Baseline characteristics
A total of 1140 patients were registered in our database, out of which 1109 were analyzed and 31 were omitted due to incomplete data on DM status. Comorbid DM was present in 373 (32.7%) patients.
Baseline clinical and demographic characteristics of the study participants by diabetes status are given in Table 1. Patients with DM had higher age and BMI than non-DM counterparts. Furthermore, DM was significantly associated with the prevalence of other medical conditions, such as hypertension, dyslipidemia, chronic obstructive pulmonary disease, heart failure, stroke, myocardial infarction, vascular and chronic kidney disease.
Overall, the most prominent AF type was persistent or permanent AF, afflicting more than half of the population (52.5% of diabetic patients and 50% of non-diabetic patients). The presence of DM was associated with a significant increase in risk stratification CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category] -since it is included in the score per se-, as well as HAS-BLED score (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly)12 (both p values <0.001).
Table 1: Baseline characteristics and comorbidities in AF patients with and without DM.
CLINICAL CHARACTERISTICS
|
Total population (n=1,109)
|
AF with DM (n=373)
|
AF without DM (n=736)
|
P value (comparing DM vs no-DM)
|
Gender
|
M: 603 F: 506
|
M:196 F: 177
|
M: 407 F: 329
|
0.350
|
Age (years)
|
73.6 ± 10.9
|
75.2 ± 8.8
|
72.9 ± 11.7
|
<0.001
|
Body mass index (kg/m2)
|
28.5 ± 5.4
|
29.5 ± 5.6
|
28.0 ± 5.4
|
<0.001
|
Glomerular filtration rate (GFR) by CKD-EPI (mL/min/1.73m2)
|
60.4 ± 23.6
|
57.0 ± 22.4
|
64.7 ± 23.6
|
<0.001
|
Left Ventricular Ejection Fraction (%)
|
49.2 ± 12.2
|
48.4 ± 12.3
|
49.7 ± 12.1
|
0.113
|
NT-pro-BNP
|
2430.2 ± 5525.3
|
2331.5 ± 4991.1
|
2289.5 ± 5460.2
|
0.915
|
Glycated Hemoglobin (%)
|
6.52 ± 1.10
|
6.85 ± 1.14
|
5.77 ± 0.43*
|
<0.001
|
Medical Histories
|
N (%)
|
|
|
|
Hypertension
|
888(80.1)
|
317(87.3)
|
571(78.0)
|
<0.001
|
Dyslipidemia
|
527(47.5)
|
223(61.4)
|
304(41.5)
|
<0.001
|
Chronic obstructive pulmonary disease
|
142(12.8)
|
59(16.2)
|
83(11.3)
|
0.028
|
Heart failure
|
553(49.9)
|
213(58.8)
|
340(46.5)
|
<0.001
|
Strokes
|
164(14.8)
|
73(20.1)
|
91(12.5)
|
0.001
|
Myocardial infarction
|
228(20.6)
|
91(25.1)
|
137(18.7)
|
0.018
|
Chronic kidney disease
|
162(14.6)
|
84(23.1)
|
78(10.7)
|
<0.001
|
Vascular disease
|
509(45.9)
|
210(57.9)
|
299(40.8)
|
<0.001
|
Treatment and risk stratification scores
|
|
|
|
|
Rhythm control treatment
|
409(36.9%)
|
109(29.2%)
|
300(40.7%)
|
0.002
|
Use of antiplatelet(s) at discharge
|
218(19.7%)
|
97 (31.5%)
|
121 (15.8%)
|
0.002
|
Use of oral anticoagulant(s) at discharge: Vitamin K antagonist
NOAC
|
282(25.4%) 522(47.1%)
|
101 (27.1%) 171 (45.8%)
|
181 (24.6%) 351 (47.7%)
|
0.672
|
HAS-BLED score at discharge
|
1.7± 1
|
2 ± 1.1
|
1.7± 1
|
<0.001
|
CHA(2)DS(2)-VASc score at discharge
|
4.4 ± 1.9
|
5.6 ±1.6
|
3.8 ± 1.8
|
<0.001
|
*Glycated hemoglobin (HbA1c) baseline value was documented only in 122/736 (16.6%) AF patients without DM participating in our study.
AF, atrial fibrillation; DM, diabetes mellitus; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration equation; NT-pro-BNP, N-terminal pro b-type natriuretic peptide; NOAC, Non-Vitamin K oral anticoagulant; HAS-BLED, Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile International Normalized Ratio, Elderly, Drugs/alcohol concomitantly; CHA2DS2-VASc: Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, Stroke, Vascular disease, Age 65-74 years, Sex category
Clinical outcomes
During a median follow-up of 2.6 years, 414 (36.3%) patients died (Table 2). In particular, 73.3% of deaths were attributed to CV cause, while the presence of DM was significantly associated with higher prevalence of CV death (34.9% versus 23.5%, p<0.001). In both diabetics and non-diabetics, the most common cause of death was cardiac arrest (DM: 19.3%, non-DM: 10.9%, p<0.001). HF-related death was the second more common cause of mortality (DM: 13.4%, non-DM: 9.6%, p=0.058).
Table 2: Follow-up Outcomes by presence of DM with corresponding HR
Outcome
|
DM
|
Non-DM
|
Adjusted HR*
(95% CI)
|
|
All-cause death
|
171/373 (45.8%)
|
243/736 (33%)
|
1.40 (1.11-1.75)
|
|
CV-death
|
130/373 (34.9%)
|
173/736 (23.5%)
|
1.39 (1.07-1.81)
|
|
Sudden cardiac death
|
72/373
(19.3%)
|
80/736 (10.9%)
|
1.73 (1.19-2.52)
|
|
HF-realetd death
|
50/373 (13.4%)
|
71/736 (9.6%)
|
1.28 (0.86-1.91)
|
|
Major bleeding**
|
18/340 (5.3%)
|
29/644 (4.5%)
|
1.50 (0.78-2.87)
|
|
Stroke**
|
24/340 (7.1%)
|
28/645 (4.3%)
|
1.87(1.01-3.45)
|
|
AF-related hospitalization**
|
59/340 (17.4%)
|
115/645 (17.8%)
|
1.17 (0.82-1.66)
|
|
HF-related hospitalization**
|
35/333 (10.5%)
|
46/640 (7.2%)
|
1.40 (0.89-2.21)
|
|
Hospitalization or CV-death
|
243/373 (65.1%)
|
399/736
(54.2%)
|
1.27 (1.06-1.53)
|
|
*Adjusted for: age, BMI, history of prior stroke, coronary artery disease or prior revascularization procedure, AF subtype, eGFR (CKD-EPI) and use of ACEI-ARB, OAC and rate control medication after discharge.
**Competing-risks regression analysis (Fine and Gray 1999) was performed with all-cause death addressed as a competing risk.
DM, diabetes mellitus; HR, hazard ratio; AF, atrial fibrillation; CV, cardiovascular; HF, heart failure.
Patients with AF and comorbid DM had worse survival rate compared with those without DM (all-cause death: HR= 1.50, 95% CI: 1.20-1.86, p<0.001) (Figure 1). Moreover, patients with DM had a significantly higher risk for CV death (HR= 1.56, 95% CI: 1.21-2.02), cardiac arrest (HR= 1.94, 95% CI: 1.41-2.67), death due to HF (HR=1.53, 95% CI: 1.06-2.19), stroke (HR= 1.92, 95% CI: 1.12-3.27), and the composite outcome of CV-death or hospitalization (HR= 1.37, 95% CI: 1.17-1.61).
After adjusting for potential covariates, DM remained significant for predicting all-cause death (aHR= 1.44, 95% CI: 1.12-1.85), CV-death (aHR= 1.44, 95% CI: 1.08-1.93), cardiac arrest (aHR= 1.73, 95% CI: 1.19-2.52), stroke (aHR= 1.87, 95% CI: 1.01-3.45) and the composite outcome of CV-death or hospitalization (aHR= 1.28, 95% CI: 1.06-1.54) during follow-up (Figure 2). Both univariable and multivariable competing-risk regression analyses on cumulative incidence of major bleeding events, AF- and HF-related hospitalizations did not yield significantly higher hazard for those events in patients with DM than in those without DM (Figure 3).
The Kaplan–Meier curves (Figure 1B) demonstrated difference in the survival rates according to the mode of DM treatment (p<0.001). Specifically, DM patients under both insulin and oral medication had higher mortality rates during follow-up (aHR= 2.06, 95% CI: 1.32-3.23) than those solely on insulin injection, whereas patients with no pharmaceutical intervention or just lifestyle measures had the best prognosis after discharge.
Our multivariable Cox regression models identified the following predictors of survival as important to AF patients, apart from the presence of DM: age, eGFR, and the use of rate control (b-blocker or/and digoxin), ACEI-ARB and NOAC medication after discharge (p value< 0.05) (Figure 4).
Glycemic status affected mortality, with a 1% increase in HbA1c corresponding to higher all-cause mortality rates (aHR: 1.72, 95% CI: 1.13-2.61) and CV mortality rates (aHR: 1.81, 95% CI: 1.16-2.82). However, HbA1c levels, as a continuous variable, did not significantly predict hospitalization (aHR: 0.81, 95% CI: 0.54-1.23) or stroke incidence (aHR: 0.31, 95% CI: 0.06-1.66) during follow-up. Multivariable-adjusted restricted cubic spline analysis (Figure 5A) suggested an almost linear association between HbA1c levels and the risk for all-cause death, in which an HbA1c value of 6.6% corresponded to aHR of 1. The risk for all-cause mortality was significantly lower at HbA1c levels less than 6.2%. Despite the existing trend towards increased mortality in HbA1c>6.6%, only HbA1c levels 7.6-8.2% were independently associated with an increased risk of all-cause death. In the spline curve analysis on CV mortality (Figure 5B) the overall shape of the curve remained linear. This curve had an even more positive slope than the corresponding for all-cause mortality, but the only statistically significant correlation depicted was the lower CV mortality risk (aHR <1) in the HbA1c range of 5.6-6.2%.