75th percentiles, or means with SDs. Baseline characteristics were compared using the χ 2 test for categorical variables or Kruskal-Wallis test for continuous variables. Event rates were expressed per 100 patient years. Hazard ratios (HRs) for edoxaban and warfarin with 95% CIs were determined using Cox proportional hazards model with treatment as the only covariate. A multivariable Cox proportional hazards model was used to identify independent predictors of SEE. Data for the meta-analysis were obtained from the main trial publications of the 4 phase 3 trials comparing a NOAC versus warfarin for stroke prevention in patients with AF (RE-LY, dabigatran; ROCKET AF, rivaroxaban; ARISTOTLE, apixaban; and ENGAGE AF-TIMI 48, edoxaban). 6-9,20 In the RE-LY and ENGAGE AF-TIMI 48 trials, 2 doses of dabigatran and edoxaban, respectively, were compared with warfarin. Rather than including data with both doses, which would merge the benefit and risk of different doses, thereby compromising interpretability, we used the higher dose dabigatran and edoxaban regimens, as they are the doses that are universally approved. The intention-to-treat population was analyzed for all trials except for ROCKET AF where only the on-treatment population was reported. We calculated the relative risk (RR) and 95% CIs for each trial separately.
The baseline characteristics of patients in the ENGAGE AF-TIMI 48 trial have been previously reported. 9 Of the 1,016 patients in the ENGAGE AF-TIMI 48 trial who experienced a primary end point, 949 (93.4%) had a stroke, 58 (5.7%) experienced an SEE, and 9 (0.9%) had both. Patients who experienced an SEE compared with those who had a stroke tended to be older (median 78 vs 74 years; P = .005) and were more likely to have permanent AF (72% vs 55%; P = .02), moderate renal impairment (creatinine clearance ≤50 mL/min; 42% vs 27%; P = .01), and more often VKA experienced (80% vs 57%; P b .001) (Table I). In a multivariable model, independent predictors of SEE included decreased creatinine clearance (HR per 10 mL/min decrease 1.30; 95% CI 1.12-1.50; P b .001), permanent AF (HR 2.97; 95% CI 1.33-6.63; P = .008), and VKA experience (HR 1.86; 95% CI 1.04-3.30; P = .04).
Location and severity of SEEs There were 73 total SEE (includes 6 recurrent events). Most SEEs were in the extremities (n = 62; 85%) (Figure 1). Of these, 82% were lodged in the lower extremities. Additional locations included the abdomen (9.6%), renal (4.1%), and other (1.4%) arteries. There were 9 fatal SEEs (13%). In addition, 52% of nonfatal SEEs and 41% of all SEEs (n = 30) required a surgical or percutaneous intervention to restore blood flow (Figure 2). Of the 41% of all SEEs requiring a procedure, 12% (n = 9) had surgery (of which 3 were amputations), 12% (n = 9) had a percutaneous intervention, and 16% (n = 12) had an embolectomy. Relative efficacy of edoxaban compared with warfarin In the warfarin group, the median time in the therapeutic range was 68.4% (interquartile range 56.5-77.4). There were 23 (0.12%/year) SEEs in the warfarin group compared with 15 in the higher dose edoxaban group (0.08%/year; HR 0.65; 95% CI 0.34-1.24; P = .19) and 29 in the lower dose edoxaban group (0.15%/year; HR 1.24; 95% CI 0.72-2.15; P = .43) (Table II). Higher dose edoxaban resulted in significantly fewer SEEs than lower dose edoxaban (HR 0.52; 95% CI 0.28-0.97;
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Figure 2
Management of patients with SEEs (includes multiple events).
Table II. Thromboembolic end points by study group (all events) Warfarin (n = 7036)
End point Primary end point in the intentionto-treat population Stroke Fatal Nonfatal SEE Fatal Nonfatal
Higher dose edoxaban (n = 7035)
Higher dose edoxaban vs warfarin
No. of patients with event
% of patients/ year
No. of patients with event
% of patients/ year
HR (95% CI)
337
1.80
296
1.57
317 86 245 23 4 19
1.69 0.45 1.31 0.12 0.02 0.10
281 80 207 15 0 15
1.49 0.42 1.10 0.08 0.00 0.08
P = .04). In the warfarin group, 4 (17%) SEEs were fatal compared with no fatal events in the higher dose edoxaban group and 5 (17%) fatal SEEs with lower dose edoxaban.
Meta-analysis of NOACs compared with warfarin In a meta-analysis of the 4 phase 3 trials comparing NOACs with warfarin, there were 29,292 patients who received a NOAC and 29,221 who received warfarin. There was a significant 37% reduction in SEEs with NOACs (n = 47) compared with warfarin (n = 78) (RR 0.63; 95% CI 0.43-0.91; P = .01) (Figure 3).
Lower dose edoxaban (n = 7034)
Lower dose edoxaban vs warfarin
P
No. of patients with event
% of patients/ year
HR (95% CI)
P
0.87 (0.74-1.02)
.08
383
2.04
1.13 (0.97-1.31)
.11
0.88 0.92 0.84 0.65
(0.75-1.03) (0.68-1.25) (0.70-1.01) (0.34-1.24)
.11 .62 .06 .19
0.78 (0.40-1.54)
.48
360 73 293 29 5 24
1.91 0.38 1.56 0.15 0.03 0.13
1.13 0.84 1.19 1.24 1.23 1.25
.12 .27 .05 .43 .76 .47
(0.97-1.31) (0.61-1.15) (1.00-1.41) (0.72-2.15) (0.33-4.58) (0.68-2.28)
Discussion Prior studies have shown that up to 10% of arterial thromboembolic complications in AF patients are due to SEEs. 6-10,14-18 Data from the ENGAGE AF-TIMI 48 trial support a similar proportion of SEE (6.6%) compared with stroke in a contemporary population of AF patients. Although the percentage of SEEs is likely an underestimate of the total thromboembolic burden, as an arterial embolus to the brain is more likely to be clinically evident and therefore diagnosed due to limited collaterals in the brain, whereas a similar size thrombus to arteries of the extremities, kidneys, or mesentery may be asymptomatic.
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Figure 3
Meta-analysis of the 4 phase 3 trials comparing a NOAC versus warfarin for prevention of SEE. Data are n/N unless otherwise indicated. Heterogeneity, I2 = 43.4%; P = .01. ⁎Dabigatran, 150 mg twice daily. †Rivaroxaban, 20 mg once daily. ‡Apixaban, 5 mg twice daily. §Edoxaban, 60 mg once daily.
With regard to SEE location, we found in ENGAGE AF-TIMI 48 that 85% of clinically significant SEEs involved the extremities, which are similar to the 60% to 85% that had been reported previously. 18,23 These data are the first to examine the severity and treatment of SEEs. Fatal SEEs accounted for 13% of the total, and, among nonfatal SEEs, there was a high degree of morbidity. Of all patients with a nonfatal SEE, 52% required some kind of invasive procedure including thromboembolectomy, bypass, or amputation. Anticoagulation with warfarin has been shown to be effective in reducing SEE. In a meta-analysis of 11,756 patients with AF treated with warfarin or aspirin, warfarin reduced SEE by 50% compared with aspirin (odds ratio [OR] 0.50; 95% CI 0.33-0.75; P b .001). 16 In the 6,706 participants in the ACTIVE W, warfarin was superior to aspirin plus clopidogrel for the prevention of SEE (OR 0.22; 95% CI 0.07-0.65; P = .006). 24 The relative efficacy of the NOACs for reducing SEE has not been firmly established, as the individual trials were relatively underpowered for this less frequent component of the primary composite end point of all-cause stroke or SEE. A prior meta-analysis that did not include data from the ENGAGE AF-TIMI 48 trial observed similar efficacy in SEE prevention with NOACs compared with warfarin (OR 0.85; 95% CI 0.39-1.84). 14 With the addition of data from the ENGAGE AF-TIMI 48, the most recent, largest, and longest of the phase 3 trials (21,105 patients followed up for an average of 2.8 years) comparing a NOAC with warfarin, our updated meta-analysis now demonstrates a significant 37% reduction in SEE with NOACs compared with warfarin (RR 0.63; 95% CI 0.43-0.91; P = .01). Interestingly, the 37% reduction in SEE with NOACs compared with warfarin is substantially greater than the nonsignificant 8% reduction observed for ischemic stroke in a meta-analysis that was performed with the same trials. 13 The reason for a differential efficacy of NOACs compared with warfarin with respect to these outcomes is unclear and may reflect chance. Another possibility is that the adjudication of SEE captured truly “cardioembolic” events in which
anticoagulation is very effective in preventing, whereas ischemic strokes represent a mixture of cardioembolic and locally thrombotic events. Non–VKA oral anticoagulants may be better at preventing thromboembolic events compared with warfarin, whereas there may be less advantage for NOACs over warfarin for the prevention of local ischemic/atherosclerotic events.
Limitations This study was performed in a clinical trial population, and the results may not be generalizable to a standard clinical practice setting where the ascertainment of SEEs may differ. In addition, only SEEs that manifested in clinical signs or symptoms were included in this analysis, and our results therefore likely underestimate the true number of SEEs that occurred. The relative low frequency of events in any 1 trial results in wide CIs; however, our meta-analysis pooling data from 4 trials provides more precision regarding the treatment benefit of NOACs as compared with warfarin. The meta-analysis does show moderate statistical heterogeneity, which could be secondary to differences across trials or between drugs. However, some heterogeneity is not unexpected given the small numbers of SEEs, and, therefore, this does not necessarily challenge the validity of the analysis. 25
Conclusion In the ENGAGE AF-TIMI 48 trial, systemic emboli were much less frequent than stroke in patients with AF but were associated with significant morbidity and mortality. Most SEEs involved the extremities, and these events often required surgical or percutaneous intervention. Edoxaban was similar to warfarin in preventing SEE, but a meta-analysis including all 4 phase 3 trials of approved NOACs found that they further reduced the risk of SEE by 37% compared with warfarin.
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References 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006;114:e257-354. 2. Prystowsky EN. The history of atrial fibrillation: the last 100 years. J Cardiovasc Electrophysiol 2008;19:575-82. 3. Heeringa J, van der Kuip DA, Hofman A, et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27:949-53. 4. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: National implications for rhythm management and stroke prevention: The anticoagulation and risk factors in atrial fibrillation (atria) study. JAMA 2001;285:2370-5. 5. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-67. 6. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361: 1139-51. 7. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883-91. 8. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365: 981-92. 9. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013;369:2093-104. 10. Bruins Slot KM, Berge E. Factor Xa inhibitors versus vitamin k antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database Syst Rev 2013;8: CD008980. 11. Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003;362:1691-8. 12. Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005;293:690-8.
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13. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955-62. 14. Andersen LV, Lip GY, Lindholt JS, et al. Upper limb arterial thromboembolism: a systematic review on incidence, risk factors, and prognosis, including a meta-analysis of risk-modifying drugs. J Thromb Haemost 2013;11:836-44. 15. Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011;364:806-17. 16. Andersen LV, Vestergaard P, Deichgraeber P, et al. Warfarin for the prevention of systemic embolism in patients with non-valvular atrial fibrillation: a meta-analysis. Heart 2008;94:1607-13. 17. Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study. Circulation 2005;112:1687-91. 18. Frost L, Engholm G, Johnsen S, et al. Incident thromboembolism in the aorta and the renal, mesenteric, pelvic, and extremity arteries after discharge from the hospital with a diagnosis of atrial fibrillation. Arch Intern Med 2001;161:272-6. 19. Ruff CT, Giugliano RP, Antman EM, et al. Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: design and rationale for the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction Study 48 (ENGAGE AF-TIMI 48). Am Heart J 2010;160:635-41. 20. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Newly identified events in the RE-LY trial. N Engl J Med 2010;363:1875-6. 21. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48. 22. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60. 23. McBane RD, Hodge DO, Wysokinski WE. Clinical and echocardiographic measures governing thromboembolism destination in atrial fibrillation. Thromb Haemost 2008;99:951-5. 24. Connolly S, Pogue J, Hart R, et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367: 1903-12. 25. Cleophas TJ, Zwinderman AH. Meta-analysis. Circulation 2007;115: 2870-5.
Background Atrial fibrillation (AF) is a major risk factor for stroke and systemic embolism. Trials comparing warfarin with non–vitamin K oral anticoagulants (NOACs) have demonstrated that, when compared with warfarin, the NOACs are at least as effective in preventing stroke, although detailed analyses characterizing systemic embolic events (SEEs) are lacking. Methods and results We performed a prespecified analysis in 21,105 patients with AF enrolled in the ENGAGE AF-TIMI 48 trial, which compared 2 once-daily regimens of edoxaban with warfarin for the prevention of stroke and SEE. Of 1,016 patients who met the primary end point, 67 (6.6%) experienced an SEE of which 13% were fatal. Of 73 total SEEs (including recurrent events), 85% involved the extremities, and 41% required a surgical or percutaneous intervention. There were 23 (0.12%/year) SEEs with warfarin versus 15 with higher dose edoxaban (0.08%/year; hazard ratio vs warfarin 0.65; 95% CI 0.34-1.24; P = .19) and 29 with lower dose edoxaban (0.15%/year; hazard ratio vs warfarin 1.24; 95% CI 0.72-2.15; P = .43). In a meta-analysis of 4 warfarincontrolled phase 3 AF trials, NOACs significantly reduced the risk of SEE by 37% (relative risk 0.63; 95% CI 0.43-0.91; P = .01). Conclusion Although considerably less frequent than stroke, systemic embolism is associated with significant morbidity and mortality in patients with AF. Although the overall number of events was too small to show a significant difference in the risk of SEE between edoxaban and warfarin, a meta-analysis of all the NOAC trials demonstrates that NOACs significantly reduce the risk of SEE compared with warfarin. (Am Heart J 2015;170:669-74.) Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia, afflicting 2.2 million Americans. 1-4 Vitamin K antagonists (VKA), such as warfarin, have been shown to reduce the risk of stroke by 60% to 70% compared with placebo. 5 Several new or non–VKA oral anticoagulants (NOACs) that directly inhibit thrombin or
activated factor Xa have been identified to be at least as effective as and safer than warfarin in preventing stroke and systemic embolic events (SEEs) in patients with AF. 6-13 Although there has been substantial investigation characterizing the types and severity of strokes in these trials as well as the comparative efficacy and safety of
From the aUniversity of Pennsylvania Health System, Philadelphia, PA, bBrigham and Women's Hospital and Harvard Medical School, Boston, MA, and cDaiichi-Sankyo Pharma Development, Edison, NJ. Conflict of interest: In addition to study support provided by Daiichi Sankyo Pharma Division for conducting the ENGAGE AF-TIMI 48 trial, the TIMI Study Group has received research grant support from Abbott, Amgen, AstraZeneca, Bayer Healthcare, Beckman Coulter, BG Medicine,
AstraZeneca, Merck & Co, and GlaxoSmithKline. He also reports serving as an unpaid consultant
BRAHMS, Bristol-Myers Squibb, Buhlmann, Critical Diagnostics, CV Therapeutics, Eli Lilly and Co, GlaxoSmithKline, Johnson & Johnson, Merck and Co, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex. Dr Geller, none to report. Dr Giugliano, reports receiving consulting fees from Bristol-Myers Squibb, Janssen, Daiichi Sankyo, Merck, Pfizer, Portola, and Sanofi; and grant support to his institution from Daiichi Sankyo, Merck, Johnson & Johnson, Sanofi, and AstraZeneca. Dr Braunwald, reports receiving consulting fees from The Medicines Company; lecture fees from
and grant support through his institution from Daiichi Sankyo, Astra Zeneca, Eisai, and Intarcia. Submitted April 3, 2015; accepted June 21, 2015. Reprint requests: Christian T. Ruff, MD, MPH, TIMI Study Group, Brigham and Women's Hospital, 350 Longwood Ave, First Floor, Boston, MA 02115. E-mail: [email protected] 0002-8703 © 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2015.06.020
Menarini and Medscape; and grant support through his institution from Daiichi Sankyo,
for Merck and Novartis and providing uncompensated lectures for Merck & Co. Ms Murphy, reports receiving grant support through her institution from Daiichi Sankyo. Dr Hanyok, employed at Daiichi Sankyo. Dr Jin, employed at Daiichi Sankyo. Dr Mercuri, employed at Daiichi Sankyo. Dr Antman, reports receiving grant support through his institution from Daiichi Sankyo. Dr Ruff, reports receiving consulting fees from Bayer, Daiichi Sankyo, Portola, and Boehringer Ingelheim
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Table I. Comparison of clinical characteristics in patients with systemic embolism versus stroke versus neither (first event only) Characteristic Age, y, median (25th,75th) Male sex, n (%) Region, n (%) North American Latin American Western Europe Eastern Europe Asia, Japan, and South Africa Type of AF, n (%) Paroxysmal Persistent Permanent CHA2DS2-VASc risk factors, n (%) Congestive heart failure Hypertension Age ≥75 y Diabetes mellitus Prior stroke or transient ischemic attack Vascular disease Age 65-74 years CHA2DS2-VASc score (mean) History of PAD (%) Current smoker Dose reduction at randomization, n (%) Creatinine clearance ≤50 mL/min Weight ≤60 kg Use of verapamil or quinidine VKA naive, n (%) Medication at time of randomization, n (%) Aspirin Thienopyridine Amiodarone Digoxin or digitalis preparation
Systemic embolism (n = 60)
Stroke (n = 956)
Neither (n = 20,089)
78 (71, 82) 32 (53.3)
74 (67, 79) 548 (57.3)
72 (64, 77) 12,485 (62.1)
10 11 10 18 11
(16.7) (18.3) (16.7) (30.0) (18.3)
181 124 140 324 187
(18.9) (13.0) (14.6) (33.9) (19.6)
4490 2526 3086 6802 3185
210 (22.0) 225 (23.5) 521 (54.5)
5150 (25.6) 4632 (23.1) 10,301 (51.3)
36 (60.0) 57 (95) 38 (63.3) 19 (31.7) 21 (35.0) 23 (38.3) 15 (25.0) 4.9 ± 1.3 9 (15.0) 5 (8.3) 29 (48.3) 25 (41.7) 14 (23.3) 0 (0.0) 12 (20.0)
530 (55.4) 876 (91.6) 459 (48.0) 310 (32.4) 414 (43.3) 378 (39.5) 316 (33.1) 4.8 ± 1.4 27 (2.8) 77 (8.1) 340 (35.6) 258 (27.0) 141 (14.7) 45 (4.7) 409 (42.8)
11,558 (57.5) 18,821 (93.7) 7977 (39.7) 7295 (36.3) 5538 (27.6) 7445 (37.1) 6803 (33.9) 4.3 ± 1.4 805 (4.0) 1470 (7.3) 4987 (24.8) 3791 (18.9) 1928 (9.6) 716 (3.6) 8242 (41.0)
16 0 4 24
297 32 91 293
(31.1) (3.3) (9.5) (30.6)
5867 455 2397 6010
P (stroke vs SEE)
b.001 .004 .04
.005 .55 .77
.001
.02
.41 .04 b.001 .04 b.001 .30 b.001 b.001 b.001 .67 b.001 b.001 b.001 .06 .002
.49 .36 .02 .90 .21 .85 .07 .38 b.001 .94 .05 .01 .07 .09 b.001
.42 .05 .04 .21
.47 .15 .46 .13
(22.4) (12.6) (15.4) (33.9) (15.9)
6 (10.0) 11 (18.3) 43 (71.7)
(26.7) (0.0) (6.7) (40.0)
3-way P
(29.2) (2.3) (11.9) (29.9)
Abbreviations: CHA2DS2-VASc, Congestive heart failure, hypertension, age ≥75 years (2 points), diabetes mellitus, stroke/transient ischemic attack (2 points), vascular disease, age 65 to 74 years, sex category; PAD, peripheral arterial disease. This table includes participants with SEE as a first event and therefore does not include all participants with SEEs.
NOACs compared with warfarin in reducing stroke, there are limited data characterizing the risk and clinical consequences of SEE, which comprise 5% to 10% of all arterial thromboembolic events. 6-10,14-18 The aim of this study was to investigate the incidence, risk factors, location, and severity of SEE in the ENGAGE AF-TIMI 48 trial as well as assess the relative efficacy and safety of edoxaban and the NOACs as a class in preventing them.
Methods Study design The ENGAGE AF-TIMI 48 design and primary results have been reported previously. 9,19 The study was a multicenter, randomized, double-blind, double-dummy trial comparing 2 once-daily regimens of edoxaban (higher and lower dose regimens) with warfarin. A total of 21,105 were enrolled and followed up for a median of 2.8 years. Eligible patients were ≥21 years of age with AF documented on an electrical tracing within 12 months, a congestive heart failure, hypertension, age
≥75 years, diabetes mellitus, stroke/transient ischemic attach (2 points) risk score ≥2, and anticoagulation planned for the duration of the trial.
Outcomes The primary efficacy end point was the time to the first SEE, a component of the composite end point in the ENGAGE AF-TIMI 48 trial of stroke (ischemic or hemorrhagic) or SEE. An SEE was defined as an abrupt episode of arterial insufficiency associated with either clinical or radiographic evidence of arterial occlusion that occurred in the absence of other likely mechanisms that included atherosclerosis or instrumentation. Arterial embolic events to the central nervous system (including the eye), coronary, and pulmonary arterial circulation were classified as stroke/transient ischemic attack, myocardial infarction, and pulmonary embolism, respectively, rather than SEE. In patients with atherosclerotic peripheral vascular disease, the diagnosis of a systemic embolism to the lower extremities required arteriographic evidence of abrupt arterial occlusion. 19 An independent
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Figure 1
Abdominal/ mesenteric 10%
Renal 4%
Other 1%
Upper Extremity 15%
Outcomes were then pooled and compared with a fixed-effects model. 21 We assessed the appropriateness of pooling data across studies with the use of the Cochran Q statistics and I 2 test for heterogeneity. 22 A 2-sided P value b.05 was considered statistically significant. Statistical analyses were performed using Stata (version 12.1; Stata, College Station, TX). The ENGAGE AF-TIMI 48 trial was funded by Daiichi Sankyo Pharma Development. The TIMI Study Group had access to all the data, performed all analyses, and had final responsibility for the decision to submit for publication.
Results Lower Extremity 70%
Location of SEEs (includes multiple events).
clinical end point events committee, blinded to the study drug assignment, adjudicated all end points.
Statistical analysis All analyses were performed on the intention-to-treat population from randomization until the end of the treatment period. Descriptive statistics of baseline characteristics were given as numbers and percentages, medians with 25th and 75th percentiles, or means with SDs. Baseline characteristics were compared using the χ 2 test for categorical variables or Kruskal-Wallis test for continuous variables. Event rates were expressed per 100 patient years. Hazard ratios (HRs) for edoxaban and warfarin with 95% CIs were determined using Cox proportional hazards model with treatment as the only covariate. A multivariable Cox proportional hazards model was used to identify independent predictors of SEE. Data for the meta-analysis were obtained from the main trial publications of the 4 phase 3 trials comparing a NOAC versus warfarin for stroke prevention in patients with AF (RE-LY, dabigatran; ROCKET AF, rivaroxaban; ARISTOTLE, apixaban; and ENGAGE AF-TIMI 48, edoxaban). 6-9,20 In the RE-LY and ENGAGE AF-TIMI 48 trials, 2 doses of dabigatran and edoxaban, respectively, were compared with warfarin. Rather than including data with both doses, which would merge the benefit and risk of different doses, thereby compromising interpretability, we used the higher dose dabigatran and edoxaban regimens, as they are the doses that are universally approved. The intention-to-treat population was analyzed for all trials except for ROCKET AF where only the on-treatment population was reported. We calculated the relative risk (RR) and 95% CIs for each trial separately.
The baseline characteristics of patients in the ENGAGE AF-TIMI 48 trial have been previously reported. 9 Of the 1,016 patients in the ENGAGE AF-TIMI 48 trial who experienced a primary end point, 949 (93.4%) had a stroke, 58 (5.7%) experienced an SEE, and 9 (0.9%) had both. Patients who experienced an SEE compared with those who had a stroke tended to be older (median 78 vs 74 years; P = .005) and were more likely to have permanent AF (72% vs 55%; P = .02), moderate renal impairment (creatinine clearance ≤50 mL/min; 42% vs 27%; P = .01), and more often VKA experienced (80% vs 57%; P b .001) (Table I). In a multivariable model, independent predictors of SEE included decreased creatinine clearance (HR per 10 mL/min decrease 1.30; 95% CI 1.12-1.50; P b .001), permanent AF (HR 2.97; 95% CI 1.33-6.63; P = .008), and VKA experience (HR 1.86; 95% CI 1.04-3.30; P = .04).
Location and severity of SEEs There were 73 total SEE (includes 6 recurrent events). Most SEEs were in the extremities (n = 62; 85%) (Figure 1). Of these, 82% were lodged in the lower extremities. Additional locations included the abdomen (9.6%), renal (4.1%), and other (1.4%) arteries. There were 9 fatal SEEs (13%). In addition, 52% of nonfatal SEEs and 41% of all SEEs (n = 30) required a surgical or percutaneous intervention to restore blood flow (Figure 2). Of the 41% of all SEEs requiring a procedure, 12% (n = 9) had surgery (of which 3 were amputations), 12% (n = 9) had a percutaneous intervention, and 16% (n = 12) had an embolectomy. Relative efficacy of edoxaban compared with warfarin In the warfarin group, the median time in the therapeutic range was 68.4% (interquartile range 56.5-77.4). There were 23 (0.12%/year) SEEs in the warfarin group compared with 15 in the higher dose edoxaban group (0.08%/year; HR 0.65; 95% CI 0.34-1.24; P = .19) and 29 in the lower dose edoxaban group (0.15%/year; HR 1.24; 95% CI 0.72-2.15; P = .43) (Table II). Higher dose edoxaban resulted in significantly fewer SEEs than lower dose edoxaban (HR 0.52; 95% CI 0.28-0.97;
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Figure 2
Management of patients with SEEs (includes multiple events).
Table II. Thromboembolic end points by study group (all events) Warfarin (n = 7036)
End point Primary end point in the intentionto-treat population Stroke Fatal Nonfatal SEE Fatal Nonfatal
Higher dose edoxaban (n = 7035)
Higher dose edoxaban vs warfarin
No. of patients with event
% of patients/ year
No. of patients with event
% of patients/ year
HR (95% CI)
337
1.80
296
1.57
317 86 245 23 4 19
1.69 0.45 1.31 0.12 0.02 0.10
281 80 207 15 0 15
1.49 0.42 1.10 0.08 0.00 0.08
P = .04). In the warfarin group, 4 (17%) SEEs were fatal compared with no fatal events in the higher dose edoxaban group and 5 (17%) fatal SEEs with lower dose edoxaban.
Meta-analysis of NOACs compared with warfarin In a meta-analysis of the 4 phase 3 trials comparing NOACs with warfarin, there were 29,292 patients who received a NOAC and 29,221 who received warfarin. There was a significant 37% reduction in SEEs with NOACs (n = 47) compared with warfarin (n = 78) (RR 0.63; 95% CI 0.43-0.91; P = .01) (Figure 3).
Lower dose edoxaban (n = 7034)
Lower dose edoxaban vs warfarin
P
No. of patients with event
% of patients/ year
HR (95% CI)
P
0.87 (0.74-1.02)
.08
383
2.04
1.13 (0.97-1.31)
.11
0.88 0.92 0.84 0.65
(0.75-1.03) (0.68-1.25) (0.70-1.01) (0.34-1.24)
.11 .62 .06 .19
0.78 (0.40-1.54)
.48
360 73 293 29 5 24
1.91 0.38 1.56 0.15 0.03 0.13
1.13 0.84 1.19 1.24 1.23 1.25
.12 .27 .05 .43 .76 .47
(0.97-1.31) (0.61-1.15) (1.00-1.41) (0.72-2.15) (0.33-4.58) (0.68-2.28)
Discussion Prior studies have shown that up to 10% of arterial thromboembolic complications in AF patients are due to SEEs. 6-10,14-18 Data from the ENGAGE AF-TIMI 48 trial support a similar proportion of SEE (6.6%) compared with stroke in a contemporary population of AF patients. Although the percentage of SEEs is likely an underestimate of the total thromboembolic burden, as an arterial embolus to the brain is more likely to be clinically evident and therefore diagnosed due to limited collaterals in the brain, whereas a similar size thrombus to arteries of the extremities, kidneys, or mesentery may be asymptomatic.
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Figure 3
Meta-analysis of the 4 phase 3 trials comparing a NOAC versus warfarin for prevention of SEE. Data are n/N unless otherwise indicated. Heterogeneity, I2 = 43.4%; P = .01. ⁎Dabigatran, 150 mg twice daily. †Rivaroxaban, 20 mg once daily. ‡Apixaban, 5 mg twice daily. §Edoxaban, 60 mg once daily.
With regard to SEE location, we found in ENGAGE AF-TIMI 48 that 85% of clinically significant SEEs involved the extremities, which are similar to the 60% to 85% that had been reported previously. 18,23 These data are the first to examine the severity and treatment of SEEs. Fatal SEEs accounted for 13% of the total, and, among nonfatal SEEs, there was a high degree of morbidity. Of all patients with a nonfatal SEE, 52% required some kind of invasive procedure including thromboembolectomy, bypass, or amputation. Anticoagulation with warfarin has been shown to be effective in reducing SEE. In a meta-analysis of 11,756 patients with AF treated with warfarin or aspirin, warfarin reduced SEE by 50% compared with aspirin (odds ratio [OR] 0.50; 95% CI 0.33-0.75; P b .001). 16 In the 6,706 participants in the ACTIVE W, warfarin was superior to aspirin plus clopidogrel for the prevention of SEE (OR 0.22; 95% CI 0.07-0.65; P = .006). 24 The relative efficacy of the NOACs for reducing SEE has not been firmly established, as the individual trials were relatively underpowered for this less frequent component of the primary composite end point of all-cause stroke or SEE. A prior meta-analysis that did not include data from the ENGAGE AF-TIMI 48 trial observed similar efficacy in SEE prevention with NOACs compared with warfarin (OR 0.85; 95% CI 0.39-1.84). 14 With the addition of data from the ENGAGE AF-TIMI 48, the most recent, largest, and longest of the phase 3 trials (21,105 patients followed up for an average of 2.8 years) comparing a NOAC with warfarin, our updated meta-analysis now demonstrates a significant 37% reduction in SEE with NOACs compared with warfarin (RR 0.63; 95% CI 0.43-0.91; P = .01). Interestingly, the 37% reduction in SEE with NOACs compared with warfarin is substantially greater than the nonsignificant 8% reduction observed for ischemic stroke in a meta-analysis that was performed with the same trials. 13 The reason for a differential efficacy of NOACs compared with warfarin with respect to these outcomes is unclear and may reflect chance. Another possibility is that the adjudication of SEE captured truly “cardioembolic” events in which
anticoagulation is very effective in preventing, whereas ischemic strokes represent a mixture of cardioembolic and locally thrombotic events. Non–VKA oral anticoagulants may be better at preventing thromboembolic events compared with warfarin, whereas there may be less advantage for NOACs over warfarin for the prevention of local ischemic/atherosclerotic events.
Limitations This study was performed in a clinical trial population, and the results may not be generalizable to a standard clinical practice setting where the ascertainment of SEEs may differ. In addition, only SEEs that manifested in clinical signs or symptoms were included in this analysis, and our results therefore likely underestimate the true number of SEEs that occurred. The relative low frequency of events in any 1 trial results in wide CIs; however, our meta-analysis pooling data from 4 trials provides more precision regarding the treatment benefit of NOACs as compared with warfarin. The meta-analysis does show moderate statistical heterogeneity, which could be secondary to differences across trials or between drugs. However, some heterogeneity is not unexpected given the small numbers of SEEs, and, therefore, this does not necessarily challenge the validity of the analysis. 25
Conclusion In the ENGAGE AF-TIMI 48 trial, systemic emboli were much less frequent than stroke in patients with AF but were associated with significant morbidity and mortality. Most SEEs involved the extremities, and these events often required surgical or percutaneous intervention. Edoxaban was similar to warfarin in preventing SEE, but a meta-analysis including all 4 phase 3 trials of approved NOACs found that they further reduced the risk of SEE by 37% compared with warfarin.
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