Outcomes in Atrial Fibrillation Patients With and Without Left Ventricular Hypertrophy When Treated With a Lenient Rate-Control or Rhythm-Control Strategy




Although left ventricular (LV) hypertrophy has been proposed as a factor predisposing to atrial fibrillation (AF), its relevance to prognosis and selection of therapeutic strategies is unclear. We identified 2,105 patients with echocardiographic data on LV mass enrolled in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial. LV hypertrophy was defined as increased LV mass, stratified by American Society of Echocardiography criteria. The primary end point was all-cause mortality, secondary end point was as per AFFIRM trial definition, and tertiary end point was cardiovascular hospitalizations. We compared “strict” versus “lenient” rate control in patients with increased LV mass, and studied association of heart failure (HF) with preserved and decreased systolic function in patients with increased LV mass. Over 6 years, 332 deaths (15.7%) were reported. Adjusted hazard ratio (HR) of severely increased LV mass for all-cause mortality was 1.34 (95% confidence interval [CI] 1.01 to 1.79, p = 0.045) for the overall population and 1.61 (95% CI 1.09 to 2.37, p = 0.016) for the rhythm-control arm. Increased LV mass was a predictor of cardiovascular hospitalizations in the lenient rate-control group (HR 1.72, 95% CI 1.05 to 2.82, p = 0.03) but not in the strict rate-control group. Severely increased LV mass was predictive of cardiovascular hospitalizations in patients with HF with preserved (HR 1.8, 95% CI 1.0 to 3.2, p = 0.03) and decreased LV systolic function (HR 2.4, 95% CI 1.1 to 5.2, p = 0.02). Thus, LV hypertrophy is a significant independent predictor of mortality in patients with AF, especially those managed with rhythm control. In patients with LV hypertrophy, strict rate control may be associated with better outcomes than lenient rate control. LV hypertrophy portends higher cardiovascular morbidity in patients with AF and HF.


From a clinical standpoint, a clear case for rhythm control or stricter rate control could be made for patients with atrial fibrillation (AF) and associated systolic or diastolic ventricular dysfunction associated with left ventricular (LV) hypertrophy, but no data are available to support either strategy. There is a need to compare various rate-control approaches in carefully defined subgroups of patients with AF. Large case registries may provide additional opportunities to evaluate therapeutic strategies in AF subgroups. Consequently, we sought to investigate whether the selection of rhythm control versus strict or lenient rate control had an impact on mortality and morbidity in patients with AF with LV hypertrophy and associated diastolic or systolic dysfunction from the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial.


Methods


We performed post hoc analysis of data from patients enrolled in the AFFIRM trial. A public use, limited-access data set devoid of patient identifiers was obtained from the National Heart, Lung and Blood Institute. None of the investigators are affiliated with the National Heart, Lung and Blood Institute or participated in the AFFIRM trial. The details of the AFFIRM study have been described previously. In brief, this was a prospective trial (n = 4,060) comparing survival in patients with AF and at least 1 risk factor for stroke randomized to a strategy of rate control (n = 2,027) versus a strategy of rhythm control (n = 2,033). Eligible patients were either aged ≥65 years or had at least 1 of the following risk factors for stroke or death: hypertension, diabetes, heart failure (HF), previous stroke or transient ischemic attack, systemic embolism, left atrial diameter >50 mm by echocardiography, LV ejection fraction (EF) <0.40, or fractional shortening <25% determined by any technique.


We identified 2,105 patients with echocardiographic data on LV mass. Patients with incomplete echocardiographic data were excluded (n = 1,945). LV mass measurements were defined as per the American Society of Echocardiography’s guidelines on chamber quantification. Mass was calculated by subtraction of the LV cavity volume from the volume enclosed by the epicardium to obtain LV muscle or shell volume. The shell volume was then converted to muscle mass by multiplying by myocardial density according to the following formula :


LV mass = 0.8 × {1.04 [(LVIDd + PWTd + SWTd) 3 − (LVIDd) 3 ]} + 0.6, where LVIDd denotes left ventricular internal diastolic diameter; PWTd, posterior wall thickness at end-diastole; and SWTd, septal wall thickness at end-diastole. LV mass was categorized as normal, mildly abnormal, moderately abnormal, or severely abnormal according to the American Society of Echocardiography criteria, which varied by gender.


To assess the relation between degree of rate control and outcomes in relation to LV mass, we performed a subanalysis including patients with available LV mass data and without pacemaker insertion before randomization, originally enrolled in the rate-control arm with documented AF both at baseline and at 2-month visit, with available data of heart rate at rest at both visits. This cohort (n = 366) was stratified according to the degree of rate control, with adequately rate-controlled patients included in the strict rate-control group (n = 105) and the remainder (n = 261) in the lenient rate-control group. Adequate control at 2 months was defined as heart rate at rest ≤80 and postexercise heart rate ≤110 beats/min after 6 minutes of exercise. To maintain power in this relatively small subgroup, LV mass was classified into just 2 categories: normal or mildly increased LV mass was considered as referent and moderately or severely increased LV mass was considered as elevated LV mass.


HF was categorized as associated with either decreased (n = 258) or preserved systolic function (n = 233) based on LVEF using 50% as cutoff.


The primary end point of this analysis was all-cause mortality. The secondary end point was a composite of all-cause mortality and events including major arrhythmia, stroke, major bleeding, myocardial infarction, and pulmonary embolism. This secondary outcome was same as used in the AFFIRM trial and the definitions were consistent. The tertiary end point was hospitalization due to cardiovascular causes.


Multivariate Cox proportional hazards models were constructed that included LV mass as the major factor and were adjusted for age, gender, history of coronary artery disease or myocardial infarction, history of hypertension, HF, stroke, diabetes, smoking status, first episode of AF, sinus rhythm at the time of randomization, treatment with warfarin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β blocker, calcium channel blocker, amiodarone, sotalol, class I antiarrhythmic medication, left atrial size, mitral regurgitation, and LVEF. This analysis was performed for the complete cohort, and separately for those in the rate and rhythm-control arms.




Results


The baseline characteristics of the study population stratified by LV mass are summarized in Table 1 . There were 2,105 patients with echocardiographic data available with a median follow-up of 41.5 ± 15.3 months. Of these, 725 (34%) had severely increased LV mass. Patients with greater LV mass were younger, more obese, and had a greater prevalence of hypertension, coronary artery disease, systolic or diastolic HF, diabetes, and treatment with digoxin, angiotensin-converting enzyme inhibitor, or angiotensin receptor blocker. Other medications were used with equal frequencies at baseline by patients irrespective of LV mass.



Table 1

Baseline characteristics of the study population stratified by the left ventricular (LV) mass











































































































































































































































































Variable Overall Population (n = 2,105) Normal LV Mass (n = 732) Mildly Increased LV Mass (n = 349) Moderately Increased LV Mass (n = 299) Severely Increased LV Mass (n = 725) p Value
Age 69.4 ± 8.1 70.1 ± 8.1 69.6 ± 8.1 69.3 ± 7.9 68.6 ± 8.2 0.004
Female gender 902 (42.8) 289 (39.4) 163 (46.7) 123 (41.1) 327 (45.1) 0.06
Body mass index (kg/m 2 ) 28.65 ± 5.91 26.80 ± 4.97 28.42 ± 5.34 29.33 ± 5.80 30.42 ± 6.52 <0.001
Medical history
History of coronary artery disease 730 (34.6) 201 (27.4) 102 (29.2) 119 (39.8) 308 (42.4) <0.001
HF 491 (23.3) 94 (12.8) 67 (19.2) 80 (26.7) 250 (34.4) <0.001
HF with preserved EF 233 (11.0) 62 (8.4) 36 (10.3) 39 (13.0) 96 (13.2) 0.02
Hypertension 1,494 (70.9) 469 (64.0) 234 (67.0) 219 (73.2) 572 (78.9) <0.001
Stroke 275 (13.0) 99 (13.5) 45 (12.8) 46 (15.3) 85 (11.7) 0.44
Diabetes 414 (19.6) 104 (14.2) 56 (16.0) 69 (23.0) 185 (25.5) <0.001
Smoker 258 (12.2) 87 (11.8) 44 (12.6) 33 (11.0) 94 (12.9) 0.89
First episode of AF 1,252 (59.4) 434 (59.2) 205 (58.7) 189 (63.2) 424 (58.4) 0.55
Sinus rhythm at time of randomization 1,108 (52.6) 424 (57.9) 189 (54.1) 156 (52.1) 339 (46.7) <0.001
Duration of AF >1 month 911 (43.28) 317 (43.31) 150 (42.98) 126 (42.14) 318 (43.86) 0.965
Medications before randomization
β Blockers 897 (42.6) 295 (40.3) 138 (39.5) 136 (45.4) 328 (45.2) 0.11
Calcium channel blockers 823 (39.1) 280 (38.2) 121 (34.6) 129 (43.1) 293 (40.4) 0.13
Digoxin 1,130 (53.6) 364 (49.7) 172 (49.2) 176 (58.8) 418 (57.6) 0.002
Warfarin 1,793 (85.2) 618 (84.4) 293 (84.0) 259 (86.6) 623 (85.9) 0.67
Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker 821 (39) 226 (30.8) 122 (34.9) 111 (37.1) 362 (49.9) <0.001
Amiodarone 376 (17.8) 139 (18.9) 49 (14.0) 50 (16.7) 138 (19.0) 0.168
Sotalol 331 (15.7) 133 (18.1) 52 (14.9) 44 (14.7) 102 (14.0) 0.157
Class I antiarrhythmics 285 (13.5) 111 (15.1) 37 (10.6) 46 (15.3) 91 (12.5) 0.127
Echocardiographic parameters
Left atrial size <0.001
<4 cm 765 (36.3) 357 (48.7) 142 (40.6) 87 (29.1) 179 (24.6)
4.1–4.5 cm 612 (29.0) 215 (29.3) 97 (27.7) 88 (29.4) 212 (29.2)
≥4.6 cm 728 (34.5) 160 (21.8) 110 (31.5) 124 (41.4) 334 (46.0)
LVEF (>50% = referent) <0.001
>50% 1,587 (75.3) 627 (85.6) 283 (81.0) 219 (73.2) 458 (63.1)
40%–49% 262 (12.4) 67 (9.1) 34 (9.7) 40 (13.3) 121 (16.6)
30%–39% 154 (7.3) 27 (3.6) 18 (5.1) 20 (6.6) 89 (12.2)
<30% 102 (4.8) 11 (1.5) 14 (4.0) 20 (6.6) 57 (7.8)
Mitral regurgitation 446 (21.1) 131 (17.9) 74 (21.2) 66 (22.0) 175 (24.1) 0.03
Rhythm-control arm 1,061 (50.4) 398 (54.3) 150 (42.9) 148 (49.5) 365 (50.3) 0.006

Data are presented as mean ± SD or n (%).


The primary outcome occurred in 332 of patients (15.7%) and the secondary outcome in 521 (24.8%). By multivariate analysis, severely increased LV mass was predictive of all-cause mortality in the complete cohort (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.01 to 1.79, p = 0.045; Table 2 , Figure 1 ). Severely increased LV mass was not predictive of the secondary outcome (HR 1.20, 95% CI 0.96 to 1.51, p = 0.1; Figure 2 ) or cardiovascular hospitalization (HR 1.17, 95% CI 0.98 to 1.40, p = 0.08; Figure 3 ) in the overall population.



Table 2

Predictors of all-cause mortality in the overall population with available left ventricular (LV) mass data (n = 2,105)






























































































Variable Adjusted HR 95% CI p Value
LV mass (normal = referent)
Mildly abnormal 0.91 0.62–1.33 0.627
Moderately abnormal 0.98 0.68–1.43 0.935
Severely abnormal 1.34 1.01–1.79 0.045
Age 1.08 1.06–1.10 <0.001
History of CAD or MI 1.44 1.13–1.83 0.003
Congestive HF 1.59 1.23–2.06 <0.001
Stroke 1.68 1.27–2.22 <0.001
Diabetes mellitus 1.48 1.15–1.91 0.002
Smoker 1.90 1.38–2.60 <0.001
Warfarin use before randomization 0.72 0.53–0.97 0.033
LVEF (>50% = referent)
40%–49% 1.16 0.83–1.60 0.386
30%–39% 1.20 0.82–1.77 0.349
<30% 2.00 1.34–2.99 0.001
Mitral regurgitation 1.29 1.00–1.66 0.047
Rhythm-control arm 1.42 0.89–2.27 0.137

Multivariate Cox proportional hazards models were adjusted for LV mass, age, gender, history of coronary artery disease or myocardial infarction, history of hypertension, stroke, congestive HF, diabetes mellitus, smoking status, first episode of AF, sinus rhythm at the time of randomization, treatment with warfarin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β blocker, calcium channel blocker, digoxin, amiodarone, sotalol, class I antiarrhythmic medications, left atrial size, mitral regurgitation, LVEF, and randomization arm.

CAD = coronary artery disease; MI = myocardial infarction.



Figure 1


Adjusted HRs of LV mass for primary outcome (all-cause mortality) in the overall population, rate-, and rhythm-control arms. (A) HR of LV mass considered as a continuous variable (per 10-g increase) and (B) HR of severely increased LV mass (with normal LV mass considered as referent).



Figure 2


Adjusted HRs of LV mass for secondary outcome in the overall population, rate-, and rhythm-control arms. (A) HR of LV mass considered as a continuous variable (per 10-g increase) and (B) HR of severely increased LV mass (with normal LV mass considered as referent).



Figure 3


Adjusted HRs of LV mass for cardiovascular hospitalizations in the overall population, rate-, and rhythm-control arms. (A) HR of LV mass considered as a continuous variable (per 10-g increase) and (B) HR of severely increased LV mass (with normal LV mass considered as referent).


Severely increased LV mass was predictive of all-cause mortality (HR 1.57, 95% CI 1.07 to 2.31, p = 0.020) among patients in the rhythm-control arm ( Table 3 , Figure 1 ). Severely increased LV mass showed a trend of increased incidence of secondary outcome (HR 1.33, 95% CI 0.98 to 1.8, p = 0.07; Figure 2 ) and was significantly predictive of recurrent cardiovascular hospitalizations in the rhythm-control group (HR 1.29, 95% CI 1.02 to 1.63, p = 0.030; Figure 3 ). In the rate-control arm, severely increased LV mass was not predictive of all-cause mortality (HR 1.06, 95% CI 0.68 to 1.64, p = 0.80; Table 4 , Figure 1 ), secondary outcome (HR 1.10, 95% CI 0.78 to 1.54, p = 0.60; Figure 2 ) or cardiovascular hospitalizations (HR 1.05, 95% CI 0.80 to 1.40, p = 0.72; Figure 3 ).



Table 3

Predictors of all-cause mortality in the rhythm-control arm with available left ventricular (LV) mass data (n = 1,061)










































































Variable Adjusted HR 95% CI p Value
LV mass (normal = referent)
Mildly abnormal 1.23 0.72–2.08 0.447
Moderately abnormal 1.04 0.61–1.78 0.883
Severely abnormal 1.57 1.07–2.31 0.022
Age 1.08 1.06–1.11 <0.001
History of CAD or MI 1.47 1.05–2.06 0.023
Stroke 1.94 1.34–2.81 <0.001
Diabetes mellitus 1.58 1.11–2.26 0.011
Smoker 1.84 1.17–2.90 0.008
LVEF (>50% = referent)
40%–49% 1.07 0.67–1.72 0.774
30%–39% 1.18 0.69–2.00 0.550
<30% 2.09 1.20–3.64 0.009

Multivariate Cox proportional hazards models were adjusted for LV mass, age, gender, history of coronary artery disease or myocardial infarction, history of hypertension, stroke, congestive HF, diabetes mellitus, smoking status, first episode of AF, sinus rhythm at the time of randomization, treatment with warfarin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β blocker, calcium channel blocker, digoxin, amiodarone, sotalol, class I antiarrhythmic medications, left atrial size, mitral regurgitation, and LVEF.

CAD = coronary artery disease; MI = myocardial infarction.


Table 4

Predictors of all-cause mortality in the rate-control arm with available left ventricular (LV) mass data (n = 1,044)
































































Variable Adjusted HR 95% CI p Value
LV mass (normal = referent)
Mildly abnormal 0.66 0.38–1.15 0.141
Moderately abnormal 0.89 0.52–1.52 0.671
Severely abnormal 1.06 0.68–1.64 0.800
Age 1.07 1.05–1.10 <0.001
Congestive HF 2.03 1.39–2.97 <0.001
Smoker 2.10 1.33–3.31 0.001
LVEF (>50% = referent)
40%–49% 1.21 0.76–1.91 0.426
30%–39% 1.24 0.69–2.22 0.470
<30% 1.94 1.06–3.54 0.032

Multivariate Cox proportional hazards models were adjusted for LV mass, age, gender, history of coronary artery disease or myocardial infarction, history of hypertension, stroke, congestive HF, diabetes mellitus, smoking status, first episode of AF, sinus rhythm at the time of randomization, treatment with warfarin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, β blocker, calcium channel blocker, digoxin, left atrial size, mitral regurgitation, and LVEF.

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Dec 5, 2016 | Posted by in CARDIOLOGY | Comments Off on Outcomes in Atrial Fibrillation Patients With and Without Left Ventricular Hypertrophy When Treated With a Lenient Rate-Control or Rhythm-Control Strategy

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