Independent and Joint Association of Statin Therapy with Adverse Outcomes in Heart Failure Patients with Atrial Fibrillation Treated with Cardiac Resynchronization Therapy

Figures & data

Figure 1 Flowchart of the study population.

Abbreviations: CRT, cardiac resynchronization therapy; AF, atrial fibrillation.

Table 1 Baseline Characteristics of the Total Population and Stratified by AF Status and Statin Use

Characteristic	Total	Non-AF/Statin	Non-AF/Non-Statin	AF/Statin	AF/Non-Statin	P-value
	(N=685)	(N=237)	(N=305)	(N=68)	(N=75)
Age, years	59.1 ± 11.5	62.6 ± 9.8	55.9 ± 11.5	65.2 ± 8.7	55.6 ± 13.4	<0.001
Sex, n (%)						0.035
Male	467 (68.1)	168 (70.9)	191 (62.6)	53 (77.9)	54 (72.0)
Female	219 (31.9)	69 (29.1)	114 (37.4)	15 (22.1)	21 (28.0)
BMI, kg/m2	24.5 ± 4.1	24.9 ± 3.9	24.3 ± 4.6	25.0 ± 3.4	23.8 ± 3.3	0.181
Current smoker, n (%)	299 (43.6)	121 (51.1)	115 (37.8)	38 (55.9)	24 (32.0)	<0.001
Current drinker, n (%)	264 (38.5)	101 (42.6)	112 (36.8)	24 (35.3)	26 (34.7)	0.422
NYHA class, n (%)						0.302
I–II	191 (28.6)	66 (28.4)	90 (30.2)	22 (33.8)	12 (16.9)
III	389 (58.3)	138 (59.5)	167 (56.0)	37 (56.9)	47 (66.2)
IV	87 (13.0)	28 (12.1)	41 (13.8)	6 (9.2)	12 (16.9)
AF, n (%)	143 (20.9)	0 (0.0)	0 (0.0)	68 (100.0)	75 (100.0)	<0.001
Ischemic CMP, n (%)	84 (12.2)	56 (23.6)	10 (3.3)	17 (25.0)	1 (1.3)	<0.001
LBBB, n (%)	501 (73.7)	194 (81.9)	231 (76.5)	39 (57.4)	37 (50.7)	<0.001
CAD, n (%)	192 (28.2)	129 (54.4)	27 (8.9)	32 (47.1)	4 (5.4)	<0.001
Stroke, n (%)	54 (7.9)	25 (10.5)	8 (2.6)	13 (19.1)	8 (10.8)	<0.001
Hypertension, n (%)	245 (36.0)	111 (46.8)	87 (28.8)	29 (42.6)	18 (24.3)	<0.001
Diabetes, n (%)	169 (24.8)	88 (37.1)	46 (15.2)	23 (33.8)	12 (16.2)	<0.001
Hyperlipidemia, n (%)	264 (38.8)	156 (65.8)	60 (19.9)	40 (58.8)	8 (10.8)	<0.001
VT/VF, n (%)	183 (26.7)	48 (20.3)	78 (25.6)	24 (35.3)	33 (44.0)	<0.001
Statin, n (%)	305 (44.5)	237 (100.0)	0 (0.0)	68 (100.0)	0 (0.0)	<0.001
β-blocker, n (%)	605 (88.2)	207 (87.3)	273 (89.5)	60 (88.2)	64 (85.3)	0.739
Diuretics, n (%)	628 (91.5)	216 (91.1)	279 (91.5)	66 (97.1)	67 (89.3)	0.358
Amiodarone, n (%)	119 (17.3)	28 (11.8)	49 (16.1)	21 (30.9)	21 (28.0)	<0.001
ACEI/ARB, n (%)	564 (82.2)	195 (82.3)	256 (83.9)	57 (83.8)	55 (73.3)	0.189
Anticoagulants, n (%)	53 (7.7)	5 (2.1)	9 (3.0)	15 (22.1)	24 (32.0)	<0.001
Antiplatelet, n (%)	172 (25.1)	100 (42.2)	37 (12.1)	23 (33.8)	12 (16.0)	<0.001
BVP percentage, %	96.9 ± 10.6	97.8 ± 6.1	97.1 ± 11.0	94.9 ± 15.0	94.8 ± 14.5	<0.001
LVEF, %	30.4 ± 8.1	29.9 ± 7.5	30.0 ± 8.1	33.0 ± 8.7	31.1 ± 8.4	0.021
≤ 35%, n (%)	541 (78.9)	199 (84.0)	242 (79.3)	47 (69.1)	52 (69.3)	0.009
QRS, ms	164.2 ± 23.8	164.6 ± 21.6	166.4 ± 22.8	154.8 ± 28.5	162.5 ± 27.9	0.06
≥ 150ms, n (%)	510 (76.1)	179 (76.5)	234 (78.5)	43 (66.2)	54 (74.0)	0.195
LVEDD, mm	69.8 ± 9.9	68.9 ± 8.9	71.3 ± 10.3	68.6 ± 9.2	67.0 ± 10.1	0.001
NT-proBNP, pg/mL	2119.1 ± 2400.8	1910.4 ± 2622.9	2149.4 ± 2234.7	2019.2 ± 1599.0	2745.8 ± 2813.6	<0.001
eGFR, mL/min/1.73 m2	98.7 ± 45.2	96.6 ± 42.0	94.9 ± 43.2	109.5 ± 54.2	110.8 ± 50.9	0.009

Abbreviations: BMI, body mass index; NYHA, New York Heart Association; AF, atrial fibrillation; CMP, cardiomyopathy; LBBB, left bundle branch block; CAD, coronary artery disease; VT/VF, ventricular tachycardia/ventricular fibrillation; ACEI/ARB, angiotensin converting enzyme inhibitor/angiotensin receptor blocker; BVP, biventricular pacing; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end-diastolic diameter; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; eGFR, estimated glomerular filtration rate.

Figure 2 Joint prevalence of atrial fibrillation and statin use among patients with cardiac resynchronization therapy, 2007 to 2019.

Table 2 Association of AF Status and Statin Use with All-Cause Mortality and HF Hospitalization

Study Outcome	Events (%)	Hazard Ratio (95% CI), P value
		Model 1^a		Model 2^b		Model 3^c
All-cause mortality
AF status
Non-AF	135 (25.2)	1 [Reference]		1 [Reference]		1 [Reference]
AF	45 (31.7)	1.58 (1.13, 2.22)	0.008	1.59 (1.13, 2.23)	0.008	1.46 (1.03, 2.07)	0.033
Statin use
Non-Statin	107 (28.5)	1 [Reference]		1 [Reference]		1 [Reference]
Statin	73 (24.0)	0.86 (0.64, 1.17)	0.340	0.85 (0.62, 1.16)	0.305	0.81 (0.58, 1.13)	0.209
HF hospitalization
AF status
Non-AF	144 (27.3)	1 [Reference]		1 [Reference]		1 [Reference]
AF	54 (38.3)	1.70 (1.24, 2.33)	0.001	1.72 (1.26, 2.36)	0.001	1.59 (1.16, 2.20)	0.005
Statin use
Non-Statin	117 (31.6)	1 [Reference]		1 [Reference]		1 [Reference]
Statin	81 (27.2)	0.84 (0.63, 1.12)	0.231	0.86 (0.64, 1.16)	0.330	0.85 (0.62, 1.17)	0.319

Notes: ^aAdjusted for none. ^bAdjusted for age, sex. ^cAdjusted for age, sex, BMI, current smoker, current drinker, hypertension, diabetes, eGFR.

Abbreviations: AF, atrial fibrillation; HF, heart failure; BMI, body mass index; eGFR, estimated glomerular filtration rate.

Table 3 Joint Association of AF Status and Statin Use with All-Cause Mortality and HF Hospitalization

Study Outcome	Events (%)	Hazard Ratio (95% CI), P value
		Model 1^a		Model 2^b		Model 3^c
All-cause mortality
Non-AF/Statin	51 (21.6)	1 [Reference]		1 [Reference]		1 [Reference]
Non-AF/Non-Statin	84 (28.0)	1.24 (0.88, 1.76)	0.221	1.25 (0.87, 1.80)	0.219	1.31 (0.90, 1.93)	0.161
AF/Statin	22 (32.4)	1.75 (1.06, 2.88)	0.029	1.74 (1.05, 2.88)	0.030	1.64 (1.02, 2.72)	0.047
AF/Non-Statin	23 (31.1)	1.86 (1.13, 3.04)	0.014	1.87 (1.14, 3.08)	0.014	1.75 (1.04, 2.93)	0.033
HF hospitalization
Non-AF/Statin	54 (23.4)	1 [Reference]		1 [Reference]		1 [Reference]
Non-AF/Non-Statin	90 (30.4)	1.33 (0.95, 1.86)	0.100	1.28 (0.91, 1.82)	0.159	1.31 (0.91, 1.89)	0.146
AF/Statin	27 (40.3)	2.06 (1.30, 3.28)	0.002	2.08 (1.31, 3.31)	0.002	1.97 (1.23, 3.14)	0.005
AF/Non-Statin	27 (36.5)	1.96 (1.23, 3.11)	0.004	1.91 (1.19, 3.05)	0.007	1.76 (1.08, 2.86)	0.022

Notes: ^aAdjusted for none. ^bAdjusted for age, sex. ^cAdjusted for age, sex, BMI, current smoker, current drinker, hypertension, diabetes, eGFR.

Abbreviations: AF, atrial fibrillation; HF, heart failure; BMI, body mass index; eGFR, estimated glomerular filtration rate.

Figure 3 Joint association of Atrial fibrillation (AF) and Statin use with All-Cause mortality and Heart Failure (HF) hospitalization Among Patients with Cardiac Resynchronization Therapy. Hazard ratios (solid symbols) with 95% CIs (error bars) of joint categories of AF and statin use for all-cause mortality (A) and HF hospitalization (B) were estimated using multivariate Cox proportional hazards regression models adjusted for age, sex, body mass index, current smoker, current drinker, hypertension, diabetes, and estimated glomerular filtration rate.

Table 4 Reclassification and Discrimination Statistics for AF Status and Statin Use

	C-Statistic		IDI		NRI
	Estimate (95% CI)	P value	Estimate (95% CI)	P value	Estimate (95% CI)	P value
All-cause mortality
Conventional model*	0.654 (0.607, 0.701)		Ref.		Ref.
Conventional model + Statin	0.660 (0.614, 0.705)	0.272	0.003 (−0.001, 0.024)	0.193	0.032 (−0.122, 0.166)	0.605
Conventional model + AF	0.691 (0.647, 0.737)	<0.001	0.044 (0.013, 0.098)	0.013	0.191 (0.053, 0.329)	0.027
Conventional model + AF and Statin	0.693 (0.648, 0.738)	<0.001	0.045 (0.016, 0.101)	0.013	0.191 (0.039, 0.348)	0.02
HF hospitalization
Conventional model*	0.613 (0.564, 0.661)		Ref.		Ref.
Conventional model + Statin	0.612 (0.562, 0.661)	0.843	0.002 (−0.001, 0.023)	0.213	0.023 (−0.073, 0.163)	0.379
Conventional model + AF	0.675 (0.630, 0.720)	<0.001	0.048 (0.020, 0.099)	<0.001	0.181 (0.097, 0.350)	0.007
Conventional model + AF and Statin	0.675 (0.630, 0.720)	<0.001	0.048 (0.023, 0.103)	<0.001	0.197 (0.093, 0.352)	<0.001

Note: *Conventional model included age, sex, BMI, current smoker, diabetes, hypertension, LVEF and eGFR.

Abbreviations: AF, atrial fibrillation; HF, heart failure; BMI, body mass index; LVEF, left ventricular ejection fraction; eGFR, estimated glomerular filtration rate; IDI, integrated discrimination improvement; NRI, net reclassification improvement.