Background
Atrial fibrillation (AF) is associated with increased risk for thromboembolism and death; however, the relationships between cardiac structure and function and adverse outcomes among individuals with AF are incompletely understood.
Methods
The Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 study tested the once-daily oral factor Xa inhibitor edoxaban in comparison with warfarin for the prevention of stroke (ischemic or hemorrhagic) or systemic embolism in 21,105 subjects with nonvalvular AF and increased risk for thromboembolic events (CHADS 2 score ≥ 2). In a prospective substudy of 971 subjects who underwent transthoracic echocardiography at baseline, Cox proportional hazards models were used to evaluate associations between cardiac structure and function and the risks for death and thromboembolism (ischemic stroke, transient ischemic attack, or systemic embolism).
Results
Over a median follow-up period of 2.5 years, 89 deaths (9.2%) and 48 incident thromboembolic events (4.9%) occurred in 971 subjects. In models adjusted for CHADS 2 score, aspirin use, and randomized treatment, larger left ventricular (LV) end-diastolic volume index (hazard ratio per 1 SD [12.9 mL/m 2 ], 1.49; 95% CI, 1.16–1.91) and higher LV filling pressures measured by E/e′ ratio (hazard ratio per 1 SD [4.6], 1.32; 95% CI, 1.08–1.61) were independently associated with increased risks for death. E/e′ ratio > 13 significantly improved the prediction of death beyond clinical factors alone. No features of cardiac structure and function were independently associated with thromboembolism in this population. Findings were similar when adjusted for CHA 2 DS 2 -VASc score in place of CHADS 2 score.
Conclusions
In a contemporary population of patients with AF at increased risk for thromboembolic events, larger LV size and higher filling pressures were significantly associated with increased risk for death, but neither left atrial nor LV measures were associated with thromboembolic risk. LV size and filling pressures may help identify patients with AF at increased risk for death.
Highlights
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In 971 moderate- to high-risk subjects (CHADS 2 score ≥ 2) with AF enrolled in the echocardiographic substudy of ENGAGE AF–TIMI 48, death was more frequent than thromboembolism.
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Larger LV size and higher filling pressures were associated with increased risks for death.
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Neither left atrial nor LV measures were associated with thromboembolic risk.
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LV size and filling pressures may help identify patients with AF at increased risk for death.
Atrial fibrillation (AF) is common, increasing in prevalence, and associated with increased risks for thromboembolism, stroke, and death. Because nonfatal thromboembolism and stroke are associated with high morbidity, a key consideration in managing patients with AF is thromboembolic risk assessment to inform antithrombotic recommendations. Despite current risk prediction tools, such as the CHADS 2 and CHA 2 DS 2 -VASc scores, decisions regarding whether to anticoagulate and choosing antithrombotic therapies in patients with AF remain challenging. Anticoagulation is associated with reduction in the risk for fatal and nonfatal strokes; however, thromboembolism accounts for a minority of deaths among patients with AF. Recent evidence demonstrates that death occurs more commonly in patients with AF than stroke, and despite therapeutic advances in stroke prevention, mortality rates in patients with AF have not substantially improved over the past decade. Therefore, a particular need exists to understand factors that contribute to the risk for death in patients with AF, which may inform clinical management strategies aimed at decreasing mortality.
Cardiac structure and function in patients with AF may be of prognostic value in refining thromboembolic and mortality risk assessments. However, there are conflicting data regarding the relationships between cardiac structure and function in patients with AF and the risk for thromboembolism. Inconsistent findings may be related in part to limitations of prior echocardiographic studies, which did not include contemporary measures of left ventricular (LV) and left atrial (LA) structure and function. To understand the impact of cardiac structure and function on the risks for thromboembolism and death, we evaluated the prognostic significance of cardiac structure and function in relation to thromboembolic events and all-cause mortality among subjects enrolled in the prespecified echocardiographic substudy of Effective Anticoagulation with Factor Xa Next Generation in AF–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF–TIMI 48). We hypothesized that LA dysfunction would be associated with increased risk for thromboembolic events and death among individuals with AF.
Methods
Study Population
ENGAGE AF–TIMI 48 was a multinational, randomized (1:1:1), double-blind, double-dummy noninferiority design trial comparing the efficacy and safety of two dosing regimens of once-daily edoxaban (high and low dose with dose reductions for patients with decreased clearance of edoxaban) versus warfarin titrated to an international normalized ratio of 2.0 to 3.0 in subjects with histories of AF. The study included subjects with AF at moderate to high risk for thromboembolic events on the basis of a CHADS 2 score ≥ 2. Inclusion and exclusion criteria and the primary results demonstrating noninferiority of edoxaban compared with warfarin for the prevention of stroke or systemic embolism have been reported. Briefly, eligible subjects were men or women ≥21 years of age with histories of AF of any duration documented by electrocardiography within the prior 12 months and in whom anticoagulation was indicated. Key exclusion criteria were AF due to reversible causes, severe renal dysfunction (creatinine clearance < 30 mL/min), high bleeding risk, moderate or severe mitral stenosis, or a mechanical valve in any position. Mitral regurgitation was not an exclusion criterion. Rate or rhythm control strategy was not specified by the study protocol and was at the discretion of the local physician. The study protocol complied with the Declaration of Helsinki and was approved by institutional review boards at each site. Written informed consent was obtained from all patients.
The prospectively designed echocardiographic substudy of ENGAGE AF–TIMI 48 was performed at 133 sites worldwide between 2009 and 2011. The echocardiographic procedures, protocol, and results of a baseline cross-sectional analysis of the ENGAGE AF–TIMI 48 echocardiographic substudy population before the availability of longitudinal outcomes have been previously reported. In the present report, the same echocardiographic substudy population is now examined with regard to longitudinal associations between baseline cardiac structure and function and the outcomes of thromboembolism and death over a median of 2.5 years of follow-up. Subjects were invited before randomization to voluntarily participate with echocardiographic imaging obtained within the first week after randomization. Standard two-dimensional and Doppler transthoracic echocardiography was performed, with images sent to the echocardiography core laboratory at Brigham and Women’s Hospital (Boston, MA). Conventional echocardiographic analyses were performed by technicians blinded to clinical information and treatment assignment, with all study measurements confirmed by a board-certified cardiologist and echocardiographer. Reproducibility of echocardiographic measurements was good to excellent, with an intraobserver intraclass correlation coefficient of 0.95 (0.91–0.99) and an interobserver intraclass correlation coefficient of 0.84 (0.75–0.93).
Echocardiographic Analyses
Echocardiography was performed according to American Society of Echocardiography guidelines. LV volumes and LV ejection fraction (LVEF) were calculated using the modified Simpson method. LV mass was calculated from LV linear dimensions using the American Society of Echocardiography–recommend formula (0.8 × {1.04[(LV internal dimension in diastole + posterior wall thickness in diastole + septal wall thickness in diastole) 3 − (LV internal dimension in diastole) 3 ]} + 0.6 g) and indexed to body surface area, with LV hypertrophy defined as LV mass index > 115 g/m 2 in men or >95 g/m 2 in women. LV geometry was categorized as normal (relative wall thickness ≤ 0.42 and no LV hypertrophy) or abnormal (relative wall thickness > 0.42 or LV hypertrophy).
LA diameter was the two-dimensional anterior-posterior length in the parasternal long-axis view. LA maximal volume was measured using the modified Simpson method using apical four- and two-chamber views at the end-systolic frame preceding mitral valve opening and was indexed to body surface area to derive LA volume index. Similarly, LA minimal volume was measured at the end-diastolic frame preceding mitral valve closure. LA emptying fraction was calculated as 100 × (maximal volume − minimal volume)/maximal volume ( Figure 1 ).
Early transmitral velocity (E) was measured by pulsed-wave Doppler from the apical four-chamber view with the sample volume positioned at the tip of the mitral leaflets. Peak lateral and septal mitral annular early relaxation velocities (e′) were assessed using tissue Doppler imaging. LV filling pressures were estimated by E wave divided by average e′ velocities (E/e′). Right ventricular systolic pressure was calculated from the peak tricuspid regurgitant velocity using the simplified Bernoulli equation and assuming a right atrial pressure of 10 mm Hg. Final values for all parameters were taken as the mean of measurements from three cardiac cycles.
Outcomes
The primary end points for this analysis were time to (1) thromboembolic event (defined as ischemic stroke, transient ischemic attack or systemic embolic event) and (2) death of any cause. All events were adjudicated by an independent clinical end point committee whose members were blinded to study assignment. The median follow-up period was 2.5 years (interquartile range, 2.3–2.8 years).
Statistical Methods
Subjects were stratified into groups according to those who did and did not have thromboembolic events during follow-up or those who were alive or dead. Summary statistics for clinical characteristics and cardiac structure and function were calculated; results are presented as median (interquartile range) and count (percentage) for continuous and categorical data, respectively. Statistical comparisons were made between subjects who did or did not have the outcome of interest during follow-up using χ 2 , Fisher exact, or Wilcoxon rank sum tests as appropriate. Incidence rates for thromboembolism and death per 100 person-years were calculated. Multivariate Cox proportional hazards models were used to assess the associations between covariates and the risk for thromboembolism and death. The echocardiographic substudy was not powered to assess effect modification of treatment (warfarin vs high-dose edoxaban vs low-dose edoxaban) by features of cardiac structure and function on the outcomes of thromboembolism or death. However, to control for treatment assignment in analyzing the association between cardiac structure and function and outcomes, randomization was included as a covariate in multivariate models. To examine the incremental value of cardiac structure and function on the prediction of the outcomes beyond clinical factors, receiver operating characteristic curve analyses were performed. All analyses were performed using Stata version 11.2 (StataCorp LP, College Station, TX), with P values < .05 considered to indicate statistical significance.
Results
Clinical Characteristics
Over a median follow-up period of 2.5 years (IQR 2.3, 2.8), incident thromboembolic events occurred in 48 subjects ( Table 1 ). Thromboembolic events were more frequent among subjects with higher CHADS 2 scores. The frequency of thromboembolic events did not differ according to paroxysmal, persistent, or permanent AF. Aspirin use was significantly lower among subjects who had thromboembolic events compared with those who did not. In contrast, there was no significant difference with regard to the occurrence of thromboembolism during follow-up in relation to randomization to warfarin or edoxaban.
| Characteristic | No TE ( n = 923) | TE ( n = 48) | P | Alive ( n = 882) | Dead ( n = 89) | P |
|---|---|---|---|---|---|---|
| Age (y) | 73 (65–79) | 74.5 (67–79) | .53 | 73 (65–78) | 76 (66–82) | .031 |
| Men | 606 (66) | 31 (65) | .88 | 571 (65) | 66 (74) | .075 |
| Caucasian | 850 (92) | 46 (96) | .34 | 811 (92) | 85 (96) | .23 |
| CHADS 2 score | .045 | .001 | ||||
| 2 | 451 (49) | 24 (50) | 440 (50) | 35 (39) | ||
| 3 | 275 (30) | 8 (17) | 248 (28) | 35 (39) | ||
| 4 | 147 (16) | 9 (19) | 143 (16) | 13 (15) | ||
| 5 or 6 | 50 (5) | 7 (15) | 51 (6) | 6 (7) | ||
| Heart failure | 499 (54) | 22 (46) | .27 | 465 (53) | 56 (63) | .066 |
| Hypertension | 872 (94) | 45 (94) | .83 | 833 (94) | 84 (94) | .98 |
| Age > 75 y | 418 (45) | 24 (50) | .52 | 394 (45) | 48 (54) | .094 |
| Diabetes mellitus | 326 (35) | 20 (42) | .37 | 306 (35) | 40 (45) | .054 |
| Stroke/TIA | 240 (26) | 18 (38) | .08 | 237 (27) | 21 (24) | .51 |
| Vascular disease | 389 (42) | 25 (52) | .18 | 366 (42) | 48 (55) | .018 |
| Smoking, current | 96 (10) | 4 (8) | .81 | 89 (10) | 11 (12) | .50 |
| Obese (BMI > 30 kg/m 2 ) | 388 (42) | 19 (40) | .74 | 371 (42) | 36 (40) | .77 |
| Baseline heart rate (beats/min) | 72 (63–81) | 74 (63–81) | .66 | 72 (62–80) | 73 (67–82) | .17 |
| CKD (CrCl 30–60 mL/min) | 306 (34) | 19 (40) | .40 | 285 (33) | 40 (47) | .007 |
| Type of AF | .22 | .98 | ||||
| Paroxysmal | 298 (32) | 21 (44) | 294 (33) | 25 (28) | ||
| Persistent | 196 (21) | 7 (15) | 183 (21) | 20 (22) | ||
| Permanent | 429 (46) | 20 (42) | 405 (46) | 44 (49) | ||
| BMI (kg/m 2 ) | 29 (26–33) | 29 (25–34) | .68 | 29 (26–33) | 28 (25–32) | .15 |
| CrCl (mL/min) | 72 (55–92) | 64 (47–93) | .15 | 72 (56–92) | 63 (41–88) | .003 |
| Antiarrhythmic medication | 177 (19) | 9 (19) | .94 | 173 (20) | 13 (15) | .32 |
| ACE inhibitor or ARB | 538 (58) | 27 (56) | .77 | 512 (58) | 53 (60) | .82 |
| β-blocker | 624 (68) | 33 (69) | .87 | 594 (67) | 63 (71) | .55 |
| Diuretic | 923 (100) | 48 (100) | NA | 882 (100) | 89 (100) | NA |
| Aspirin use at baseline | 285 (31) | 8 (17) | .037 | 271 (31) | 22 (25) | .24 |
| Randomized | .17 | .69 | ||||
| Warfarin | 316 (34) | 11 (23) | 297 (34) | 30 (34) | ||
| Edoxaban (low) | 315 (34) | 22 (46) | 303 (34) | 34 (38) | ||
| Edoxaban (high) | 292 (32) | 15 (31) | 282 (32) | 25 (28) |
A total of 89 deaths occurred over the follow-up period ( Table 1 ). Death was more frequent among subjects with higher CHADS 2 scores. Vascular disease and chronic kidney disease were also more common among subjects who died. Aspirin use did not significantly differ between those who were alive versus dead at follow-up. Similarly, no significant difference was observed with regard to death in relation to randomization to warfarin or edoxaban.
Cardiac Structure and Function
LV size, LV mass, LVEF, and LV filling pressures did not significantly differ between subjects who had thromboembolic events during follow-up compared with those who did not ( Table 2 ). LA size and function were also similar between these two groups.
| Characteristic | No TE ( n = 923) | TE ( n = 48) | P | Alive ( n = 882) | Dead ( n = 89) | P |
|---|---|---|---|---|---|---|
| Sinus rhythm on echocardiography | 298 (32) | 23 (48) | .028 | 295 (33) | 26 (29) | .48 |
| Left ventricle | ||||||
| LVEF (%) | 59 (53–61) | 59 (57–61) | .061 | 59 (54–61) | 57 (44–60) | .003 |
| LVEF < 50% | 210 (23) | 7 (15) | .19 | 185 (21) | 32 (36) | .001 |
| LVEDVI (mL/m 2 ) | 56 (51–62) | 57 (53–63) | .32 | 56 (51–62) | 58 (53–69) | .010 |
| LV mass (g) | 136 (113–172) | 145 (120–178) | .50 | 135 (112–171) | 151 (125–183) | .003 |
| LVMI (g/m 2 ) | 68 (58–88) | 72 (60–91) | .33 | 68 (58–88) | 76 (63–98) | .003 |
| Abnormal LV geometry ∗ | 258 (28) | 18 (38) | .15 | 252 (29) | 24 (27) | .75 |
| Left atrium | ||||||
| LA diameter (cm) | 3.6 (3.4–3.8) | 3.5 (3.4–3.8) | .17 | 3.6 (3.4–3.8) | 3.7 (3.4–4.0) | .055 |
| LAVI (mL/m 2 ) | 33 (26–39) | 33 (27–38) | .95 | 33 (26–39) | 34 (28–45) | .031 |
| LAVI > 34 ml/m 2 | 413 (45) | 19 (40) | .55 | 386 (44) | 46 (52) | .18 |
| LA emptying fraction (%) | 38 (30–45) | 40 (33–49) | .12 | 38 (31–46) | 35 (27–43) | .015 |
| Doppler | ||||||
| DTI e′ average (cm/sec) | 7.7 (6.2–9.1) | 7.2 (6.6–9.0) | .65 | 7.7 (6.2–9.1) | 7.1 (5.9–9.1) | .18 |
| E/e′ average | 10.7 (8.6–13.8) | 10.2 (7.9–12.4) | .22 | 10.6 (8.5–13.5) | 12.3 (9.3–16.7) | .004 |
| E/e′ ≥ 13 | 403 (44) | 20 (42) | .88 | 367 (42) | 56 (63) | <.001 |
| Moderate or greater MR | 93 (11) | 6 (13) | .69 | 85 (10) | 14 (17) | .07 |
| RVSP (mm Hg) † | 32 (29–36) | 34 (28–39) | .57 | 32 (28–36) | 36 (30–42) | <.001 |
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