Anaesthesia, 2009, 64, pages 416–424 doi:10.1111/j.1365-2044.2008.05786.

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REVIEW ARTICLE
A meta-analysis of the utility of C-reactive protein
in predicting early, intermediate-term and long term
mortality and major adverse cardiac events in vascular
surgical patients
L. Padayachee,1 R. N. Rodseth1 and B. M. Biccard1,2,3
1 Nelson R Mandela School of Medicine, KwaZulu-Natal, South Africa
2 Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital, Oxford, UK
3 Principal Specialist, Inkosi Albert Luthuli Central Hospital, Mayville, South Africa

Summary
We conducted a meta-analysis of the utility of pre-operative C reactive protein (CRP) in
predicting early (< 30 days), intermediate (30–180 days) and long term (> 180 days) mortality and
major adverse cardiac events (MACE; cardiac mortality and nonfatal myocardial infarction (MI)
combined) following vascular surgery. Of 291 studies identified, ten prospective patient cohorts
were identified. A pre-operative CRP > 3 mg.l)1 was not associated with 30-day all-cause
mortality, cardiac mortality, nonfatal myocardial infarction or MACE. Intermediate-term all-cause
mortality, cardiac death and MACE showed a trend to a worse outcome (odds ratio (OR) 9.07,
95% confidence interval (CI) 0.86–96.28, p = 0.07; OR 8.71, 95% CI 0.5–153.1, p = 0.14
and OR 2.81, 95% CI 0.78–5.18, p = 0.15 respectively). Long term all cause mortality (OR 2.40,
95% CI 1.15–5.02, p = 0.02), cardiac death (OR 5.66, 95% CI 1.71–18.73, p = 0.005) and
MACE (OR 2.76, 95% CI 1.38–5.55, p = 0.004) were significantly increased.
. ......................................................................................................
Correspondence to: B. M. Biccard
E-mail: biccardb@ukzn.ac.za
Accepted: 15 October 2008

Vascular surgery is associated with major adverse peri- There is increasing awareness of the utility of bio-
operative cardiac events. Unfortunately, currently used markers as predictors of an adverse cardiac outcome.
pre-operative diagnostic tests for these patients are not A recent meta-analysis of major adverse cardiac events
statistically robust enough to accurately predict these associated with vascular surgery suggests that the pre-
events [1]. A meta-analysis of six pre-operative tests for operative brain natriuretic peptide (BNP) level is at least
vascular surgical patients which included; ambulatory as predictive as dobutamine stress echocardiography, with
ECG, exercise ECG, radionuclide ventriculography, a positive LR of 3.1 and a negative LR of 0.23 [3].
myocardial perfusion scintigraphy, dipyridamole stress C-reactive protein (CRP) and high-sensitivity
echocardiography and dobutamine stress echocardio- C-reactive protein (hs-CRP) may be useful prognostic
graphy, showed that dobutamine stress echocardiography markers for cardiovascular disease (CVD) [4]. Athero-
had a trend to the best performance of the six tests for the sclerosis is an inflammatory disease, and patients with
prediction of major adverse cardiac events (MACE; elevated inflammatory markers (such as CRP) have a
defined as peri-operative cardiac death and non-fatal worse prognosis following acute coronary events [5, 6].
myocardial infarction (MI) within 30 days of surgery [2]), Recent publications suggest that an elevated CRP may
with a positive likelihood ratio (LR) and negative LR of also be an independent predictor of adverse cardiac events
2.8 and 0.21 respectively. As statistically, good discrim- following vascular surgery [7, 8].
ination requires a LR of > 10 and < 0.2, there are clearly The aim of this meta-analysis was to assess the utility of
clinical limitations to the utility of these pre-operative pre-operative CRP or hs-CRP in predicting all-cause
tests for vascular surgical patients [1]. mortality and major adverse cardiac events in vascular

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416 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 416–424 L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein
. ....................................................................................................................................................................................................................

surgical patients. It was a prerequisite that this meta- excluded studies where the patients were known to be
analysis included the 30-day MACE outcome. This complicated by infection [10–12] or chronic inflamma-
would allow comparison of the utility of pre-operative tion [13, 14].
CRP with that of dobutamine stress echocardiography [2]
and pre-operative BNP in vascular surgical patients [3]. Data extraction and quality assessment
LP and RR independently screened citations, abstracted
data and assessed methodological quality, using a standar-
Methods
dised data extraction sheet. A third reviewer (BB)
We conducted a meta-analysis of the utility of CRP and resolved any disagreements. If data needed clarification
hs-CRP in predicting early (< 30 days), intermediate or was not presented in the publication, we contacted the
(30–180 days) and late (> 180 days) postoperative mor- original authors. Data which was not forthcoming within
tality and MACE in patients following vascular surgery. 6 months of initiation of correspondence with authors
The Meta-analysis of Observational Studies in Epidemi- was considered irretrievable.
ology (MOOSE) guidelines were adhered to in conduct-
ing and reporting this meta-analysis [9]. Data analysis
The quality of each study was assessed according to the
Study identification and selection Newcastle Ottawa Quality Assessment Scale for cohort
On the 9 August 2007 BB conducted a search of Pubmed studies (NOS) [15]. The NOS scale and the defini-
Central from 1966 to 2007 and a search of EMBASE tions used for this meta-analysis are shown in Table 1.
from 1988 to week 40 of 2007. The terms used in the Comparability of the cohorts from the included studies
search strategy were: ‘C-reactive protein’ and ‘vascular were analysed using an ANOVA test for age or a chi-
surgery’ and ‘human’ and ‘adults; for the Pubmed Central squared test for gender, ischaemic heart disease (IHD),
search and ‘C-reactive protein’ and ‘vascular surgery’ and congestive heart failure (CHF), diabetes mellitus (DM),
‘human’ for the EMBASE search. The search was renal dysfunction and pre-operative medical therapy
repeated and updated on 10 January 2008 by BB. We (GRAPHPAD INSTAT version 3.06, GraphPad Software,
then manually searched the reference lists of all studies La Jolla, CA, USA, 2003).
and reviews identified. The Centers for Disease Control ⁄ American Heart
We included observational peri-operative studies of Association (CDC ⁄ AHA) Workshop on Markers of
pre-operative CRP or hs-CRP that reported mortality Inflammation and Cardiovascular Disease [4, 16, 17]
(all-cause and ⁄ or cardiac) and cardiac morbidity (nonfatal suggests that a CRP > 3 mg.l)1 be considered a cardio-
MI) in patients undergoing vascular surgery. We excluded vascular risk factor. A CRP > 3 mg.l)1 represents the
studies published only in abstract form, non-human cut-off for the upper third for cardiovascular risk in the
studies, cardiac surgical studies, paediatric studies and medical (nonsurgical) population with a relative risk of
in-vitro or non-operative human studies. We also approximately two when compared with the lowest third

Table 1 The Newcastle Ottawa Quality Assessment Scale for cohort studies (NOS) [15] as adapted for use in this meta-analysis.

Maximum
number
Category Criteria of stars

Selection 1. Is the cohort representative of vascular surgical patients? 1

2. Are the patients with a high or normal CRP or hs-CRP from the same vascular surgical 1
cohort?
3. Is it possible to ascertain the plasma CRP or hs-CRP in all patients? 1
4. Is it possible to exclude the presence of major cardiac morbidity at the start of the study? 1
For example, through examination of pre-operative troponin levels.
Comparability 1. The data analysed in this meta-analysis must only include vascular surgical patients. 1
2. The age, gender and prevalence of IHD, DM and renal dysfunction should be comparable 1
between studies. Exclusion of comorbidities was undesirable.
Outcome 1. Assessment must be independent blinded, record linkage or secure records. 1
2. Follow-up must be long enough for outcome to occur. Defined as 30 days, 30–180 days 1
or > 180 days.
3. Follow up must be adequate. Defined as complete follow up, or description of drop outs 1
to ensure that they were not secondary to any of the outcomes being investigated.

CRP, C-reactive protein; hs-CRP, high-sensitivity C-reactive protein; IHD, ischaemic heart disease; DM, diabetes mellitus.

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 417
L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein Anaesthesia, 2009, 64, pages 416–424
. ....................................................................................................................................................................................................................

(hs-CRP < 1 mg.l)1) [17]. In accordance with this
definition, the authors of all the included studies were
asked to present their data according to the CDC ⁄ AHA
CRP cut-off, if it had not been presented in this manner
in the original publication.
From each study we extracted data on mortality (all-
cause and cardiac), non-fatal MI and MACE for patients
with a pre-operative CRP < and ‡ 3 mg.l)1. We
examined these outcomes in the peri-operative period
(< 30 days), in the intermediate-term (30–180 days) and
the long term (> 180 days). All statistical analyses were
performed using REVMAN version 4.2.10 software (The
Nordic Cochrane Centre, Kobehavn, Denmark). Hetero-
geneity between studies was assessed using univariate
Potentially relevant studies
identified by electronic
database search and hand
searching (n = 291)
Potential studies retrieved
for more detailed
evaluation (n = 57)
Selected studies
included in the meta-
analysis (n = 11),
representing 10 patient
cohorts
Figure 1 Flow chart of included and excluded studies.
chi-squared analysis. Random or fixed effects models
were used based on the presence or absence of significant
heterogeneity between studies respectively. Pooled
dichotomous outcomes were reported as the odds ratio
(OR) and the 95% confidence intervals (CI). To assess
whether the studies retrieved in our meta-analysis were
affected by bias (as a result of selection bias or data
irregularities) we constructed a funnel plot for the
outcome of long term MACE.
Results
Included studies
We identified 291 studies between 1966 and January
2008, of ten patient cohorts reported in eleven studies
[7, 8, 18–26] which fulfilled our inclusion criteria
(Fig. 1). All the included studies were prospective
Trials excluded by screening observational studies. Additional, unpublished data was
of abstracts (n = 234) obtained from the authors of all the included studies.
Letters, editorials, reviews = 18
Not CRP study = 12
All 11 patient cohorts were of only vascular surgical
Cardiac surgery = 5 patients. All patients underwent either elective aortic,
Not vascular surgery = 13
carotid, renal or peripheral vascular surgery. The nature of
Medical (not surgical) = 185
German language –1 the vascular surgery, demographics of the patients and the
reported pre-operative medical therapy are shown in
Trials excluded by review of
full article (n = 46) Table 2.
Not vascular surgery = 2 The NOS assessment [15] for all included studies are
Plaque CRP study = 1 listed in Table 3. Some studies received three stars for
Infection/Inflammation present = 5
Same cohort = 3 ‘selection’, as they had not excluded the presence of
Incomplete data major cardiac morbidity at the start of the study. All the
No follow up = 2
Entire cohort with normal CRP = 2
studies were given one star for ‘comparability’, which was
Incomplete data = 25 for providing data only for vascular surgical patients. No
Data unavailable for author = 6
study was awarded a second star for ‘comparability’, as the
age, the proportion of patients who were male, or with
IHD, DM, renal dysfunction, and receiving pre-operative

Table 2 Patient demographics of studies included in the meta-analysis. Values are number (proportion), mean (SD) or median (range).

First author Patient Renal Pre-operative Pre-operative

year Type of surgery (n) Age Male CAD CCF Diabetes failure statin beta blocker

Rossi 2002 [7] Limb revascularisation 51 67 (9) 36 (71) 14 (27) 0 37 (73) 0 NA NA

Schoder 2003 [20] EVAR 28 71.6 (9.9) 17 (61) 8 (29) NR NR 5 (18) 1 (4)* 9 (32)†
Alveraz Garcia Carotid endarterectomy 62 67.1 (9.2) 57 (92) 10 (16) NR 20 (32) 8 (13) 12 (19) 3 (5)
2003 [19]
Li 2004 [18] Renal artery stenting 22 50 (8) 19 (86) 7 (32) 0 3 (14) 0 0 0
Dosa 2004 [25] Carotid endarterectomy 117 67 (7.5) 78 (67) 39 (33) 0 37 (32) 3 (3) 23 (20) 62 (53)
Wolowczyk 2005 [21] Aortic surgery 34 (71–75)‡ 23 (68) 12 (35) NR 1 (3) 0 4 (12) 2 (6)
Wahlgren 2006 [23] Peripheral arterial 34 69 (54–81) 20 (59) 10 (29) NR 10 (29) 2 (6) 15 (44) 10 (29)
angioplasty
Gabriel 2007 [22] EVAR 25 64.2 21 (84) 9 (36) 0 2 (8) 2 (8) 25 (100) 25 (100)
Owens 2007 [8] Vascular-lower extremity 91 63 (11.5) 63 (69) 44 (48) 0 48 (53) 5 (5.5) 65 (71) 79 (87)
Mahla 2007 [24] Major elective vascular 218 70 (9) 170 (78) 171 (78) 0 78 (36) 0 78 (36) 167 (77)
surgery

SD, standard deviation; CAD, coronary artery disease; CCF, congestive cardiac failure; EVAR, endovascular aneurysm repair; NR, not reported;
NA, not available; *data on 3 patients missing; †data on 2 patients missing; ‡range only available.

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418 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 416–424 L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein
. ....................................................................................................................................................................................................................

Table 3 Characteristics of the studies included in the meta-analysis.

Study CRP NOS score [15]

discriminatory
First author, year Follow up period CRP assay threshold* Selection Comparability Outcome

Short term studies

Rossi 2002 [7] 30 days hs-CRP > 9 mg.l)1† *** * ***
Alveraz Garcia 2003 [19] 30 days hs-CRP > 10 mg.l)1 **** * ***
Li 2004 [18] 48 h CRP NR *** * ***
Wolowczyk 2005 [21] 30 days CRP NR **** * ***
Intermediate term studies
Wahlgren 2006 [23] 180 days hs-CRP >2 mg.l)1 *** * ***
Mahla 2007 [24] 180 days hs-CRP >3 mg.l)1 **** * ***
Gabriel 2007 [22] 3 months CRP NR *** * **
Long term studies
Rossi 2002 [7] 24 months hs-CRP > 9 mg.l)1† *** * ***
Dosa 2004 [25] 13.8 months hs-CRP NR *** * ***
Mahla 2007 [24] 826 days hs-CRP > 3 mg.l)1 **** * ***
Owens 2007 [8] 342 days hs-CRP > 5 mg.l)1 **** * **

NOS, Newcastle Ottawa Quality Assessment Scale; CRP, C-reactive protein; hs-CRP, high-sensitivity C-reactive protein; NR, not reported; *as defined
by study methodology; †upper third.

Review: CRP meta-analysis

Comparison: 17 30 day MACE
Outcome: 01 30 day MACE

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Rossi 1/14 0/36 19.69 8.11 (0.31, 211.49)

Alvarez Garcia 0/38 0/24 Not estimable
Schoder 0/3 0/25 Not estimable
Li 0/6 0/16 Not estimable
Wolowczyk 1/10 2/24 80.31 1.22 (0.10, 15.23)

Total (95% CI) 71 125 100.00 2.58 (0.42, 16.01)

Total events: 2 (high CRP), 2 (normal CRP)
Test for heterogeneity: Chi = 0.81, df = 1 (p = 0.37), I 2 = 0%
2

Test for overall effect: Z = 1.02 (p = 0.31)

0.01 0.1 1 10 100
Improved outcome Adverse outcome

Figure 2 Pre-operative CRP and hs-CRP and 30-day major adverse cardiac events.

Review: CRP meta-analysis

Comparison: 18 180 day all cause mortality
Outcome: 01 180 day all cause mortality

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Gabriel 1/3 1/22 20.15 10.50 (0.46, 239.78)

Wahlgren 0/20 0/14 Not estimable
Mahla 8/147 0/71 79.85 8.71 (0.50, 153.12)

Total (95% CI) 170 107 100.00 9.07 (0.86, 96.28)

Total events: 9 (high CRP), 1 (normal CRP)
Test for heterogeneity: Chi = 0.01, df = 1 (p = 0.92), I 2 = 0%
2

Test for overall effect: Z = 1.83 (p = 0.07)

0.01 0.1 1 10 100
Improved outcome Adverse outcome

Figure 3 Pre-operative CRP and hs-CRP and 180 day all cause mortality.

statin or beta-blocker were all significantly different as it was not possible to determine the pre-operative CRP
between the studies (p < 0.01 for all comparisons). The level for a patient known to have sustained a nonfatal MI
study by Owens et al. [8] received two stars for ‘outcome’ (Owens, personal correspondence).

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 419
L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein Anaesthesia, 2009, 64, pages 416–424
. ....................................................................................................................................................................................................................

The definition of a positive test for CRP varied Outcomes

between studies. Authors of all the included studies Outcomes were categorised according to whether the
supplied data categorising outcomes according to a CRP pre-operative CRP was < or ‡ 3 mg.l)1. Of the included
cut-off of 3 mg.l)1. The studies by Shindo et al. and Galle studies, five reported early (< 30 day) outcomes (196
et al. were excluded as all the patients in these cohorts had patients) [7, 18–21], three studies [22–24] collected
a CRP < 3 mg.l)1 [27, 28]. data on intermediate term (30–180 day) outcomes (277

Review: CRP meta-analysis

Comparison: 19 long-term all cause mortality
Outcome: 01 long-term all cause mortality

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Rossi 11/36 3/15 27.21 1.76 (0.41, 7.51)

Dosa 4/87 2/30 26.25 0.67 (0.12, 3.88)
Mahla 25/147 4/71 41.42 3.43 (1.15, 10.28)
Owens 4/55 0/36 5.12 6.38 (0.33, 122.16)

Total (95% CI) 325 152 100.00 2.40 (1.15, 5.02)

Total events: 44 (high CRP), 9 (normal CRP)
Test for heterogeneity: Chi = 3.03, df = 3 (p = 0.39), I 2 = 0.9%
2

Test for overall effect: Z = 2.33 (p = 0.02)

0.1 0.2 0.5 1 2 5 10
Improved outcome Adverse outcome

Figure 4 Pre-operative CRP and hs-CRP and long term all cause mortality.

Review: CRP meta-analysis

Comparison: 20 long-term cardiac death
Outcome: 01 long-term cardiac death

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Rossi 10/36 1/15 28.18 5.38 (0.62, 46.50)

Dosa 3/87 1/30 39.69 1.04 (0.10, 10.35)
Mahla 16/147 0/71 16.52 17.94 (1.06, 303.50)
Owens 3/55 0/36 15.60 4.87 (0.24, 97.08)

Total (95% CI) 325 152 100.00 5.65 (1.71, 18.73)

Total events: 32 (high CRP), 2 (normal CRP)
Test for heterogeneity: Chi2 = 2.74, df = 3 (p = 0.43), I 2 = 0%
Test for overall effect: Z = 2.83 (p = 0.005)

0.01 0.1 1 10 100

Improved outcome Adverse outcome

Figure 5 Pre-operative CRP and hs-CRP and long term cardiac death.

Review: CRP meta-analysis

Comparison: 20 long-term nonfatal myocardial infarction
Outcome: 01 long-term myocardial infarction

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Rossi 5/36 1/15 10.80 2.26 (0.24, 21.17)

Dosa 2/87 0/30 6.38 1.78 (0.08, 38.21)
Mahla 20/147 8/71 82.82 1.24 (0.52, 2.97)

Total (95% CI) 270 116 100.00 1.38 (0.63, 3.03)

Total events: 27 (high CRP), 9 (normal CRP)
Test for heterogeneity: Chi = 0.27, df = 2 (p = 0.87), I 2 = 0%
2

Test for overall effect: Z = 0.82 (p = 0.41)

0.1 0.2 0.5 1 2 5 10
Improved outcome Adverse outcome

Figure 6 Pre-operative CRP and hs-CRP and long term nonfatal myocardial infarction. The study by Owens et al. was omitted due
to an incomplete data set [8].

 2009 The Authors

420 Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland
Anaesthesia, 2009, 64, pages 416–424 L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein
. ....................................................................................................................................................................................................................

Review: CRP meta-analysis

Comparison: 22 long-term MACE
Outcome: 01 long-term MACE

Study High CRP Normal CRP OR (fixed) Weight OR (fixed)

or sub-category n/N n/N 95% CI % 95% CI

Rossi 15/36 2/15 14.71 4.64 (0.91, 23.68)

Dosa 5/87 1/30 12.52 1.77 (0.20, 15.77)
Mahla 36/147 8/71 72.77 2.55 (1.12, 5.83)

Total (95% CI) 270 116 100.00 2.76 (1.38, 5.55)

Total events: 56 (high CRP), 11 (normal CRP)
Test for heterogeneity: Chi2 = 0.58, df = 2 (p = 0.75), I 2 = 0%
Test for overall effect: Z = 2.86 (p = 0.004)
0.1 0.2 0.5 1 2 5 10
Improved outcome Adverse outcome

Figure 7 Pre-operative CRP and hs-CRP and long term major adverse cardiac events (MACE). The study by Owens et al. was
omitted due to an incomplete data set [8].

patients) and four studies collected long term data on 477 inconclusive. Although, the incidence of MACE at 30 days
patients; to 342 days [8], 13.8 months [25], 24 months [7] is similar between the negative test results presented in the
and 826 days [24]. meta-analysis of dobutamine stress echocardiography
There was no significant association with short term (1.1%) [2], pre-operative BNP (2.7%) [3] and pre-operative
(30 day) outcomes and an elevated pre-operative CRP; CRP (1.6%) (Chi-squared 4.924, p = 0.09), the incidence
all cause mortality (OR 1.22, 95% CI 0.1–15.23, of MACE is significantly different for the patients with a
p = 0.88) [20, 21], cardiac mortality (OR 0.75, 95% CI positive test result for dobutamine stress echocardiography
0.03–19.87, p = 0.86) [18–21], nonfatal MI (OR 2.56, (17.4%) [2], pre-operative BNP (25.9%) [3] and pre-
95% CI 0.14–45.39, p = 0.52) [18–21] and MACE (OR operative CRP (2.8%) (Chi-squared 18.24, p = 0.0001).
2.58, 95% CI 0.42–16.01, p = 0.31) [7, 18–21]. Thirty- With such a low event rate in patients with an elevated
day MACE is shown in Fig. 2. pre-operative CRP in this meta-analysis, the sample size
Intermediate term mortality was reported in two presented here is too small to determine the prognos-
studies [22, 24] with a trend towards an adverse outcome tic efficacy of pre-operative CRP on vascular surgical
(Fig. 3). Only the study by Mahla et al. [24] reported outcome.
events for intermediate term cardiac mortality and It is also likely that the cardiac risk profile of the
nonfatal MI. Cardiac death, nonfatal MI and MACE all patients differed between these three meta-analyses, as the
showed a trend to a worse outcome (OR 8.71, 95% incidence of MACE at 30 days differed significantly
CI 0.5–153.1, p = 0.14; OR 1.23, 95% CI 0.46–3.32, between the vascular surgical populations of the dobuta-
p = 0.68; and OR 2.81, 95% CI 0.78–5.18, p = 0.15 mine stress echocardiography (4.6%) [2], pre-operative
respectively). Adverse long term outcomes were all BNP (10.3%) [3] and pre-operative CRP (2%) (Chi-
significantly associated with an elevated pre-operative squared 29.14, p < 0.0001). It is therefore apparent that
CRP, with the exception of non fatal MI (Figs 4–7). A the vascular surgical patients in this meta-analysis of CRP
funnel plot of the studies reporting long term MACE did were of a lower risk than that reported in the other meta-
not suggest selection bias (figure not shown). analyses. There may be at least three explanations for this.
Firstly, a pre-operative history of congestive heart failure
(CHF) was not reported in a single study in this meta-
Discussion
analysis in comparison to CHF that was reported in most
The predictive value of CRP/hs-CRP for MACE of the studies of the pre-operative BNP meta-analysis [3].
following vascular surgery Secondly, only a single study evaluating short term
The methodology of this meta-analysis should theoretically outcomes had a primary endpoint of major cardiac events
allow the reader to compare the performance of pre- [7], thus it is likely that there is under-reporting of major
operative CRP or hs-CRP with meta-analytical data cardiac morbidity in this meta-analysis. Finally, six
presented for ambulatory ECG, exercise ECG, radionuclide [18–20, 22, 23, 25] of the 10 patient cohorts examined
ventriculography, myocardial perfusion scintigraphy, predominantly intermediate-risk vascular surgery; carotid
dypridamole stress echocardiography and dobutamine stress endarterectomy, endovascular aortic aneurysm repair
echocardiography [2] and the pre-operative BNP in (EVAR) or peripheral angioplasty [29].
vascular surgical patients [3]. Unfortunately, the CRP data Unfortunately, this meta-analysis is also underpowered
presented in this paper does not allow this, as it is to evaluate the prognostic performance of pre-operative

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Journal compilation  2009 The Association of Anaesthetists of Great Britain and Ireland 421
L. Padayachee et al. Æ A meta-analysis of the utility of C-reactive protein
. ....................................................................................................................................................................................................................
CRP on intermediate term cardiac outcomes. This would
have allowed a comparison with the data presented in the
pre-operative BNP meta-analysis [3].
However, a pre-operative CRP > 3 mg.l)1 is associ-
ated with a significantly increased risk of late all-cause
mortality, cardiac death and MACE.
Should we continue to investigate the performance
of pre-operative CRP on short term cardiac
outcomes following vascular surgery?
It would certainly be premature to abandon investigation
of the utility of pre-operative CRP on short term car-
diac outcomes. It is well described in the medical
(non-surgical) patients, that the CRP is an independent
predictor of adverse outcome following acute coronary
syndromes [30]. As vulnerable plaque is probably respon-
sible for approximately half of peri-operative MI [31, 32],
it is likely that an elevated pre-operative CRP may be an
important predictor of patients at risk of plaque rupture.
Potential limitations to the utility of pre-operative
CRP
The prognostic utility of pre-operative CRP may be
adversely affected by local or systemic infection [17]. It is
controversial whether infection is a predictor of cardiovas-
cular disease [4]. Indeed, from a prognostic viewpoint, it is
recommended that patients with a CRP of > 10 mg.l)1 in
the presence of active infection, should have the test
repeated in 2 weeks, as the clinical significance of the test is
questionable [17]. Clearly, in vascular surgical patients with
infections associated with ischaemic ulcers this may be a
major limiting factor to the prognostic utility of pre-
operative CRP. Infections would be expected to increase
false negative test results and decrease the utility of the test.
Secondly, the appreciation that the risk of mortality
following surgery is significantly increased in patients with
heart failure when compared with patients with coronary
artery disease [33, 34] would suggest that a biomarker more
specific to heart failure (such as BNP) may have better
prognostic performance in the peri-operative period.
Unfortunately, the evidence presented in this meta-analysis
does not allow us to test this hypothesis, by comparing BNP
[3] and CRP meta-analytical data, as in the short and
intermediate term there are insufficient CRP data; and in
the long term there are insufficient BNP data [3].
The current utility of pre-operative CRP
for vascular surgical patients
The evidence presented in this paper shows that vascular
surgical patients with a pre-operative CRP > 3 mg.l)1
are at significantly increased risk of long term mortality
and cardiac morbidity. The funnel plot suggests that there
is no selection bias in this observation [35]. We recom-
422
Anaesthesia, 2009, 64, pages 416–424
mend that these patients should have optimisation of
medical therapy and continued postoperative surveillance
and secondary prevention following surgery in an attempt
to improve long term outcome.
Conclusion
This meta-analysis could not confirm the prognostic
utility of an elevated pre-operative CRP in the short and
intermediate term, due to an insufficient sample size. An
elevated pre-operative CRP is a risk factor of long term
mortality and major cardiac morbidity.
Acknowledgements
We would like to thank Drs. Alveraz-Garcia, Bolke, Dosa,
Entz, Gabriel, Galle, Haynes, Johnston, Kummer,
Lammer, Li, Lusic, Maddedu, Mahla, Marrocco-
Trischitta, McCollum, Nevelsteen, Nielsen, Odegard,
Owens, Pape, Parapanissiou, Perier, Porcu, Prager, Rossi,
Schillinger, Schoder, Shindo, Szeplaki and Wolowczyk for
additional trial information or responding to our queries.
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