Stable State Proadrenomedullin Level in COPD Patients: A Validation Study

Figures & data

Figure 1. Flow chart of patient inclusion.

Table 1. Baseline characteristics.

	Stable state N = 490				AECOPD N = 101
	Total	Alive	Dead	p	Total	Alive	Dead	p
Mean age at enrolment in years (SD)	67 (9)	66 (9)	72 (9)	p < 0.001	71 (11)	66 (10)	75(9)	p < 0.001
Male (number (%))	290 (59)	234 (58)	56 (66)	p = 0.17	66 (65)	32 (62)	34 (69)	p = 0.407
Smoking status (number (%))
Current smokers	122 (25)	104 (26)	18 (21)	p = 0.38	33 (33)	19 (37)	14 (29)	p = 0.394
Lung function (post-bronchodilator) ^*
Mean FEV1 in liters (SD)	1.51 (0.6)	1.58 (0.6)	1.16 (0.5)	p < 0.001	1.22 (0.5)	1.35 (0.5)	1.08 (0.4)	p = 0.006
Mean FEV1 as % of predicted (SD)	55.22 (19)	57.25 (18)	45.58 (18)	p < 0.001	46.99 (20)	50.15 (19)	43.49 (20)	p = 0.099
Mean FEV1/VC in % of predicted (SD)	45.58 (13)	46.43 (13)	41.56 (13)	p = 0.002	42.67 (14)	43.33 (14)	41.94 (14)	p = 0.631
GOLD classification 2005 (number (%))
I	48 (10)	44 (11)	4 (5)	p < 0.001	7 (7)	4 (8)	3 (6)	p = 0.180
II	237 (48)	211 (52)	26 (30)		29 (29)	20 (39)	9 (19)
III	171 (35)	128 (32)	43 (51)		48 (48)	21 (40)	27 (58)
IV	33 (7)	21 (5)	12 (14)		15 (15)	7 (13)	8 (17)
Mean BMI at enrolment (SD)	28 (5)	28 (5)	26 (5)	p = 0.005	26 (6)	27 (6)	25 (5)	p = 0.118
MMRC (0–4) (SD) ^**	1.6 (1.2)	1.5 (1.1)	2.2 (1.3)	p = 0.001	2.1 (1.3)	1.8 (1.1)	2.7 (1.3)	p = 0.015
ADO score (SD) ^***	3.9 (1.8)	3.6 (1.6)	5.1 (2.0)	p = 0.001	4.7 (1.8)	4.2 (1.6)	5.9 (1.7)	p = 0.001
Co-morbidity (number (%))
Heart failure	79 (16)	55 (14)	24 (28)	p = 0.001	24 (24)	2 (4)	0 (0)	p = 0.166
Myocardial infarction	13 (3)	11 (3)	2 (2)	p = 0.850	5 (5)	11 (21)	13 (27)	p = 0.526
Hypertension	28 (6)	27 (7)	1 (1)	p = 0.047	2 (2)	5 (10)	0 (0)	p = 0.026

^*Lung function test of 1 and 2 patient missing at stable state and AECOPD

^**ADO of 17 and 46 patients missing at stable state and AECOPD,

^***MMRC of 17 and 46 patients missing at stable state and AECOPD

Table 2. MR-proADM results.

	MR-proADM nmol/l (median(IQR))
Stable state
Non-survivors (N = 127)	0.83 (0.61–1.05)
Survivors (N = 363)	0.69 (0.56–0.84)
Difference between groups	p < 0.001
AECOPD
Non-survivors (N = 55)	1.03 (0.80–1.28)
Survivors (N = 46)	0.83 (0.67–1.09)
Difference between groups	p = 0.013

Table 3. Survival analysis based on different cut-off values of MR-proADM as well in stable state as in AECOPD.

	HR (95% CI)	^*cHR (95% CI)	C statistic
MR-proADM
Stable state (0.71 nmol/)^a	2.82 (1.75–4.55)	1.67 (0.98–2.85)	0.76
Stable state (0.75 nmol/)^b	3.20 (2.01–5.07)	2.02 (1.20–3.41)	0.77
AECOPD (0.79 nmol/)^c	2.17 (1.10–4.26)	1.51 (0.69–3.33)	0.73
AECOPD (0.84 nmol/)^d	2.82 (1.46–5.43)	1.91 (0.87–4.20)	0.74

^*cHR is HR corrected for age, sex, BMI HF, and GOLD status.

^aStudy median in stable state as found in Zuur-Telgen et al.

^bStudy median in stable state as found in Stolz et al.

^cStudy median at AECOPD as found in Zuur-Telgen et al.

^dStudy median at AECOPD as found in Stolz et al.

Figure 2. Kaplan-Meier survival curve MR-proADM stable state.

Table 4. One–and two-year mortality risk based on different cut-off values of MR-proADM as well in stable state as in AECOPD.

MR-proADM	<Median(non-survivors/total (%))	>Median(non-survivors/total (%))	RR (95% CI)	OR (95% CI)	^*cOR (95% CI)	AUC (95% CI)
Stable state (0.71 nmol/)
1 year	4/236 (2)	28/254 (11)	6.49 (2.31–18.2)	7.19 (2.48–20.8)	3.70 (1.18–11.6)	0.85 (0.78–0.91)
2 year	17/220 (8)	49/237 (21)	2.67 (1.59–4.50)	3.11 (1.73–5.59)	1.94 (0.99–3.79)	0.76 (0.70–0.83)
Stable state (0.75 nmol/)
1 year	6/271 (2)	26/219 (12)	5.38 (2.25–12.8)	5.95 (2.04–14.7)	3.15 (1.15–8.64)	0.85 (0.78–0.91)
2 year	20/252 (8)	46/205 (22)	2.82 (1.73–4.63)	3.36 (1.91–5.89)	2.23 (1.15–4.32)	0.77 (0.70–0.83)
AECOPD (0.79 nmol/)
1 year	5/32 (16)	21/68 (31)	1.98 (0.82–4.76)	2.41 (0.82–7.13)	1.77 (0.45–6.92)	0.78 (0.68–0.87)
2 year	9/27 (33)	33/57 (58)	1.74 (0.97–3.10)	2.75 (1.06–7.16)	2.28 (0.68–7.60)	0.78 (0.67–0.88)
AECOPD (0.84 nmol/)
1 year	6/40 (15)	20/60 (33)	2.22 (0.97–5.05)	2.83 (1.02–7.86)	1.76 (0.49–6.40)	0.78 (0.68–0.87)
2 year	10/31 (32)	32/53 (60)	1.87 (1.07–3.26)	3.20 (1.26–8.13)	2.66 (0.82–8.64)	0.77 (0.67–0.88)

^*cOR is corrected Odds ratio for sex, age, BMI, HF, and GOLD stage.

Table 5. Sensitivity and specificity of MR-proADM for 1-year survival (a priori 6.5%) and 2-year survival (a priori 13.5%).

Cut-off point MR-proADM (ng/ml)	Sensitivity (%)	Specificity (%)	Positive predictive value (%)	Negative predictive value (%)
(a) 1-year survival (a priori 6.5%)
0.7	87.5	49.8	10.9	98.3
0.71	87.5	50.7	11.0	98.3
0.75	81.3	57.9	11.9	97.8
0.79	68.8	64.8	12.0	96.7
0.8	68.8	65.9	12.4	96.8
0.84	68.8	71.4	14.4	97.0
0.9	62.5	76.4	15.6	96.7
1.0	43.8	84.7	16.7	95.6
1.1	31.3	88.9	16.4	94.9
1.2	25.0	93.2	20.5	94.7
1.3	18.8	95.0	20.7	94.4
1.4	15.6	96.5	23.8	94.2
1.5	12.5	97.4	25.0	94.1
(b) 2-year survival (a priori 13.5%)
0.7	74.2	50.7	19.0	92.7
0.71	74.2	51.7	19.3	92.8
0.75	69.7	59.2	21.0	92.6
0.79	62.1	66.5	22.4	91.9
0.8	60.6	67.5	22.5	91.7
0.84	59.1	73.1	25.5	92.0
0.9	53.0	78.1	27.3	91.4
1.0	37.9	86.1	29.8	89.9
1.1	30.3	90.3	32.8	89.3
1.2	18.2	93.6	30.8	88.0
1.3	15.2	95.5	34.5	87.9
1.4	13.6	97.2	42.9	87.8
1.5	12.1	98.1	50.0	87.8

Figure 3. Kaplan-Meier survival curves MR-proADM at hospitalization for AECOPD.

Figure 4. (a) ROC curve at stable state for one-year survival. Cut-off values in nmol/l marked. (b) ROC curve at stable state for two-year survival. Cut-off values in nmol/l marked.