Download Peak C-Reactive Protein Level Predicts Long-Term

Peak C-Reactive Protein Level Predicts Long-Term
Outcomes in Type B Acute Aortic Dissection
Kenichi Sakakura, Norifumi Kubo, Junya Ako, Hiroshi Wada, Naoki Fujiwara, Hiroshi Funayama,
Nahoko Ikeda, Tomohiro Nakamura, Yoshitaka Sugawara, Takanori Yasu,
Masanobu Kawakami, Shin-ichi Momomura
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Abstract—Acute aortic dissection (AAD) is associated with an inflammatory reaction, as evidenced by elevated inflammatory
markers, including C-reactive protein (CRP). The association between the peak CRP level and long-term outcomes in type
B AAD has not been systematically investigated. The purpose of this study was to investigate whether the peak CRP level
during admission predicts long-term outcomes in type B AAD. We conducted a clinical follow-up study of type B AAD.
We divided the study population into 4 groups according to the tertiles of peak CRP levels (T1: 0.60 to 9.37 mg/dL;
T2: 9.61 to 14.87 mg/dL; T3: 14.90 to 32.60 mg/dL; and unavailable peak CRP group). Multivariate Cox regression
analysis was applied to investigate whether the tertiles of peak CRP predict adverse events even after adjusting for other
variables. A total of 232 type B AAD patients were included in this analysis. The median follow-up period was 50
months. CRP reached its peak on day 4.5⫾1.7. Mean peak CRP values in T1, T2, and T3 were 6.4⫾2.4, 12.0⫾1.5, and
19.5⫾4.0 mg/dL, respectively. There were 65 events (39 deaths and 26 aortic events) during the follow-up. T3 and T2
(versus T1) were strong predictors of adverse events (T3: hazard ratio: 6.02 [95% CI: 2.44 to 14.87], P⫽0.0001; T2:
hazard ratio: 3.25 [95% CI: 1.37 to 7.71], P⫽0.01) after controlling for all of the confounding factors. In
conclusion, peak CRP is a strong predictor for adverse long-term events in patients with type B AAD.
(Hypertension. 2010;55:422-429.)
Key Words: C-reactive protein 䡲 peak CRP 䡲 initial CRP 䡲 type B acute aortic dissection 䡲 long-term outcomes
T
ype B acute aortic dissection (AAD) is often successfully
managed by medical therapy during the acute phase, with
a lower in-hospital mortality rate compared with type A
AAD.1 However, the long-term prognosis of type B AAD is
associated with both higher morbidity and mortality.2–5 In an
attempt to identify high-risk patients, several predictors of longterm adverse events in type B AAD have been reported.4,6–9
These predictors include false lumen closure status and
maximum aortic diameter, which can be evaluated using 2D
imaging studies, such as computed tomography (CT). However, the anatomy of the dissection is often complex, making
it difficult to estimate the severity of disease by 2D imaging
markers alone.
AAD is associated with an inflammatory reaction,10 –12 as
evidenced by a significant elevation in inflammatory markers,
including C-reactive protein (CRP).13–16 Although CRP levels
during hospital admission show significant temporal variations, the peak CRP level has been reported to be a useful
marker to estimate the whole severity of acute illness or to
predict adverse events.17,18 However, the association between
peak CRP and long-term outcomes in type B AAD has not
been systematically investigated. Therefore, the purpose of
this study was to investigate whether the peak CRP level
predicts long-term outcomes in type B AAD.
Methods
Patients and Follow-Up
We identified type B AAD patients from hospital admission records
between December 1989 and December 2008. The inclusion criteria
were type B AAD presenting within 14 days of symptom onset and
CT with contrast confirming a dissected descending aorta containing
both a true and false lumen. The exclusion criteria were an
in-hospital death in the index admission and loss to follow-up.
Follow-up was performed via office visit, letter, or telephone
contact. The day of the index discharge was determined as the
beginning of follow-up. The study primary end points were all-cause
death and aortic events, such as surgery of the thoracic aorta
(ascending, arch, or descending), recurrence of an aortic dissection,
and an aortic rupture. Because other follow-up studies in type B
AAD had used all-cause mortality as the end point, we adopted
all-cause mortality as the end point.3,9,19,20 However, we also
collected information about the cause of each death, which allowed
us to perform a secondary analysis using cardiovascular death and
aortic events as the secondary end points. Patients were followed
until meeting a study primary end point (death or an aortic event) or
until the study end date (April 2009). Patients who did not experi-
Received September 17, 2009; first decision October 8, 2009; revision accepted November 30, 2009.
From the Division of Cardiovascular Medicine, Department of Integrated Medicine I, Jichi Medical University Saitama Medical Center, Omiya,
Saitama, Japan.
Correspondence to Norifumi Kubo, Division of Cardiovascular Medicine, Department of Integrated Medicine I, Jichi Medical University Saitama
Medical Center, Amanuma 1-847, Omiya, Saitama 330-8503, Japan. E-mail [email protected]
© 2010 American Heart Association, Inc.
Hypertension is available at http://hyper.ahajournals.org
DOI: 10.1161/HYPERTENSIONAHA.109.143131
422
Sakakura et al
ence an outcome of interest were censored at the last known date of
contact.
This study was performed in accordance with the Helsinki
Declaration and was approved by the internal review board. All of
the study patients had previously granted permission for use of their
medical charts for research purposes.
Definition of Peak CRP
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Circulating CRP was mostly measured daily or every other day until
it reached its initial peak in our institution. Initial peak CRP level
was defined as the peak CRP. From December 1989 to November
2003, CRP was measured by turbidimetric immunoassay (Iatron
CRP-TIA, Iatron) using an autoanalyzer (JCA-RX20, JEOL Ltd).
From November 2003 to December 2008, CRP was measured by
latex agglutination nephelometry (NanopiaCRP, Sekisui Medical)
using an autoanalyzer (JCA-BM2250, JEOL Ltd). When the admission or predischarge CRP level was higher than the rest of the CRP
levels, we were unable to determine the peak CRP level. We divided
the patients who had peak CRP levels into 3 groups according to the
tertiles of peak CRP, with T1 being the lowest and T3 being the
highest (CRP level; T1: 0.60 to 9.37 mg/dL; T2: 9.61 to 14.87
mg/dL; T3: 14.90 to 32.60 mg/dL). The patients who did not have
peak CRP levels were included in an unavailable peak CRP group
(UG). The initial CRP level, which was measured after admission,
was defined as the initial CRP.
Definition of Other Clinical Criteria
Clinical criteria were defined as described here. Hypertension was
defined as systolic blood pressure ⬎140 mm Hg, diastolic blood
pressure ⬎90 mm Hg, or medical treatment for hypertension before
admission. Hyperlipidemia was total cholesterol level ⬎220 mg/dL,
low-density lipoprotein cholesterol level ⬎140 mg/dL, or treatment
for hyperlipidemia before admission. Diabetes mellitus was hemoglobin A1c level ⬎6.5% or treatment for diabetes mellitus before
admission. Estimated glomerular filtration rate was calculated from
the serum creatinine level, age, weight, and sex, according to the
Cockroft-Gault formula,21 and estimated glomerular filtration rate
ⱕ60 mL/min was considered impaired renal function. CT scan with
intravenous contrast was performed ⱖ1 time in all of the patients.
The initial examination was used for the statistical analysis. Partial
enhancement of the false lumen was defined as a nonthrombosed
type, and an intramural hematoma of the aorta was included as a
thrombosed type. Maximum aortic diameter of the dissected aorta
was also measured in all of the patients.
Statistical Analysis
Data are presented as frequencies and percentages for categorical
variables and mean⫾SD for continuous variables. Patient characteristics are compared between the groups divided by the
tertiles of peak CRP. Parametrical data were compared using a
1-way ANOVA, whereas nonparametrical data were compared
using the Kruskal-Wallis test. Categorical data were compared
using the ␹2 test. The Kaplan–Meier curves stratified according to
the tertiles of peak CRP were constructed. Multivariate Cox
regression analysis was applied to investigate whether the tertiles
of peak CRP predict adverse events even after adjusting for other
variables using 3 models. In model 1, we selected independent
variables by a statistical selection. We used significantly different
characteristics among the 4 groups as the independent variables.
In model 2, we selected independent variables by a clinical
selection. We adopted known factors such as age, sex, maximum
aortic diameter, false lumen closure status, the extent of dissection, statin use, antihypertensive medications at discharge, and
impaired renal function as independent variables.3,4,6 –9,22 The
difference between CRP measurements was also adopted in this
model. In model 3, we selected independent variables by a
combination of statistical selection and clinical selection. We
adopted all of the independent variables used in model 1 and
Peak CRP in Type B Aortic Dissection
423
model 2. All of the variables were simultaneously adjusted in 1
step. Hazard ratios (HRs) and the 95% CI were calculated. We
constructed a conventional receiver operating characteristic curve
to analyze peak CRP levels to determine the cutoff points that
yielded the highest combined sensitivity and specificity with
respect to distinguishing patients with adverse events from those
without such events. A P⬍0.05 was considered statistically
significant. All of the analyses were performed using statistical
software, SPSS 13.0/Windows (SPSS Inc).
Results
Between December 1989 and December 2008, there were 263
patients with type B AAD admitted to Saitama Medical
Center. Ten patients were excluded from the study because of
the lack of critical information, such as a CT. Nine patients
died during the index admission. Twelve patients were lost to
follow-up. Thus, a total of 232 type B AAD patients were
included in this analysis. The median follow-up for the 232
patients was 50 months. Although peak CRP levels were
available in 200 patients, peak CRP levels were unavailable
in 32 patients (admission CRP levels higher than the rest of
the CRP levels [n⫽22]; predischarge CRP levels higher than
the rest of the CRP levels [n⫽8]; serial measurements of CRP
data not obtained [n⫽2]). The 200 patients who had peak
CRP levels were divided into 3 groups according to the
tertiles of peak CRP, with T1 being the lowest and T3 being
the highest. The 32 patients who did not have peak CRP
levels were included in a UG. A patient flowchart is shown in
Figure S1 (available in the online Data Supplement at
http://hyper.ahajournals.org).
In 88% of the patients who had an available peak CRP
(176 of 200), CRP reached its peak between day 3 and day
6 (day: 4.5⫾1.7). The correlation coefficient between
initial CRP levels and peak CRP levels was 0.23 (Spearman rank coefficient: P⫽0.001). The clinical characteristics among all, T1, T2, T3, and UG are shown in Table 1.
Mean peak CRP values in the total population, T1, T2, and
T3 groups were 12.6⫾6.1, 6.4⫾2.4, 12.0⫾1.5, and
19.5⫾4.0 mg/dL, respectively. Initial CRP levels, time
from onset to admission, being overweight (body mass
index ⬎25 kg/m2), current smoking, impaired renal function at admission, white blood cell counts, heart rate at
discharge, and diuretics as an antihypertensive medication
at discharge were significantly different among groups.
The Kaplan–Meier curves stratified according to the tertiles of peak CRP and unavailable peak CRP are shown in
the Figure. Log-rank testing revealed a significant increase
in adverse events in the T3 group and UG as compared
with the T1 group (P⫽0.0001 for T3 versus T1; P⫽0.0004
for UG versus T1). There were 65 events (39 deaths and 26
aortic events) during the follow-up period (Table S1).
Multivariate Cox regression analysis was performed in 3
ways. In model 1, the tertiles of peak CRP and significant
confounding factors, such as tertiles of initial CRP, time from
onset to admission, being overweight, current smoking,
impaired renal function at admission, white blood cell counts,
heart rate at discharge, and diuretics as antihypertensive
medication at discharge, were adopted as independent variables (Table 2). UG, T3, and T2 (versus T1) were strong
predictors of adverse events (UG: HR: 7.07 [95% CI: 2.60 to
424
Table 1.
Hypertension
February 2010
Patients Characteristics Compared Among Tertiles of Peak CRP
Patient Characteristics
Peak CRP range, mg/dL
No.
Median follow-up period, mo
Peak CRP, n, mg/dL
Frequency of CRP measurements, times
All
Lowest
Tertile (T1)
Middle
Tertile (T2)
Highest
Tertile (T3)
Unavailable
Peak (UG)
P
0.60 to 32.60
0.60 to 9.37
9.61 to 14.87
14.90 to 32.60
…
…
232
67
67
66
32
…
50
71
50
38
50
…
6.4⫾2.4, 67
12.0⫾1.5, 67
19.5⫾4.0, 66
12.6⫾6.1, 200
12⫾7
12⫾7
13⫾8
15⫾7
…
7⫾5
…
⬍0.0001
Methods of CRP measurements
Turbidimetric immunoassay, n (%)
128/232 (55.2)
40/67 (59.7)
34/67 (50.7)
34/66 (51.5)
20/32 (62.5)
Latex agglutination nephelometry, n (%)
104/232 (44.8)
27/67 (40.3)
33/67 (49.3)
32/66 (48.5)
12/32 (37.5)
…
2.7⫾4.8, 232
1.2⫾2.0, 67
1.6⫾3.1, 67
2.9⫾4.6, 66
8.1⫾7.6, 32
⬍0.0001
Age, n, y
64.1⫾11.9, 232
63.4⫾11.9, 67
62.4⫾12.1, 67
65.4⫾12.0, 66
66.3⫾11.0, 32
0.31
Male sex, n (%)
165/232 (71.1)
45/67 (67.2)
48/67 (71.6)
53/66 (80.3)
19/32 (59.4)
Time from onset to admission, d
1.1⫾2.3
0.6⫾1.1
0.5⫾0.9
0.5⫾0.9
4.7⫾4.3
Initial CRP, n, mg/dL
Overweight (BMI ⬎25 kg/m2), n (%)
0.54
0.15
⬍0.0001
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78/230 (33.9)
13/67 (19.4)
29/67 (43.3)
26/66 (39.4)
10/30 (33.3)
0.02
167/232 (72.0)
47/67 (70.1)
45/67 (67.2)
51/66 (77.3)
24/32 (75.0)
0.58
Hyperlipidemia, n (%)
74/232 (31.9)
22/67 (32.8)
17/67 (25.4)
27/66 (40.9)
8/32 (25.0)
0.21
Diabetes mellitus, n (%)
23/232 (9.9)
7/67 (10.4)
4/67 (6.0)
7/66 (10.6)
5/32 (15.6)
0.5
Current smoking, n (%)
111/232 (47.8)
25/67 (37.3)
41/67 (61.2)
32/66 (48.5)
13/32 (40.6)
0.04
Asthma, n (%)
8/232 (3.4)
2/67 (3.0)
1/67 (1.5)
4/66 (6.1)
1/32 (3.1)
0.54
Marfan syndrome, n (%)
6/232 (2.6)
3/67 (4.5)
0/67 (0)
2/66 (3.0)
1/32 (3.1)
0.42
Atrial fibrillation, n (%)
10/227 (4.4)
2/66 (3.0)
1/66 (1.5)
5/64 (7.8)
2/31 (6.5)
0.3
Previous MI or angina pectoris, n (%)
19/232 (8.2)
5/67 (7.5)
3/67 (4.5)
8/66 (12.1)
3/32 (9.4)
0.44
0/67 (0)
0/67 (0)
3/66 (4.5)
0/32 (0)
0.05
Hypertension, n (%)
Previous aortic dissection, n (%)
3/232 (1.3)
Aortoiliac aneurysm, n (%)
36/232 (15.5)
8/67 (11.9)
9/67 (13.4)
15/66 (22.7)
4/32 (12.5)
0.29
Creatinine at admission, n, mg/dL
1.0⫾1.2, 232
1.1⫾1.7, 67
1.0⫾1.4, 67
1.1⫾0.7, 66
0.8⫾0.3, 32
0.11
Creatinine at discharge, n, mg/dL
1.1⫾1.4, 225
1.0⫾1.0, 64
1.1⫾1.5, 67
1.4⫾1.9, 65
0.9⫾0.3, 29
0.07
Impaired renal function at admission, n (%)
63/232 (27.2)
13/67 (19.4)
14/67 (20.9)
27/66 (40.9)
9/32 (28.1)
0.02
Impaired renal function at discharge, n (%)
73/225 (32.4)
18/64 (28.1)
17/67 (25.4)
28/65 (43.1)
10/29 (34.5)
0.14
White blood cell counts (⫻103/mm3), n
12.0⫾3.9, 232
10.5⫾3.7, 67
12.7⫾3.7, 67
13.4⫾4.0, 66
10.5⫾3.4, 32
⬍0.0001
Surgery at initial hospitalization, n (%)*
17/232 (7.3)
3/67 (4.5)
3/67 (4.5)
3/32 (9.4)
0.26
8/66 (12.1)
CT findings
Nonthrombosed type, n (%)
102/232 (44.0)
28/67 (41.8)
25/67 (37.3)
36/66 (54.5)
13/32 (40.6)
0.21
Maximum aorta diameter, n, mm
39.0⫾8.0, 232
37.7⫾7.3, 67
38.2⫾6.8, 67
40.1⫾8.9, 66
40.9⫾9.3, 32
0.31
45/232 (19.4)
16/67 (23.9)
14/67 (20.9)
10/66 (15.2)
5/32 (15.6)
0.57
DeBakey IIIa (did not across diaphragm), n/N (%)
Systolic BP at admission, n, mm Hg
156⫾29, 232
156⫾25, 67
159⫾29, 67
155⫾33, 66
153⫾25, 32
0.65
Diastolic BP at admission, n, mm Hg
84⫾18, 232
83⫾17, 67
88⫾17, 67
82⫾21, 66
85⫾14, 32
0.11
Heart rate at admission, n, per min
82⫾16, 232
80⫾17, 67
81⫾18, 67
83⫾14, 66
87⫾17, 32
0.26
Systolic BP at discharge, n, mm Hg
121⫾16, 232
119⫾15, 67
120⫾17, 67
122⫾19, 66
123⫾12, 32
0.53
Diastolic BP at discharge, n, mm Hg
70⫾10, 232
70⫾9, 67
71⫾11, 67
68⫾9, 66
72⫾9, 32
0.13
Heart rate at discharge, n, per min
67⫾12, 232
66⫾11, 67
63⫾10, 67
68⫾13, 66
73⫾15, 32
0.01
Calcium channel blockers, n (%)
217/232 (93.5)
62/67 (92.5)
63/67 (94.0)
63/66 (95.5)
29/32 (90.6)
0.8
␤-Blockers, n (%)
Antihypertensive medication at discharge
188/232 (81.0)
54/67 (80.6)
57/67 (85.1)
52/66 (78.8)
25/32 (78.1)
0.77
ACE inhibitors, n/N (%)
66/232 (28.4)
23/67 (34.3)
19/67 (28.4)
15/66 (22.7)
9/32 (28.1)
0.53
ARBs, n/N (%)
60/232 (25.9)
16/67 (23.9)
22/67 (32.8)
16/66 (24.2)
6/32 (18.8)
0.43
␣-Blockers, n/N (%)
38/232 (16.4)
8/67 (11.9)
12/67 (17.9)
16/66 (24.2)
2/32 (6.3)
0.09
Diuretics, n/N (%)
40/232 (17.2)
9/67 (13.4)
8/67 (11.9)
19/66 (28.8)
4/32 (12.5)
0.03
28/232 (12.1)
4/67 (6.0)
7/67 (10.4)
13/66 (19.7)
4/32 (12.5)
0.11
Statins at discharge, n/N (%)
Data are expressed as mean⫾SD or percentage unless otherwise specified. ␹2 test was used for categorical variables. One-way ANOVA or Kruskal-Wallis test was
used for continuous variables. BMI indicates body mass index; BP, blood pressure; ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin
receptor blockers; MI, myocardial infarction.
*No patient had fenestrating or stenting at initial hospitalization.
Sakakura et al
Peak CRP in Type B Aortic Dissection
425
Event-free survival rate
1.00
Lowest Tertile (T1)
of Peak CRP
0.75
Middle Tertile (T2)
of Peak CRP
0.50
P values
Overall, <0.0001
T1 vs. T2, 0.09
T1 vs. T3, 0.0001
T1 vs. UG, 0.0004
T2 vs. T3, 0.01
T2 vs. UG, 0.06
T3 vs. UG, 0.63
0.25
Unavailable peak
CRP (UG)
Highest Tertile (T3)
of Peak CRP
Figure. Kaplan–Meier curve stratified
according to the tertiles of peak CRP. The
P value was calculated by the log-rank
test.
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
0.00
No. at risk
0
1000
2000
3000
Days since Follow-up
Lowest Tertile (T1)
67
48
35
23
Middle Tertile (T2)
67
45
28
10
Highest Tertile (T3)
66
36
19
6
Unavailable peak (UG) 32
24
13
8
19.26], P⫽0.0001; T3: HR: 5.13 [95% CI: 2.26 to 11.62],
P⬍0.0001; T2: HR: 2.59 [95% CI: 1.13 to 5.94], P⫽0.02)
even after controlling for all of the confounding factors. In
this model, we also divided patients into 3 groups according
Table 2. Multivariate Cox Regression Analysis Predicting
Death or Event: Model 1
Variables
HR
95% CI
P
Middle tertile (T2) of peak CRP
(vs lowest tertile 关T1兴)
2.59
1.13 to 5.94
0.02
Highest tertile (T3) of peak CRP
(vs lowest tertile 关T1兴)
5.13
2.26 to 11.62
⬍0.0001
Unavailable peak CRP group (UG)
(vs lowest tertile 关T1兴)
7.07
2.60 to 19.26
0.0001
Middle tertile of initial CRP
(vs lowest tertile of initial CRP)
1.37
0.69 to 2.73
0.37
Highest tertile of initial CRP
(vs lowest tertile of initial CRP)
1.14
0.57 to 2.30
0.71
Time from onset to admission
0.88
0.76 to 1.02
0.10
Overweight
0.92
0.51 to 1.65
0.78
Current smoking
1.09
0.63 to 1.90
0.76
Impaired renal function at admission
(eGFR ⬍60 mL/min)
1.22
0.67 to 2.21
0.51
White blood cell counts (⫻103/mm3)
0.95
0.88 to 1.02
0.14
Heart rate at discharge (per 1/min
incremental)
1.02
1.00 to 1.04
0.10
Diuretics
1.69
0.90 to 3.17
0.10
Peak CRP
Initial CRP
eGFR indicates estimated glomerular filtration rate. In this model, all of the
significant confounding factors among tertiles of peak CRP (P⬍0.05 in Table 1) are
adopted as independent variables. All of the variables are adjusted in 1 step.
to the tertiles of initial CRP levels. However, neither the
highest tertile of initial CRP (versus the lowest tertile of
initial CRP group: HR: 1.14 [95% CI: 0.57 to 2.30]; P⫽0.71)
nor the middle tertile of initial CRP (versus the lowest tertile of
initial CRP group: HR: 1.37 [95% CI: 0.69 to 2.73]; P⫽0.37)
was a significant predictor of adverse events. In model 2, the
tertiles of peak CRP and known variables such as age, sex,
maximum aortic diameter, false lumen closure status, the extent
of dissection (DeBakey IIIa or IIIb), impaired renal function,
statins, calcium channel blockers, ␤-blockers, and angiotensinconverting enzyme inhibitors at discharge were included as
independent variables. The 2 different methods of CRP measurement at our institution were also included as independent
variables. UG (HR: 4.28 [95% CI: 1.78 to 10.32]; P⫽0.001), T3
(HR: 3.99 [95% CI: 1.78 to 8.99]; P⫽0.0008), and T2 (HR: 2.42
[95% CI: 1.04 to 5.61]; P⫽0.04) were associated with adverse
events in long-term follow-up (Table 3). In model 3, we adopted
all of the independent variables used in model 1 and model 2.
UG (HR: 7.45 [95% CI: 2.20 to 25.28]; P⫽0.001), T3 (HR: 6.02
[95% CI: 2.44 to 14.87]; P⫽0.0001), and T2 (HR: 3.25 [95%
CI: 1.37 to 7.71]; P⫽0.01) were associated with adverse events
(Table 4).
We performed a secondary analysis using cardiovascular
deaths and aortic events as a secondary end point. In 65 total
events, there were 11 deaths that were less associated with aortic
dissection (cancer [n⫽4], pneumonia [n⫽3], emphysema [n⫽1],
renal failure [n⫽1], nephritic syndrome [n⫽1], and hemorrhagic
shock [n⫽1]). After excluding these deaths, multivariate Cox
regression analysis revealed that the tertiles of peak CRP were
still significantly associated with adverse events even after
controlling for all of the variables used in model 3 (T2 versus T1:
HR: 2.64 [95% CI: 1.00 to 6.98], P⫽0.05; T3 versus T1: HR:
426
Hypertension
February 2010
Table 3. Multivariate Cox Regression Analysis Predicting
Death or Event: Model 2
Variables
HR
95% CI
Middle tertile (T2) of peak CRP
(vs lowest tertile 关T1兴)
2.42
Highest tertile (T3) of peak CRP
(vs lowest tertile 关T1兴)
Table 4. Multivariate Cox Regression Analysis Predicting
Death or Event: Model 3
P
Variables
HR
95% CI
1.04 to 5.61
0.04
Peak CRP
3.99
1.78 to 8.99
0.0008
Unavailable peak CRP group (UG)
(vs lowest tertile 关T1兴)
4.28
1.78 to 10.32
Age (per 10-y incremental)
1.09
Male sex
Maximum aorta diameter
(per 1-mm incremental)
P
Middle tertile (T2) of peak CRP
(vs lowest tertile 关T1兴)
3.25
1.37 to 7.71
0.01
Highest tertile (T3) of peak CRP
(vs lowest tertile 关T1兴)
6.02
2.44 to 14.87
0.0001
0.001
2.20 to 25.28
0.001
0.50
Unavailable peak CRP group (UG)
(vs lowest tertile 关T1兴)
7.45
0.85 to 1.39
1.78
0.87 to 3.61
0.11
1.01
0.98 to 1.05
0.41
Middle tertile of initial CRP
(vs lowest tertile of initial CRP)
1.48
0.71 to 3.09
0.29
Highest tertile of initial CRP
(vs lowest tertile of initial CRP)
0.84
0.38 to 1.87
0.67
Time from onset to admission
0.91
0.78 to 1.07
0.25
Overweight
0.80
0.41 to 1.53
0.49
Initial CRP
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Nonthrombosed type
1.24
0.69 to 2.22
0.47
DeBakey IIIa (vs IIIb)
0.90
0.40 to 2.04
0.80
Impaired renal function at
discharge (eGFR ⬍60 mL/min)
2.27
1.26 to 4.11
0.01
Turbidimetric immunoassay (vs
latex agglutination nephelometry)
0.36
0.15 to 0.84
0.02
Current smoking
0.77
0.41 to 1.44
0.41
0.18 to 1.07
0.07
1.11
0.44 to 2.82
0.83
Impaired renal function at admission
(eGFR ⬍60 mL/min)
0.44
Statins at discharge
CCB at discharge
0.46
0.18 to 1.17
0.10
White blood cell counts (⫻103/mm3)
0.95
0.87 to 1.03
0.20
Heart rate at discharge (per 1/min
incremental)
1.02
0.99 to 1.04
0.25
Diuretics
1.14
0.52 to 2.51
0.75
␤-Blockers at discharge
1.01
0.52 to 1.96
0.98
ACE inhibitors at discharge
0.50
0.25 to 0.97
0.04
ACE indicates angiotensin-converting enzyme; CCB, calcium channel
blocker; eGFR, estimated glomerular filtration rate. In this model, age, sex, the
difference of CRP measurements, and previously reported risk factors, such as
maximum aorta diameter, nonthrombosed type, the extent of dissection,
impaired renal function, statins, and antihypertensive medications are adopted
as independent variables. All of the variables are adjusted in 1 step.
5.28 [95% CI: 1.94 to 14.41], P⫽0.001; UG versus T1: HR:
6.03 [95% CI: 1.66 to 21.90], P⫽0.006).
We constructed receiver operating characteristic curves
and calculated statistics for the area under the curve. The area
under the curve was 0.60 (95% CI: 0.51 to 0.69; P⫽0.03). A
peak CRP value of 9.5 mg/dL, which is the cutoff value
between T1 and T2, has a 76% sensitivity and a 37%
specificity for the occurrence of adverse events. A peak CRP
value of 14.9 mg/dL, which is the cutoff value between T2
and T3, has a 46% sensitivity and a 71% specificity for the
occurrence of adverse events.
Because the timeline of the study is fairly long, the time
effect might affect patient outcomes. To investigate the time
effect, we divided the 232-patient study group in half and
compared outcomes between the former 116 patients (from
December 1989 to November 2002) and the latter 116
patients (from November 2002 to December 2008) by logrank test. Event-free survival at 3 years was not different
(91% in former patients versus 88% in latter patients;
P⫽0.12). The prescription rate of calcium channel blockers,
␤-blockers, ␣-blockers, and diuretics at discharge was not
significantly different between the former and the latter
patients. Although the prescription rate of angiotensinconverting enzyme inhibitors was higher in the former
patients (39.7% versus 17.2%; P⫽0.0002), that of angiotensin receptor blocker was higher in the latter patients (11.2%
versus 40.5%; P⬍0.0001).
Age (per 10-y incremental)
1.08
0.80 to 1.46
0.62
Male sex
2.06
0.96 to 4.43
0.06
Maximum aorta diameter (per 1-mm
incremental)
1.03
1.00 to 1.07
0.07
Nonthrombosed type
1.31
0.68 to 2.55
0.42
DeBakey IIIa (vs IIIb)
0.92
0.39 to 2.18
0.85
Impaired renal function at discharge
(eGFR ⬍60 mL/min)
3.98
1.86 to 8.50
0.0004
Turbidimetric immunoassay (vs latex
agglutination nephelometry)
0.36
0.15 to 0.87
0.02
Statins at discharge
0.99
0.35 to 2.83
0.99
CCB at discharge
0.68
0.21 to 2.18
0.51
␤-Blockers at discharge
1.18
0.57 to 2.44
0.65
ACE inhibitors at discharge
0.45
0.21 to 0.94
0.03
ACE indicates angiotensin-converting enzyme; CCB, calcium channel
blocker; eGFR, estimated glomerular filtration rate. In this model, all of the
variables used in model 1 and model 2 are adopted as independent variables.
All of the variables are adjusted in 1 step.
Discussion
We investigated whether the peak CRP level has any prognostic value in predicting long-term outcomes in 232 type B
AAD patients. Although initial CRP levels were not associated
with adverse events, peak CPR levels were significantly associated with adverse events. Peak CRP levels were a better marker
than initial CRP levels in the risk stratification of type B AAD
patients. Because it takes several days to reach a peak CRP,
initial CRP levels might not reflect the whole severity of aortic
dissection. Our results showed that the peak CRP level was a
strong predictor of long-term outcomes in type B AAD.
Although type A AAD is a life-threatening disease and
needs emergent surgery, type B AAD is considered to be a
relatively benign condition, with few cases requiring emer-
Sakakura et al
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
gent surgery during hospital admission. However, long-term
outcomes of type B AAD are not necessarily better than that
of type A AAD.2,3 Type B AAD is associated with a high
mortality rate (⬇20% at 3 years3) and a high morbidity rate
(⬇30% morbidity at 2 years) in the long term.4,5 Therefore,
identifying high-risk patients is of special clinical importance.
Earlier studies have identified long-term predictors of
morbidity and mortality in type B AAD, including female
sex, a history of previous aortic aneurysm, a history of
atherosclerosis, and impaired renal function.3,19,20,22 In particular, multiple groups have reported that the maximum aortic
diameter (ⱖ40 mm) and false lumen closure status are
long-term predictors in type B AAD.4,6 –9 Some of these
predictors, including sex, history of previous aneurysm, and
history of atherosclerosis, may be more representative of a
patient’s high-risk clinical background rather than the nature
of the aortic dissection itself. On the other hand, false lumen
closure status and the maximum aortic diameter may represent the nature of the aortic dissection for each individual
patient. These parameters are relatively simply derived from
2D CT. False lumen closure status is generally classified as 1
of 2 patterns (thrombosed and nonthrombosed) or 3 patterns
(thrombosed, nonthrombosed, and partially thrombosed).4,6,8,9
Maximum aortic diameter is calculated from 1 cross-sectional
image.4,6,8 However, the anatomy of the aortic dissection is
often complex and is not necessarily consistent, even during
the initial hospital stay.23–25 It may be difficult to estimate the
whole nature of the AAD by these simple imaging parameters
alone.
The possible explanation for why an elevated peak CRP
level was associated with long-term adverse events may be
several fold. In general, the peak CRP level is an excellent
marker for the severity of a variety of acute illnesses. For
instance, an elevated peak CRP level during hospitalization
for an acute myocardial infarction has been reported to be an
independent predictor of cardiac rupture, left ventricular
aneurysmal formation, 1-year cardiac death, and left ventricular remodeling.17,18,26,27 Peak CRPs in acute myocardial
infarction might reflect the myocardial damage and severity
of myocardial infarction itself in the acute phase. In our study,
peak CRP levels are presumably reflective of the severity of
AAD in the acute phase. Our results also suggest the
possibility that the severity expressed by the peak CRP has a
lasting impact on long-term clinical events.
Another possible explanation is that the peak CRP may
represent the extent of the inflammatory reaction in the
dissected aortic wall and may also reflect the damage to the
lesion. Recent studies have revealed the close relationship
between local inflammation in the aortic wall and the aortic
dissection.10,12,28 Kuehl et al10 have demonstrated the association of inflammation with aortic dissection using positron
emission tomography. He et al28 have immunopathologically
demonstrated that T lymphocytes and macrophages are common features in medial degeneration in the aortic dissection.
These studies suggest that inflammation is present in the
dissected aortic wall. The severely damaged aortic wall may
more easily expand, may be more prone to redissection, and
may be at higher risk of rupture during the chronic phase
versus a less severely damaged aortic wall.
Peak CRP in Type B Aortic Dissection
427
The major part of CRP is synthesized by hepatocytes,
driven by interleukin 6 with synergistic enhancement of
interleukin 1 or tumor necrosis factor.29,30 CRP can also be
produced locally in atherosclerotic lesions.31 Although CRP
is generally considered to be an inflammatory marker or an
atherosclerotic marker,32–34 CRP also plays a role as a
mediator of atherosclerosis. CRP directly influences several
phases of atherosclerosis via complement activation, apoptosis, vascular cell activation, monocyte recruitment, lipid
accumulation, and thrombosis.31,35 Therefore, exaggerated
CRP itself might exert harmful effects that promote the
atherosclerosis of the dissected aortic wall.
Of the 232 study patients, there were 32 patients whose
peak CRP was unavailable. Interestingly, the outcomes of
these patients were comparable to the highest tertile of the
peak CRP group. One possible explanation is the difference
in “time from onset to admission.” The mean time from onset
to admission in these 32 patients was 4.7⫾4.3 days, which
was longer than the other 3 groups. Some of these patients
might not have received adequate medical therapy, such as
aggressive blood pressure lowering in the days after the onset
of dissection. Another possible explanation is a selection bias
before admission to our medical center. Because our medical
center is a tertiary referral hospital, patients who had developed complications over the course of several days may have
subsequently been referred to our hospital.
Peak CRP as a long-term predictor has several advantages
over other predictors. First, the predictive power is potent
with a high HR (3.99 to 6.02 adjusted for all of the
confounders) in the highest tertile of peak CRP levels. Even
the middle tertile of peak CRP has a moderate HR (2.42 to
3.25). In addition, CRP is a relatively simple marker widely
available for clinical use.
Study Limitations
Although our study population is fairly large and the
follow-up period is relatively long, this single-center retrospective study design poses a risk for patient selection bias.
Because the timeline of the study period is fairly long, the
change in the standard of care might have been a confounder
of this study. Because CRP is a nonspecific inflammatory
marker, it reflects not only the aortic dissection itself but
also secondary processes, such as pneumonia. In addition,
initial management, such as blood pressure control or pain
control, might also affect the CRP. Although the CRP level
was measured daily or every other day in most patients, it
was measured less frequently in some patients. The methods to measure CRP have also changed from turbidimetric
immunoassay to latex agglutination nephelometry during
the study period. Although these 2 methods have been
reported to be highly associated (r⫽0.9916; mean difference
0.19 mg/L; limits of agreement: ⫺0.36 to 0.74 mg/L),36 latex
agglutination nephelometry was a more accurate method.
However, the accuracy of the latex agglutination nephelometry is more important in detecting chronic inflammation in
the general population and does not have as much significance during acute illness, whereas CRP levels are naturally
much higher. Therefore, we do not think that changing the
428
Hypertension
February 2010
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method of CRP measurement would have a significant effect
on our results. Because the time from onset to admission was
different in each patient, the time from onset to initial CRP
measurement after admission was also different in each
patient. This time difference might limit the value of initial
CRP. Our main diagnostic tool for the AAD has been CT with
contrast. Therefore, it is often difficult to differentiate intramural hematoma from thrombosed type AAD. In addition, we
could not evaluate the presence of rapid aortic expansion as a
study end point, because each interval between follow-up CT
analyses was not consistent. However, our institution recommended elective surgery to patients who had rapid aortic
expansion. Therefore, it is possible that we were able to
capture rapid aortic expansion in a portion of patients.
Finally, because the surgeons had access to laboratory values
reflecting an increased inflammatory status during the index
admission, there is a possibility that such information affected
their decision to operate during long-term follow-up.
7.
8.
9.
10.
11.
Perspectives
In our retrospective study, the peak CRP is a strong predictor
for adverse long-term events in patients with type B AAD,
but this should be validated by a prospective study. Peak CRP
would be a better prognostic marker than an initial CRP.
Obtaining an initial CRP level at 1 time point might be
insufficient to identify high-risk patients. Our results may
support the effort to find a peak CRP level for the risk
stratification of type B AAD. Careful clinical follow-up may
be warranted in those patients who have a high peak CRP
during their index admission.
12.
13.
14.
15.
16.
Disclosures
None.
17.
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Peak C-Reactive Protein Level Predicts Long-Term Outcomes in Type B Acute Aortic
Dissection
Kenichi Sakakura, Norifumi Kubo, Junya Ako, Hiroshi Wada, Naoki Fujiwara, Hiroshi
Funayama, Nahoko Ikeda, Tomohiro Nakamura, Yoshitaka Sugawara, Takanori Yasu,
Masanobu Kawakami and Shin-ichi Momomura
Downloaded from http://hyper.ahajournals.org/ by guest on June 18, 2017
Hypertension. 2010;55:422-429; originally published online December 28, 2009;
doi: 10.1161/HYPERTENSIONAHA.109.143131
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2009 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/55/2/422
Data Supplement (unedited) at:
http://hyper.ahajournals.org/content/suppl/2010/01/04/HYPERTENSIONAHA.109.143131.DC1
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Online supplement
Peak C-Reactive Protein Level Predicts Long-term Outcomes in Type B Acute
Aortic Dissection
Kenichi Sakakura, Norifumi Kubo, Junya Ako, Hiroshi Wada, Naoki Fujiwara,
Hiroshi Funayama, Nahoko Ikeda, Tomohiro Nakamura, Yoshitaka Sugawara,
Takanori Yasu, Masanobu Kawakami, and Shin-ichi Momomura.
Division of Cardiovascular Medicine, Department of Integrated Medicine I, Jichi
Medical University Saitama Medical Center.
Running title; Peak CRP in type B aortic dissection
Address correspondence to Norifumi Kubo, M.D. Division of Cardiovascular
Medicine, Department of Integrated Medicine I, Jichi Medical University Saitama
Medical Center, Amanuma 1-847,Omiya, Saitama, 330-8503
Tel: +81-48-647-2111, FAX: +81-48-648-5188
E-mail: [email protected]
Figure S1 Flow chart of study populations.
263 patients with type B AAD was admitted
10 patients excluded due to lack of critical data such as CT.
253 patients was included in the study cohort
9 patients died during index admission
244 patients discharged from index admission
12 patients were lost to follow-up
232 patients was final study cohort
Peak CRP was available?
Yes
No
200 patients were divided
according to tertile of peak CRP
Lowest teritle
0.60-9.37 mg/dl
67 patients as T1
Middle tertile
9.61-14.87 mg/dl
67 patients as T2
Highest tertile
14.90-32.60 mg/dl
Unavailable peak
66 patients as T3
32 patients
as unavailable group
(UG)
Table S1. Each event among tertiles of peak CRP
Lowest tertile of peak CRP (T1)
Total event 12 ( death 9 and event 3)
Middle tertile of peak CRP (T2)
N
Deaths
Total event 15 (death 7 and event 8)
Highest tertile of peak CRP (T3)
N
Deaths
Total event 23 ( death 13 and event 10)
Unavailable peak CRP gourp (UG)
N
Deaths
Total events 15 (death 10 and event 5)
N
Deaths
Sudden death
4
Sudden death
2
Sudden death
2
Sudden death
1
Complication of aortic dissection
2
Renal failure
1
Complication of aortic dissection
3
Rupture of aortic aneurysm
2
Recurrence of aortic dissection
1
Cerebral hemorrhage
1
Rupture of abdominal aneurysm
1
Recurrence of aortic dissection
1
Pneumonia
1
Cancer
3
AMI
1
AMI
2
Cancer
1
Cerebral infarction
1
Heart failure
2
Nephrotic syndrome
1
Cerebral hemorrhage
1
Pneumonia
2
Hemorrhagic Shock
1
Emphysema
1
Unknown cause
1
Events
Replacement of descending thoracic aorta
Events
3
Events
Events
Recurrence of aortic dissection
5
Replacement of total arch
2
Stent graft to thoracic aneurysm
1
Replacement of descending thoracic aorta
1
Replacement of ascending and arch
2
Replacement of descending thoracic aorta
2
Replacement of total arch
1
Replacement of distal arch
1
Surgery of aortic dissection
1
Surgery of modified Bentall procedure
1
Replacement of arch
1
Recurrence of aortic dissection
1
Replacement of thoraco abdominal aorta
2
Rupture of thoracic aneurysm
1
Recurrence of aortic dissection
1