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The Influence of Preoperative Anemia on Clinical Outcomes After Infrainguinal Bypass Surgery
Journal Pre-proof The influence of pre-operative anaemia on clinical outcomes following infra-inguinal bypass surgery S. Nandhra, L. Boylan, J. Prentis, C. Nesbitt, the Northern Vascular Centre PII:
S0890-5096(19)31042-8
DOI:
https://doi.org/10.1016/j.avsg.2019.11.043
Reference:
AVSG 4811
To appear in:
Annals of Vascular Surgery
Received Date: 4 October 2019 Revised Date:
22 November 2019
Accepted Date: 25 November 2019
Please cite this article as: Nandhra S, Boylan L, Prentis J, Nesbitt C, the Northern Vascular Centre, The influence of pre-operative anaemia on clinical outcomes following infra-inguinal bypass surgery, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/j.avsg.2019.11.043. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Crown Copyright © 2019 Published by Elsevier Inc. All rights reserved.
1 2 3
The influence of pre-operative anaemia on clinical outcomes following infra-inguinal bypass surgery Nandhra.S1,2, Boylan. L1, Prentis.J3, Nesbitt.C1 and the Northern Vascular Centre
4 5
Author Affiliations
6
1
7
Hospital, Newcastle-upon-Tyne, NE77DN
8
2
9
Newcastle upon Tyne, NE2 4AX UK
Northern Vascular Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman
Institute of Health & Society, Newcastle University, Baddiley-Clark, Richardson Road,
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3
11
Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN UK.
Department of Anaesthesia, the Newcastle upon Tyne Hospitals NHS Foundation Trust,
12 13 14 15
Corresponding Author:
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Sandip Nandhra; [email protected]
17
Northern Vascular Centre
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Freeman Hospital
19 20
Declarations:
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None to be declared
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Word Count – body 3066
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With references - 4256
26 27 28 29 30 31 32 33 34
1
Abstract
35 36 37
Introduction
38
Within chronic limb-threatening ischaemia (CLTI) the effect of anaemia is becoming
39
apparent. This study aimed to further understand the influence of anaemia in patients
40
undergoing surgical revascularisation for lower-limb ischaemia.
Anaemia is associated with a greater mortality and complications in cardiovascular surgery.
41 42
Methods
43
A retrospective review of all patients undergoing infra-inguinal surgical revascularisation
44
between 2016 and 2018 at a tertiary centre was performed. Anaemia was defined as a
45
haemoglobin (Hb) of less than 120g/L. Primary outcome was overall survival by Kaplan-
46
Meier analysis. Secondary outcomes included, length of hospital stay, blood-transfusion
47
requirements, wound infection, myocardial infarction, limb-loss and all-cause mortality. Cox-
48
proportional hazard analysis and receiver operator characteristics (ROC) were performed.
49 50
Results
51
124 patients were followed up for a mean of 23(8) months. 45 patients were anaemic. There
52
were comparable baseline demographics, comorbidity and severity of symptoms. Overall
53
survival was significantly worse (Log rank p<0.01) in the anaemic group as was the duration
54
of stay; 27(23) days vs. 14(16) days (P=0.001). Anaemic patients received more blood
55
transfusions; 19 (42%) compared to 13 (16.5%) (p=0.001) and had more cardiac
56
complications (11.1% vs 3.8%) (P=0.02). Surgical Site infection rates were also higher (20%
57
vs. 6.3% P=0.036). There was no difference in graft patency or subsequent ipsilateral major
58
lower extremity amputation. 30-day mortality was comparable between the anaemic versus
59
the non-anaemic; 3 (6.7%) vs. 1 (1.3%) (P=0.132). At 1-year there was a greater mortality in
60
the anaemic group of 8 (18%) vs. 4 (5%) in the non-anaemic group (P=0.037) which persisted
61
into the long-term.
62
Anaemia was independently associated with mortality; Hazard Ratio 4.0 (1.14-12.1). A ‘cut-
63
off’ Hb of 112g/L was identified by ROC analysis.
64 65
Conclusion
66
2
67
Pre-operative anaemia in infra-inguinal bypass surgery has a significant association with
68
mortality and morbidity. Pre-operative anaemia should prompt the vascular team to
69
consider these patients as higher risk and consider optimisation of haemoglobin.
70 71 72
Introduction
73
Anaemia, defined by the world health organisation as a circulating haemoglobin (Hb)
74
concentration below 130g/l for men and 120g/l for women [1], is a disease of multifactorial
75
aetiologies but present in a third of patients undergoing surgery [1].
76
There is existing evidence that anaemic patients undergoing elective surgery or intervention
77
are at an increased risk of mortality at 30 days [2] and the effect is most notable In patients
78
undergoing cardiac surgery where pre-operative anaemia is associated with an increased
79
risk of death [2] along with longer inpatient hospital stay and a three times greater
80
likelihood of requiring a red blood cell transfusion compared to non-anaemic patients [3].
81
Within vascular surgery there is some evidence that suggests increasing age and cardiac co-
82
morbidities, which are common in patients having vascular procedures and in the presence
83
of anaemia may be associated with even greater mortality and post-operative morbidity[4-
84
6] but these studies predate significant recommendations by NICE (National Institute for
85
Clinical and Healthcare Excellence, UK) in 2016 [7]. Following this guidance there has also
86
been the increased recognition that a patient blood management (PBM) pathway is
87
important. PBM is a three-pillar WHO endorsed process (WHA63.12). The first pillar of PBM
88
is to manage pre-operative anaemia in surgical patients. The implementation of PBM
89
strategies have shown benefits in-terms of outcome and reduction in cost[8] but not all
90
healthcare settings have been able to apply PBM strategies due to a number of challenges
91
that have been reported to limit implementation before surgery[9, 10]. Whilst the
92
recognition of anaemia and poor outcome is not a new concept there has been little
93
evidence change in practice within vascular surgery. none-the-less the importance of
94
improving outcomes among peripheral arterial patients remains a key priority. In 2017 a UK
95
Delphi consensus endorsed by the Vascular society of Great Britain and the Royal college of
96
Surgeons England identified that improving outcomes in chronic limb threatening ischaemia
97
(CLTI) are a top ten research priority within the vascular community, furthermore the
98
publication of the global guidance on the management of Chronic Limb-threatening
99
Ischaemia[11] have confirmed its priority within world-wide vascular surgery. One area for
100
improvement is perhaps the recognition of anaemia because this has been proposed to be
101
associated with a higher incidence of major amputation in patients admitted with critical
3
102
limb threatening ischaemia (CLTI) [12], equally pre-operative Red Blood Cell (RBC)
103
transfusion optimisation strategies have been shown to be not without risk; being
104
associated with poorer outcomes, including wound infection and death [1] amid the risk of a
105
transfusion related systemic reaction. Pre-optimisation with intravenous and oral iron
106
replacements have been proven to be effective in patients undergoing colorectal and
107
orthopaedic procedures [1, 13] but the specific evidence in vascular surgery is limited.
108
The aim of this cohort study is to assess the relationship between pre-operative anaemia
109
and post-operative outcomes, particularly since the advent of the NICE guidelines and the
110
recommendation of PBM practice, in those patients undergoing urgent surgical lower-limb
111
revascularisation.
112 113
Methods
114
Study design
115
A prospectively maintained database of all vascular procedures at the Northern Vascular
116
Centre, Freeman Hospital, Newcastle (a UK tertiary centre) was retrospectively reviewed.
117
Any missing data were queried by the investigators retrospectively. All patients undergoing
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primary infra-inguinal bypass surgery for Rutherford classification of 3 and above (severe
119
quality of life (QoL) limiting short distance claudication and/or CLTI) between December
120
2016 and December 2018 were included. Patients undergoing surgery for peripheral
121
aneurysmal disease or acute limb ischaemia were excluded.
122 123
Study population
124
Anaemia was defined as a Haemoglobin (Hb) of less than 120 g/L, this adopts the lower limit
125
of the WHO guidelines for men and women [1]. Baseline characteristics were collected,
126
including demographics, indication for surgery (Rutherford Classification)[14], co-
127
morbidities, statin and anti-platelet medication and pre-operative haemoglobin (Hb),
128
sodium, creatinine and eGFR. All patients had an estimated glomerular filtration rate based
129
on the CKD-EPI formula [15] within 4 weeks prior to surgery.
130
Comorbidities were defined as per SVS guideline where possible[16]; diabetes was defined
131
by documented medical history, the use of oral antidiabetic agents or insulin or fasting
132
plasma glucose levels of at least 1.26 g/L; hypertension was defined by documented medical
133
history and use of antihypertensive drugs for this purpose, or systolic blood pressure (SBP)
134
of at least 140 mmHg or diastolic blood pressure (DBP) of at least 90 mmHg at admission
4
135
determined by the average of the first two measurements. The following diseases were
136
noted, according to the documented medical history: Ischaemic heart disease, heart failure,
137
cerebrovascular disease (stroke; including ischemic or haemorrhagic stroke as well as
138
transient ischemic attack), end-stage renal failure requiring dialysis and a documented
139
diagnosis of chronic obstructive pulmonary disease (COPD). Pre-operative statin and anti-
140
platelet use was recorded in the pre-assessment clinic. Duration of bypass revascularisation
141
surgery was recorded as were the conduits used.
142
Follow-up
143
Information regarding patient follow-up visits was entered prospectively into the
144
Departmental database. Follow-up for patients undergoing bypass of the peripheries in the
145
department consists of a 6 week out-patient clinical assessment, 3-month graft ultrasound
146
(DUS) surveillance and follow-up in the clinic thereafter at suitable intervals based upon
147
wound healing or symptom status. All other data was collected by review of electronic
148
records.
149
Patients were followed up using online electronic patient records and review of paper
150
records. Electronic general practice records were also reviewed in case of missing
151
information by the study team retrospectively.
152 153
Ethics
154
The study was approved by the Newcastle-Upon-Tyne Hospital research department and the
155
Newcastle University review board. Written informed consent was obtained from all
156
participating subjects according to the Declaration of Helsinki.
157
Outcomes
158
The primary outcome of interest is all-cause mortality at the end of follow-up.
159
Secondary outcomes included the all-cause mortality for CLTI only patients, length of
160
hospital stay, number of myocardial events within 30 days, post-operative red blood cell
161
transfusion, surgical site infection, renal function, Duplex Ultrasound (DUS) detected graft
162
patency, overall re-intervention rates, limb-loss and interval mortality (30 days and 1 year).
163
Complications were recorded as per SVS/AHA guidelines where possible[16]. Length of stay
164
was defined as the duration (in days) spent in the tertiary arterial centre until discharge
165
home or to a ‘step-down’ rehabilitation hospital. Surgical site infection was determined by
5
166
the presence of cellulitis, erythema requiring antibiotics and as part of a clinical diagnosis by
167
a member of the vascular surgical team within 30 days of surgery.
168
Follow-up renal function was recorded as eGFR. Overall re-intervention rate was defined as
169
the absolute number of patients who underwent either an endovascular (angioplasty) or
170
open surgical procedure (revision and/or redo) during the follow-up period. Limb-loss is
171
defined as any ipsilateral major lower limb amputation following the bypass surgery within
172
the follow-up period (above or below knee).
173 174
Statistical analysis
175
Data were recorded in a dedicated database. Normally distributed data are presented as
176
mean (SD), and hypothesis testing performed with paired and unpaired t-tests. Non-
177
normally distributed data are presented as median (IQR) values with analysis using Mann-
178
Whitney U test for unrelated samples and Wilcoxon signed rank test (WSR) for paired data.
179
Categorical data were analysed by means of chi squared (χ2) or, if necessary, Fisher’s exact
180
test. All data were collected during the dedicated clinic follow-up. Statistical analysis was
181
performed using SPSS version 24 (SPSS, IBM, Chicago, Illinois, USA). A p value of <0.05 was
182
considered statistically significant for single comparisons. Kaplan-Meier survival curves were
183
used with log-rank test to compare the overall mortality. Cox regression model was used to
184
assess the survival according to the presence of anaemia. Regression analysis was
185
performed by a number of models. The first was to understand the impact of anaemia on
186
survival, the second was to take into account baseline demographics (age and gender), the
187
third was to understand the additional impact of co-morbidity and the fourth to appreciate
188
any influence of preventative medication and post-operative transfusion. Hazards ratios (HR)
189
with 95% confidence intervals (CI’s) are reported along with p-values. A HR of greater than 1
190
indicates a shorter time to death and a HR of less than 1 indicates a longer time-to-death.
191
Binary logistic regression analysis was used to identify associations with complications and
192
multiple variates were tested. The resultant significant variables are presented as odds
193
ratios (OR) with 95% CI’s. An OR of greater than 1 indicates and increased likelihood of the
194
event occurring.
195 196
Results
197
Overall, 124 patients undergoing infra-inguinal bypass were included of which 45 were
198
found to be anaemic and all patients were followed-up for an overall mean (s.d) of 23(8)
199
months. Patients in each group had comparable baseline metrics for age, co-morbidity,
6
200
creatinine, antiplatelets, statins and Rutherford classification. There was a pre-ponderance
201
of females in the anaemia group; 13 (28.8%) vs 11 (13.9%) P=0.02. These are summarised in
202
Table 1.
203 204
The duration of surgery was equivalent between the two groups with the anaemic group
205
having a mean (s.d) operative duration of 256.7 (180) minutes versus the non-anaemic
206
group of 241.5 (153) minutes (P=0.781). There were equivalent vein and prosthetic bypass
207
conduits utilised.
208 209
Primary Outcome
210
Overall survival was worse in the anaemic patients and can be seen in the Kaplan-Meier plot
211
(P=0.017) (Figure 1). This shows a statistically significant difference in overall survival across
212
the follow-up period with those in the anaemic group fairing worse. Mean survival can be
213
found in Table 1.
214 215
Secondary Outcomes
216
Of the 124 patients studied, one-hundred and six were patients underwent a lower-limb
217
bypass for CLTI (Rutherford 4 or above). A Kaplan-Meier performed for this groups
218
demonstrated a significantly worse survival analysis for the 41 anaemic patients (Log rank
219
p=0.025).
220
Overall, the anaemic patients had a significantly greater mean duration of tertiary hospital
221
stay of 27(23) days compared to 14(16) days (P=0.001) with a significantly greater number of
222
patients who received a post-operative blood transfusion in the anaemic group with 19
223
(42%) compared to 13 (16.5%) (p=0.001). Although, the absolute number of units of blood
224
transfused were similar (see Table 3).
225
In terms of post-operative complications there was a significantly greater rate of 30-day
226
myocardial events in anaemic group (11.1% vs 3.8%) (P=0.02). Surgical site infection rates
227
were also higher in this group (20% vs. 6.3% P=0.036). There was no difference in graft
228
patency at three-month Duplex follow-up and there were comparable re-intervention rates
229
(see Table 2). There were similar rates of subsequent overall major lower limb amputation
230
with 14 undergoing amputation in the anaemic group and 17 in the non-anaemic group
231
(P=0.189), this remained non-significant when comparing the CLTI-only patients.
232
Renal function (eGFR) was comparable between each group at any time point within follow-
233
up (See Table 3).
7
234
Mortality at 30-days was comparable between the anaemic versus the non-anaemic; 3
235
(6.7%) vs. 1 (1.3%) respectively (P=0.132). At 1-year this had become significant with a
236
greater mortality in the anaemic patients of 8 (18%) compared to 4 (5%) in the non-anaemic
237
patients (P=0.037).
238 239
Regression analysis
240
Cox proportional hazards analysis was performed. Anaemia alone was a significantly
241
associated with a shorter time to death (HR 3.7 (1.1-12.3)) (p=0.034). Adjusting for
242
demographics continued to identify anaemia as the single significant variable. Further
243
adjustment for pre-operative co-morbidity again identified anaemia as the single significant
244
variable for an increased HR for death of 4.0 (1.14-12.1). The adjustment for medication and
245
transfusion high-lighted anti-platelet use as protective for death (see Table 5); transfusion of
246
RBC’s did not impact on survival.
247 248
For significant complications, multivariate binary regression analysis was performed. This
249
identified that anaemic patients had greater likelihood of MI with an OR of 9 (1.02 - 80)
250
P=0.048 and similarly a greater likelihood of wound infection (OR of 4.3 (1.2 – 15.6)
251
P=0.028); these were independent of demographics or pre-operative comorbidity and
252
medications.
253
In terms of requirement for post-operative RBC transfusion there was an increased
254
likelihood of transfusion amongst the anaemic patients with an OR of 4 (1.7 – 9.4) P=0.001.
255
When controlling for co-morbidity and medication, anaemia made the likelihood of
256
transfusion greater (OR 7 (2.3 – 21.4) P=0.001) but a pre-operative diagnosis of renal failure
257
was a significant associated variable (p=0.047).
258 259
Receiver operating characteristics (ROC) curve
260
A ROC analysis enabled identification of a ‘cut-off’ Hb for the primary outcome of overall
261
mortality. This demonstrated that a Hb of 112g/L was the most sensitive (66.7%) and specific
262
(79.5%) for mortality following bypass surgery (Area under the curve (AUC) 0.749, (see
263
Figure 2).
264
Similar analysis identified a cut-off Hb of below 122g/L for the requirement of a post -
265
operative transfusion (75% Sensitivity, 66.3% specificity, AUC 0.737) and the risk of a post-
266
operative MI (sensitivity 63% and specificity of 86%, AUC 0.683).
267 268 8
269 270
Discussion
271
This study demonstrates that patients with anaemia have a greater overall mortality
272
following infra-inguinal bypass surgery. Anaemia is also independently associated with death
273
irrespective of pre-operative co-morbidity and as such anaemic patients have a shorter
274
expected survival (HR 4.0 (1.14-12.1) than non-anaemic patient.
275
Additionally, anaemic patients spent on average 13 days longer in hospital (27 vs.14 days
276
(P=0.001)), more frequently received a post-operative blood transfusion (42.2% vs. 16.5%)
277
(OR of 4 (1.7 – 9.4) P=0.001) and experienced more post-operative complications; with a
278
higher rate 30-day myocardial events (11.1% vs 3.8%) (P=0.02) and surgical site infection
279
(20% vs. 6.3% P=0.036) (OR of 4.3 (1.2 – 15.6) P=0.028). This was irrespective of bypass
280
conduit or baseline comorbidity. These associations highlighted are stark and aligns with
281
other findings within the current literature. A large cohort study (5081patients) by Bodewes
282
et. al [17] compared the 30-day outcomes for a similar group of bypass patients using (USA)
283
registry data between 2011 and 2014. They identified that there was an increased mortality
284
rate with increasing severity of anaemia (severe, 3.1%; moderate, 3.0%; mild, 1.8%; no
285
anaemia: 0.7%; all P < .01) whilst there was a trend towards greater mortality at 30-days
286
within our data this did not reach significance (p=0.106). Furthermore, direct comparison by
287
stratification of anaemia was not performed due to the small sample size within the present
288
study. A French study of 925 patients using registry data from 2004 through to 2010 found
289
similar outcomes for anaemic patients with a greater HR for death and amputation[18] and
290
that amputation was associated with a lower haemoglobin (HR 1.20(1.07 – 1.36) irrespective
291
of comorbidity. Our study data did not find this relationship, but this may be a reflection of
292
a smaller sample size but also the thresholds for anaemia were much lower in the Desomais
293
group paper. Interestingly both Bodewes and Desomais found there to be a significant
294
difference in the baseline demographics with the anaemic patients tending to be older and
295
more co-morbid. The population within our study was comparable without difference in age
296
or comorbidity. This could be related to sample size but all of these studies will suffer from
297
the limitations of an observational study.
298
Interestingly our patients were average aged between 65.8 and 67.2 whish is lower than the
299
anaemic groups for both existing large cohort studies (70 and 73.7 respectively) and could
300
well reflect a different demographic within the UK population that highlight some
301
uniqueness when applying this data to other populations.
9
302
Surgical site infection rates were higher in our anaemic patients and but overall the
303
Bodewes group did not detect a similar difference; our records recorded only the presence
304
of infection based upon clinical assessment which may be subject to bias.
305
Within our sample a cut-off haemoglobin of 112g/L (see Error! Reference source not found.)
306
was identified, and is reasonably comparable to Spanish study for both endovascular and
307
open surgery of 100g/L for patients with CLTI[19].
308
Combining the ROC ‘cut-off’ for MI with that for mortality; may indicate that a target pre-
309
operative haemoglobin level between 112 and 122g/L to reduce the likelihood of adverse
310
outcome. This is a useful however for planning a prospective trial into targets for
311
optimisation. A randomised study comparing high (9.7g/L) to low (<8g/L) intra-operative
312
triggers for red blood cell transfusion in vascular surgery, powered to detect change in post-
313
operative Hb found that the lower <8.0g/L Hb trigger was associated with a higher rate of
314
death or major vascular complication (hazard ratio, 3.20; P=0.006) and fewer days alive
315
outside hospital within 90 days (median [IQR], 76 [67-82] vs. 82 [76-84] days; P=0.049) [20],
316
evidencing association of anaemia with poor outcome but also suggesting a Hb of 97 is
317
perhaps acceptable.
318
There are clearly limitations within this study. It is a small cohort from a single tertiary
319
centre which could limit broader generalisability to the wider population with the sample
320
size may limiting our ability to detect differences in amputation rates. Certainly, the nature
321
of an observational study means that control and matching of potential confounders is
322
challenging and the probability of bias remains high whilst multivariate analysis was used to
323
adjust for the impact of individual variables it is acknowledged that this is not a fail-proof
324
process and potentially reduces the impact of any identified associations.
325
The absolute cause of anaemia has not been evaluated which may present confounding
326
issues such as occult malignancy or other missed diagnosis such as heart or renal failure
327
which could influence prognosis within the anaemic patients[21].
328
The overall outcomes of medium to long term poor survival in the presence of anaemia are
329
congruent with other similar duration vascular studies[19]. Equally, our findings corroborate
330
findings from outside the UK in terms of shorter-term outcomes and the negative
331
association with anaemia. It is clear that anaemia plays a role in elective cardiac and vascular
332
surgery with finding a higher rate of mortality and cardiac events over 5 years[22]
333
irrespective of comorbidity among anaemic patients. Similarly, anaemia leads to greater
334
likelihood of myocardial events following vascular surgery in the Netherlands[23].
10
335
In terms of longer-term outcomes following revascularisation this study demonstrates a
336
negative implication on long-term survival but once again this as yet only an association.
337
There are existing causative mechanisms that may explain why anaemia results in death,
338
such as changes in cardiac physiology [21] leading to dysfunctional
339
hypertrophy (LVH), a risk-factor for myocardial infraction and all-cause mortality[24, 25].
340
However, association does not necessarily equate to causation and prospective work is now
341
required to further investigate this question. This paper has demonstrated that anaemia
342
must be carefully considered prior to surgical intervention as appears to be a poor
343
prognostic marker. It may help with planning care in the post-operative environment. Given
344
that the duration of surgery for both groups of patients was approximately 4 hours it could
345
perhaps guide treatment planning in terms of the appropriateness of open surgical
346
intervention. With the recent SVS/ESVS guidelines[11] in mind it seems that the pre-
347
optimisation of haemoglobin to improve survival following revascularisation is a relevant
348
avenue of future research.
349 350
Conclusion
351
This UK study highlights the prevalence and subsequent impact of pre-operative anaemia in
352
patients undergoing lower limb bypass surgery. Anaemia is associated with a greater
353
mortality and significantly greater rates of cardiac complication, wound infection, length of
354
hospital stay and post-operative blood transfusion. Low Haemoglobin levels as part of the
355
pre-operative work up should signal the potential for greater risks of morbidity and
356
mortality for urgent bypass patients.
357 358 359 360
Funding No funding sources to declare.
361 362
Acknowledgements The authors would like to acknowledge the contributions of the vascular consultants; Miss
363
Anne Burdess, Mr Mike Clarke, Mr Tim Lees, Mr James McCaslin, Miss Lucy Wales and Mr
364
Mike Wyatt at the Northern Vascular Centre. In addition, offer special thanks to the research
365
nurses, Deborah Amis, Martin Catterson and Noala Parr.
left ventricular
366 367 368 369 370
1. Hogan M, Klein AA, Richards T. the impact of anaemia and intravenous iron replacement therapy on outcomes in caridac surgery. European Journal Of Cardio-Thoracic Surgery 2014; 1-9.
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2. Fowler AJ, Ahmad T, Phull MK et al. Meta-analysis of the association between preoperative anaemia and mortality after surgery. British Journal Of Surgery 2015; 102. 3. Sanders J, Cooper JA, Farrar D et al. Pre-operative anaemia is associated with total morbidity burden on days 4 and 5 after cardiac surgery: a cohort study. Perioperative Medicine 2017; 6. 4. Horwich TB, Fonarow GC, Hamilton MA et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. Journal of the American College of Cardiology 2002; 39: 1780-1786. 5. Szachniewicz J, Petruk-Kowalczyk J, Majda J et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. International Journal of Cardiology 2003; 90: 303-308. 6. Ezekowitz Justin A, McAlister Finlay A, Armstrong Paul W. Anemia Is Common in Heart Failure and Is Associated With Poor Outcomes. Circulation 2003; 107: 223-225. 7. National Clinical Guideline C. Blood transfusion (NG24). In. 2017. 8. Leahy MF, Hofmann A, Towler S et al. Improved outcomes and reduced costs associated with a health-system-wide patient blood management program: a retrospective observational study in four major adult tertiary-care hospitals. Transfusion 2017; 57: 1347-1358. 9. Munoz M, Gomez-Ramirez S, Kozek-Langeneker S et al. 'Fit to fly': overcoming barriers to preoperative haemoglobin optimization in surgical patients. Br J Anaesth 2015; 115: 15-24. 10. Kotze A, Harris A, Baker C et al. British Committee for Standards in Haematology Guidelines on the Identification and Management of Pre-Operative Anaemia. Br J Haematol 2015; 171: 322-331. 11. Conte MS, Bradbury AW, Kolh P et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur J Vasc Endovasc Surg 2019. 12. Desormais I, Aboyans V, Bura A et al. Anemia, an independant predictive factor for amputation and mortality in patients hospitalised for peripheral arterial disease. European Society For vascular Surgery 2014; 48. 13. Chau M, Richards T, Evans C et al. The UK cardiac and vascular surgery interventional anaemia response (CAVIAR) study: protocol for an observational cohort study to determine the impact and effect of pre-operative anaemia management in cardiac and vascular surgical patients. BMJ Open 2017; 7. 14. Rutherford RB, Baker JD, Ernst C et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997; 26: 517-538. 15. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Annals of internal medicine 2009; 150: 604-612. 16. Al Falluji N, Lawrence-Nelson J, Kostis JB et al. Effect of anemia on 1-year mortality in patients with acute myocardial infarction. Am Heart J 2002; 144: 636-641. 17. Bodewes TCF, Pothof AB, Darling JD et al. Preoperative anemia associated with adverse outcomes after infrainguinal bypass surgery in patients with chronic limb-threatening ischemia. J Vasc Surg 2017; 66: 1775-1785 e1772.
12
419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445
18. Desormais I, Aboyans V, Bura A et al. Anemia, an independent predictive factor for amputation and mortality in patients hospitalized for peripheral artery disease. Eur J Vasc Endovasc Surg 2014; 48: 202-207. 19. Velescu A, Clará A, Cladellas M et al. Anemia Increases Mortality After Open or Endovascular Treatment in Patients with Critical Limb Ischemia: A Retrospective Analysis. European Journal of Vascular and Endovascular Surgery 2016; 51: 543-549. 20. Møller A, Nielsen HB, Wetterslev J et al. Low vs. high hemoglobin trigger for Transfusion in Vascular surgery (TV): a randomized clinical feasibility trial. Blood 2019; blood-2018-2010-877530. 21. McClellan WM, Flanders WD, Langston RD et al. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13: 1928-1936. 22. Dunkelgrun M, Hoeks SE, Welten GM et al. Anemia as an independent predictor of perioperative and long-term cardiovascular outcome in patients scheduled for elective vascular surgery. Am J Cardiol 2008; 101: 1196-1200. 23. Goei D, Flu WJ, Hoeks SE et al. The interrelationship between preoperative anemia and N-terminal pro-B-type natriuretic peptide: the effect on predicting postoperative cardiac outcome in vascular surgery patients. Anesth Analg 2009; 109: 1403-1408. 24. Lipsic E, van der Horst IC, Voors AA et al. Hemoglobin levels and 30-day mortality in patients after myocardial infarction. Int J Cardiol 2005; 100: 289292. 25. Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985; 110: 1100-1107.
446 447
13
Demographics Number AGE Gender Haemoglobin Rutherford Class. 3 – Claudication (modified) 4 - Rest Pain 5 - Tissue loss (digits) 6 - Extensive tissue loss Comorbidities and Medications Diabetes Hypertension IHD Heart Failure Renal Failure COPD Antiplatelets Statins Creatinine (Mean (s.d)) Sodium (mean (s.d)) Operative Data Duration in minutes (mean (s.d)) Conduit Vein Prosthetic
Non-Anaemic 79 (64%) 67.2(9.4) M68 F11 140.9 (14.8)
Anaemic 45 (36%) 65.8(11.2) M32 F13 105.5(9.5)
0.687 0.017 (<0.001)
14 (18%) 25 (32%) 9 (11%) 31 (39%)
4 (9%) 10 (22%) 6 (13%) 25 (56%)
0.118 0.139 0.918 0.214
23 (29.1%) 52 (65.8%) 23 (29.1%) 3 (4%) 3 (4%) 17 (21.5%) 54 (68.3%) 54 (68.3%) 86.4 (47.4) 137.6 (3.5)
18 (40%) 16 (35.6%) 33 (73.3%) 3 (6.7%) 2 (4.4%) 12 (26.7%) 29 (64.4%) 33 (73.3%) 89.4 (41.7) 137.2 (3.8)
0.193 0.699 0.364 0.297 0.550 0.514 0.241 0.875 0.272 0.591
241.5 (153) 69 (87.3%) 10 (12.7%)
256.7 (180) 39 (86.7%) 6 (13.3%)
0.781 0.701
Table 1 - Baseline demographics, co-morbidity and operative data
P Value
Group
Months (Mean (s.e)) 95% Confidence Interval
Non-anaemic
37.8 (1.4)
35.9 – 39.7
Anaemic
32.9 (2.1)
28.9 – 37.0
Overall
36.1(0.99)
34.2 – 38.1
Table 1-Mean survival in months
Non-Anaemic (79)
Anaemic (45)
P-Value
Myocardial Infarction
3 (3.8%)
5 (11.1%)
0.020
Wound infection
5 (6.3%)
9 (20%)
0.036
Graft Occlusion 3m
20 (25%)
16 (35.6%)
0.229
Re-intervention (endovas. or open)
32 (40.5%)
20 (44.4%)
0.495
Limb-loss
17 (21.5%)
14 (31.1%)
0.189
14 (16)
27 (23)
0.001
1 (1.3%)
3 (6.7%)
0.106
4 (5%)
8 (17.8%)
0.037
13 (16.5%)
19 (42.2%)
0.001
2 (2-3)
2 (1-3)
0.324
Complications
Length of Stay
Mortality 30d Mortality 1-year mort
Post -operative Red Blood Cell (RBC) transfusion Number of patients receiving RBC’s Median Quantity (IQR) (in units)
Table 1 – Complications, Length of Stay and Mortality, by Group
Renal Function (eGFR (ml/kg/min))
Non-Anaemic
Anaemic
Baseline
86.5 (28.2)
77.7 (26.6)
0.098
Day 1 Post-op
89.0 (31.6)
85.0 (34.9)
0.691
Week 1 Post-op
86.3 (31.2)
80.1 (30.8)
0.361
Year 1 Post-op
103.8 (43.2)
67.7 (25.0)
0.178
Table 1 – Renal function over time, by group
P-Value
1
Significant Variable
HR
95% CI
P-value
Anaemia1
3.7
1.1 – 12.3
0.034* 0.034*
Anaemia2
3.6
1.1 – 12.1
0.037* 0.037*
Anaemia3
4.0
1.14 – 12.1
0.031* 0.031*
Antiplatelet4
0.17
0.04 – 0.67
0.011* 0.011*
2
3
4
Anaemia, Anaemia, age, gender, +Comorbidities, +Medication and RBC transfusion (*significant p-value)
Table 1 - Cox Proportional Hazard table of significant variable by model of regression analysis
Non- anaemic Anaemic
Log rank, sig p=0.017
Months 0
6
12
18
24
30
36
Not anaemic
79
77
63
42
31
26
10
Anaemic
45
42
28
24
12
9
4
Figure 1 - Kaplan-Meier Survival Analysis; (Non-Anaemic = Blue, Anaemic = Red,)
Non- anaemic Anaemic
Log rank, sig p=0.025
Months 0
6
12
18
24
30
36
Not anaemic
65
63
50
33
23
18
7
Anaemic
41
38
25
21
9
6
4
Figure 1 - Kaplan-Meier Survival Analysis for sub-group of CLTI patients; (Non-Anaemic = Blue, Anaemic = Red)
ROC for mortality
Figure 1- ROC curve for mortality and Haemoglobin (AUC= 0.749)
S0890-5096(19)31042-8
DOI:
https://doi.org/10.1016/j.avsg.2019.11.043
Reference:
AVSG 4811
To appear in:
Annals of Vascular Surgery
Received Date: 4 October 2019 Revised Date:
22 November 2019
Accepted Date: 25 November 2019
Please cite this article as: Nandhra S, Boylan L, Prentis J, Nesbitt C, the Northern Vascular Centre, The influence of pre-operative anaemia on clinical outcomes following infra-inguinal bypass surgery, Annals of Vascular Surgery (2020), doi: https://doi.org/10.1016/j.avsg.2019.11.043. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Crown Copyright © 2019 Published by Elsevier Inc. All rights reserved.
1 2 3
The influence of pre-operative anaemia on clinical outcomes following infra-inguinal bypass surgery Nandhra.S1,2, Boylan. L1, Prentis.J3, Nesbitt.C1 and the Northern Vascular Centre
4 5
Author Affiliations
6
1
7
Hospital, Newcastle-upon-Tyne, NE77DN
8
2
9
Newcastle upon Tyne, NE2 4AX UK
Northern Vascular Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman
Institute of Health & Society, Newcastle University, Baddiley-Clark, Richardson Road,
10
3
11
Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7 7DN UK.
Department of Anaesthesia, the Newcastle upon Tyne Hospitals NHS Foundation Trust,
12 13 14 15
Corresponding Author:
16
Sandip Nandhra; [email protected]
17
Northern Vascular Centre
18
Freeman Hospital
19 20
Declarations:
21
None to be declared
22 23 24
Word Count – body 3066
25
With references - 4256
26 27 28 29 30 31 32 33 34
1
Abstract
35 36 37
Introduction
38
Within chronic limb-threatening ischaemia (CLTI) the effect of anaemia is becoming
39
apparent. This study aimed to further understand the influence of anaemia in patients
40
undergoing surgical revascularisation for lower-limb ischaemia.
Anaemia is associated with a greater mortality and complications in cardiovascular surgery.
41 42
Methods
43
A retrospective review of all patients undergoing infra-inguinal surgical revascularisation
44
between 2016 and 2018 at a tertiary centre was performed. Anaemia was defined as a
45
haemoglobin (Hb) of less than 120g/L. Primary outcome was overall survival by Kaplan-
46
Meier analysis. Secondary outcomes included, length of hospital stay, blood-transfusion
47
requirements, wound infection, myocardial infarction, limb-loss and all-cause mortality. Cox-
48
proportional hazard analysis and receiver operator characteristics (ROC) were performed.
49 50
Results
51
124 patients were followed up for a mean of 23(8) months. 45 patients were anaemic. There
52
were comparable baseline demographics, comorbidity and severity of symptoms. Overall
53
survival was significantly worse (Log rank p<0.01) in the anaemic group as was the duration
54
of stay; 27(23) days vs. 14(16) days (P=0.001). Anaemic patients received more blood
55
transfusions; 19 (42%) compared to 13 (16.5%) (p=0.001) and had more cardiac
56
complications (11.1% vs 3.8%) (P=0.02). Surgical Site infection rates were also higher (20%
57
vs. 6.3% P=0.036). There was no difference in graft patency or subsequent ipsilateral major
58
lower extremity amputation. 30-day mortality was comparable between the anaemic versus
59
the non-anaemic; 3 (6.7%) vs. 1 (1.3%) (P=0.132). At 1-year there was a greater mortality in
60
the anaemic group of 8 (18%) vs. 4 (5%) in the non-anaemic group (P=0.037) which persisted
61
into the long-term.
62
Anaemia was independently associated with mortality; Hazard Ratio 4.0 (1.14-12.1). A ‘cut-
63
off’ Hb of 112g/L was identified by ROC analysis.
64 65
Conclusion
66
2
67
Pre-operative anaemia in infra-inguinal bypass surgery has a significant association with
68
mortality and morbidity. Pre-operative anaemia should prompt the vascular team to
69
consider these patients as higher risk and consider optimisation of haemoglobin.
70 71 72
Introduction
73
Anaemia, defined by the world health organisation as a circulating haemoglobin (Hb)
74
concentration below 130g/l for men and 120g/l for women [1], is a disease of multifactorial
75
aetiologies but present in a third of patients undergoing surgery [1].
76
There is existing evidence that anaemic patients undergoing elective surgery or intervention
77
are at an increased risk of mortality at 30 days [2] and the effect is most notable In patients
78
undergoing cardiac surgery where pre-operative anaemia is associated with an increased
79
risk of death [2] along with longer inpatient hospital stay and a three times greater
80
likelihood of requiring a red blood cell transfusion compared to non-anaemic patients [3].
81
Within vascular surgery there is some evidence that suggests increasing age and cardiac co-
82
morbidities, which are common in patients having vascular procedures and in the presence
83
of anaemia may be associated with even greater mortality and post-operative morbidity[4-
84
6] but these studies predate significant recommendations by NICE (National Institute for
85
Clinical and Healthcare Excellence, UK) in 2016 [7]. Following this guidance there has also
86
been the increased recognition that a patient blood management (PBM) pathway is
87
important. PBM is a three-pillar WHO endorsed process (WHA63.12). The first pillar of PBM
88
is to manage pre-operative anaemia in surgical patients. The implementation of PBM
89
strategies have shown benefits in-terms of outcome and reduction in cost[8] but not all
90
healthcare settings have been able to apply PBM strategies due to a number of challenges
91
that have been reported to limit implementation before surgery[9, 10]. Whilst the
92
recognition of anaemia and poor outcome is not a new concept there has been little
93
evidence change in practice within vascular surgery. none-the-less the importance of
94
improving outcomes among peripheral arterial patients remains a key priority. In 2017 a UK
95
Delphi consensus endorsed by the Vascular society of Great Britain and the Royal college of
96
Surgeons England identified that improving outcomes in chronic limb threatening ischaemia
97
(CLTI) are a top ten research priority within the vascular community, furthermore the
98
publication of the global guidance on the management of Chronic Limb-threatening
99
Ischaemia[11] have confirmed its priority within world-wide vascular surgery. One area for
100
improvement is perhaps the recognition of anaemia because this has been proposed to be
101
associated with a higher incidence of major amputation in patients admitted with critical
3
102
limb threatening ischaemia (CLTI) [12], equally pre-operative Red Blood Cell (RBC)
103
transfusion optimisation strategies have been shown to be not without risk; being
104
associated with poorer outcomes, including wound infection and death [1] amid the risk of a
105
transfusion related systemic reaction. Pre-optimisation with intravenous and oral iron
106
replacements have been proven to be effective in patients undergoing colorectal and
107
orthopaedic procedures [1, 13] but the specific evidence in vascular surgery is limited.
108
The aim of this cohort study is to assess the relationship between pre-operative anaemia
109
and post-operative outcomes, particularly since the advent of the NICE guidelines and the
110
recommendation of PBM practice, in those patients undergoing urgent surgical lower-limb
111
revascularisation.
112 113
Methods
114
Study design
115
A prospectively maintained database of all vascular procedures at the Northern Vascular
116
Centre, Freeman Hospital, Newcastle (a UK tertiary centre) was retrospectively reviewed.
117
Any missing data were queried by the investigators retrospectively. All patients undergoing
118
primary infra-inguinal bypass surgery for Rutherford classification of 3 and above (severe
119
quality of life (QoL) limiting short distance claudication and/or CLTI) between December
120
2016 and December 2018 were included. Patients undergoing surgery for peripheral
121
aneurysmal disease or acute limb ischaemia were excluded.
122 123
Study population
124
Anaemia was defined as a Haemoglobin (Hb) of less than 120 g/L, this adopts the lower limit
125
of the WHO guidelines for men and women [1]. Baseline characteristics were collected,
126
including demographics, indication for surgery (Rutherford Classification)[14], co-
127
morbidities, statin and anti-platelet medication and pre-operative haemoglobin (Hb),
128
sodium, creatinine and eGFR. All patients had an estimated glomerular filtration rate based
129
on the CKD-EPI formula [15] within 4 weeks prior to surgery.
130
Comorbidities were defined as per SVS guideline where possible[16]; diabetes was defined
131
by documented medical history, the use of oral antidiabetic agents or insulin or fasting
132
plasma glucose levels of at least 1.26 g/L; hypertension was defined by documented medical
133
history and use of antihypertensive drugs for this purpose, or systolic blood pressure (SBP)
134
of at least 140 mmHg or diastolic blood pressure (DBP) of at least 90 mmHg at admission
4
135
determined by the average of the first two measurements. The following diseases were
136
noted, according to the documented medical history: Ischaemic heart disease, heart failure,
137
cerebrovascular disease (stroke; including ischemic or haemorrhagic stroke as well as
138
transient ischemic attack), end-stage renal failure requiring dialysis and a documented
139
diagnosis of chronic obstructive pulmonary disease (COPD). Pre-operative statin and anti-
140
platelet use was recorded in the pre-assessment clinic. Duration of bypass revascularisation
141
surgery was recorded as were the conduits used.
142
Follow-up
143
Information regarding patient follow-up visits was entered prospectively into the
144
Departmental database. Follow-up for patients undergoing bypass of the peripheries in the
145
department consists of a 6 week out-patient clinical assessment, 3-month graft ultrasound
146
(DUS) surveillance and follow-up in the clinic thereafter at suitable intervals based upon
147
wound healing or symptom status. All other data was collected by review of electronic
148
records.
149
Patients were followed up using online electronic patient records and review of paper
150
records. Electronic general practice records were also reviewed in case of missing
151
information by the study team retrospectively.
152 153
Ethics
154
The study was approved by the Newcastle-Upon-Tyne Hospital research department and the
155
Newcastle University review board. Written informed consent was obtained from all
156
participating subjects according to the Declaration of Helsinki.
157
Outcomes
158
The primary outcome of interest is all-cause mortality at the end of follow-up.
159
Secondary outcomes included the all-cause mortality for CLTI only patients, length of
160
hospital stay, number of myocardial events within 30 days, post-operative red blood cell
161
transfusion, surgical site infection, renal function, Duplex Ultrasound (DUS) detected graft
162
patency, overall re-intervention rates, limb-loss and interval mortality (30 days and 1 year).
163
Complications were recorded as per SVS/AHA guidelines where possible[16]. Length of stay
164
was defined as the duration (in days) spent in the tertiary arterial centre until discharge
165
home or to a ‘step-down’ rehabilitation hospital. Surgical site infection was determined by
5
166
the presence of cellulitis, erythema requiring antibiotics and as part of a clinical diagnosis by
167
a member of the vascular surgical team within 30 days of surgery.
168
Follow-up renal function was recorded as eGFR. Overall re-intervention rate was defined as
169
the absolute number of patients who underwent either an endovascular (angioplasty) or
170
open surgical procedure (revision and/or redo) during the follow-up period. Limb-loss is
171
defined as any ipsilateral major lower limb amputation following the bypass surgery within
172
the follow-up period (above or below knee).
173 174
Statistical analysis
175
Data were recorded in a dedicated database. Normally distributed data are presented as
176
mean (SD), and hypothesis testing performed with paired and unpaired t-tests. Non-
177
normally distributed data are presented as median (IQR) values with analysis using Mann-
178
Whitney U test for unrelated samples and Wilcoxon signed rank test (WSR) for paired data.
179
Categorical data were analysed by means of chi squared (χ2) or, if necessary, Fisher’s exact
180
test. All data were collected during the dedicated clinic follow-up. Statistical analysis was
181
performed using SPSS version 24 (SPSS, IBM, Chicago, Illinois, USA). A p value of <0.05 was
182
considered statistically significant for single comparisons. Kaplan-Meier survival curves were
183
used with log-rank test to compare the overall mortality. Cox regression model was used to
184
assess the survival according to the presence of anaemia. Regression analysis was
185
performed by a number of models. The first was to understand the impact of anaemia on
186
survival, the second was to take into account baseline demographics (age and gender), the
187
third was to understand the additional impact of co-morbidity and the fourth to appreciate
188
any influence of preventative medication and post-operative transfusion. Hazards ratios (HR)
189
with 95% confidence intervals (CI’s) are reported along with p-values. A HR of greater than 1
190
indicates a shorter time to death and a HR of less than 1 indicates a longer time-to-death.
191
Binary logistic regression analysis was used to identify associations with complications and
192
multiple variates were tested. The resultant significant variables are presented as odds
193
ratios (OR) with 95% CI’s. An OR of greater than 1 indicates and increased likelihood of the
194
event occurring.
195 196
Results
197
Overall, 124 patients undergoing infra-inguinal bypass were included of which 45 were
198
found to be anaemic and all patients were followed-up for an overall mean (s.d) of 23(8)
199
months. Patients in each group had comparable baseline metrics for age, co-morbidity,
6
200
creatinine, antiplatelets, statins and Rutherford classification. There was a pre-ponderance
201
of females in the anaemia group; 13 (28.8%) vs 11 (13.9%) P=0.02. These are summarised in
202
Table 1.
203 204
The duration of surgery was equivalent between the two groups with the anaemic group
205
having a mean (s.d) operative duration of 256.7 (180) minutes versus the non-anaemic
206
group of 241.5 (153) minutes (P=0.781). There were equivalent vein and prosthetic bypass
207
conduits utilised.
208 209
Primary Outcome
210
Overall survival was worse in the anaemic patients and can be seen in the Kaplan-Meier plot
211
(P=0.017) (Figure 1). This shows a statistically significant difference in overall survival across
212
the follow-up period with those in the anaemic group fairing worse. Mean survival can be
213
found in Table 1.
214 215
Secondary Outcomes
216
Of the 124 patients studied, one-hundred and six were patients underwent a lower-limb
217
bypass for CLTI (Rutherford 4 or above). A Kaplan-Meier performed for this groups
218
demonstrated a significantly worse survival analysis for the 41 anaemic patients (Log rank
219
p=0.025).
220
Overall, the anaemic patients had a significantly greater mean duration of tertiary hospital
221
stay of 27(23) days compared to 14(16) days (P=0.001) with a significantly greater number of
222
patients who received a post-operative blood transfusion in the anaemic group with 19
223
(42%) compared to 13 (16.5%) (p=0.001). Although, the absolute number of units of blood
224
transfused were similar (see Table 3).
225
In terms of post-operative complications there was a significantly greater rate of 30-day
226
myocardial events in anaemic group (11.1% vs 3.8%) (P=0.02). Surgical site infection rates
227
were also higher in this group (20% vs. 6.3% P=0.036). There was no difference in graft
228
patency at three-month Duplex follow-up and there were comparable re-intervention rates
229
(see Table 2). There were similar rates of subsequent overall major lower limb amputation
230
with 14 undergoing amputation in the anaemic group and 17 in the non-anaemic group
231
(P=0.189), this remained non-significant when comparing the CLTI-only patients.
232
Renal function (eGFR) was comparable between each group at any time point within follow-
233
up (See Table 3).
7
234
Mortality at 30-days was comparable between the anaemic versus the non-anaemic; 3
235
(6.7%) vs. 1 (1.3%) respectively (P=0.132). At 1-year this had become significant with a
236
greater mortality in the anaemic patients of 8 (18%) compared to 4 (5%) in the non-anaemic
237
patients (P=0.037).
238 239
Regression analysis
240
Cox proportional hazards analysis was performed. Anaemia alone was a significantly
241
associated with a shorter time to death (HR 3.7 (1.1-12.3)) (p=0.034). Adjusting for
242
demographics continued to identify anaemia as the single significant variable. Further
243
adjustment for pre-operative co-morbidity again identified anaemia as the single significant
244
variable for an increased HR for death of 4.0 (1.14-12.1). The adjustment for medication and
245
transfusion high-lighted anti-platelet use as protective for death (see Table 5); transfusion of
246
RBC’s did not impact on survival.
247 248
For significant complications, multivariate binary regression analysis was performed. This
249
identified that anaemic patients had greater likelihood of MI with an OR of 9 (1.02 - 80)
250
P=0.048 and similarly a greater likelihood of wound infection (OR of 4.3 (1.2 – 15.6)
251
P=0.028); these were independent of demographics or pre-operative comorbidity and
252
medications.
253
In terms of requirement for post-operative RBC transfusion there was an increased
254
likelihood of transfusion amongst the anaemic patients with an OR of 4 (1.7 – 9.4) P=0.001.
255
When controlling for co-morbidity and medication, anaemia made the likelihood of
256
transfusion greater (OR 7 (2.3 – 21.4) P=0.001) but a pre-operative diagnosis of renal failure
257
was a significant associated variable (p=0.047).
258 259
Receiver operating characteristics (ROC) curve
260
A ROC analysis enabled identification of a ‘cut-off’ Hb for the primary outcome of overall
261
mortality. This demonstrated that a Hb of 112g/L was the most sensitive (66.7%) and specific
262
(79.5%) for mortality following bypass surgery (Area under the curve (AUC) 0.749, (see
263
Figure 2).
264
Similar analysis identified a cut-off Hb of below 122g/L for the requirement of a post -
265
operative transfusion (75% Sensitivity, 66.3% specificity, AUC 0.737) and the risk of a post-
266
operative MI (sensitivity 63% and specificity of 86%, AUC 0.683).
267 268 8
269 270
Discussion
271
This study demonstrates that patients with anaemia have a greater overall mortality
272
following infra-inguinal bypass surgery. Anaemia is also independently associated with death
273
irrespective of pre-operative co-morbidity and as such anaemic patients have a shorter
274
expected survival (HR 4.0 (1.14-12.1) than non-anaemic patient.
275
Additionally, anaemic patients spent on average 13 days longer in hospital (27 vs.14 days
276
(P=0.001)), more frequently received a post-operative blood transfusion (42.2% vs. 16.5%)
277
(OR of 4 (1.7 – 9.4) P=0.001) and experienced more post-operative complications; with a
278
higher rate 30-day myocardial events (11.1% vs 3.8%) (P=0.02) and surgical site infection
279
(20% vs. 6.3% P=0.036) (OR of 4.3 (1.2 – 15.6) P=0.028). This was irrespective of bypass
280
conduit or baseline comorbidity. These associations highlighted are stark and aligns with
281
other findings within the current literature. A large cohort study (5081patients) by Bodewes
282
et. al [17] compared the 30-day outcomes for a similar group of bypass patients using (USA)
283
registry data between 2011 and 2014. They identified that there was an increased mortality
284
rate with increasing severity of anaemia (severe, 3.1%; moderate, 3.0%; mild, 1.8%; no
285
anaemia: 0.7%; all P < .01) whilst there was a trend towards greater mortality at 30-days
286
within our data this did not reach significance (p=0.106). Furthermore, direct comparison by
287
stratification of anaemia was not performed due to the small sample size within the present
288
study. A French study of 925 patients using registry data from 2004 through to 2010 found
289
similar outcomes for anaemic patients with a greater HR for death and amputation[18] and
290
that amputation was associated with a lower haemoglobin (HR 1.20(1.07 – 1.36) irrespective
291
of comorbidity. Our study data did not find this relationship, but this may be a reflection of
292
a smaller sample size but also the thresholds for anaemia were much lower in the Desomais
293
group paper. Interestingly both Bodewes and Desomais found there to be a significant
294
difference in the baseline demographics with the anaemic patients tending to be older and
295
more co-morbid. The population within our study was comparable without difference in age
296
or comorbidity. This could be related to sample size but all of these studies will suffer from
297
the limitations of an observational study.
298
Interestingly our patients were average aged between 65.8 and 67.2 whish is lower than the
299
anaemic groups for both existing large cohort studies (70 and 73.7 respectively) and could
300
well reflect a different demographic within the UK population that highlight some
301
uniqueness when applying this data to other populations.
9
302
Surgical site infection rates were higher in our anaemic patients and but overall the
303
Bodewes group did not detect a similar difference; our records recorded only the presence
304
of infection based upon clinical assessment which may be subject to bias.
305
Within our sample a cut-off haemoglobin of 112g/L (see Error! Reference source not found.)
306
was identified, and is reasonably comparable to Spanish study for both endovascular and
307
open surgery of 100g/L for patients with CLTI[19].
308
Combining the ROC ‘cut-off’ for MI with that for mortality; may indicate that a target pre-
309
operative haemoglobin level between 112 and 122g/L to reduce the likelihood of adverse
310
outcome. This is a useful however for planning a prospective trial into targets for
311
optimisation. A randomised study comparing high (9.7g/L) to low (<8g/L) intra-operative
312
triggers for red blood cell transfusion in vascular surgery, powered to detect change in post-
313
operative Hb found that the lower <8.0g/L Hb trigger was associated with a higher rate of
314
death or major vascular complication (hazard ratio, 3.20; P=0.006) and fewer days alive
315
outside hospital within 90 days (median [IQR], 76 [67-82] vs. 82 [76-84] days; P=0.049) [20],
316
evidencing association of anaemia with poor outcome but also suggesting a Hb of 97 is
317
perhaps acceptable.
318
There are clearly limitations within this study. It is a small cohort from a single tertiary
319
centre which could limit broader generalisability to the wider population with the sample
320
size may limiting our ability to detect differences in amputation rates. Certainly, the nature
321
of an observational study means that control and matching of potential confounders is
322
challenging and the probability of bias remains high whilst multivariate analysis was used to
323
adjust for the impact of individual variables it is acknowledged that this is not a fail-proof
324
process and potentially reduces the impact of any identified associations.
325
The absolute cause of anaemia has not been evaluated which may present confounding
326
issues such as occult malignancy or other missed diagnosis such as heart or renal failure
327
which could influence prognosis within the anaemic patients[21].
328
The overall outcomes of medium to long term poor survival in the presence of anaemia are
329
congruent with other similar duration vascular studies[19]. Equally, our findings corroborate
330
findings from outside the UK in terms of shorter-term outcomes and the negative
331
association with anaemia. It is clear that anaemia plays a role in elective cardiac and vascular
332
surgery with finding a higher rate of mortality and cardiac events over 5 years[22]
333
irrespective of comorbidity among anaemic patients. Similarly, anaemia leads to greater
334
likelihood of myocardial events following vascular surgery in the Netherlands[23].
10
335
In terms of longer-term outcomes following revascularisation this study demonstrates a
336
negative implication on long-term survival but once again this as yet only an association.
337
There are existing causative mechanisms that may explain why anaemia results in death,
338
such as changes in cardiac physiology [21] leading to dysfunctional
339
hypertrophy (LVH), a risk-factor for myocardial infraction and all-cause mortality[24, 25].
340
However, association does not necessarily equate to causation and prospective work is now
341
required to further investigate this question. This paper has demonstrated that anaemia
342
must be carefully considered prior to surgical intervention as appears to be a poor
343
prognostic marker. It may help with planning care in the post-operative environment. Given
344
that the duration of surgery for both groups of patients was approximately 4 hours it could
345
perhaps guide treatment planning in terms of the appropriateness of open surgical
346
intervention. With the recent SVS/ESVS guidelines[11] in mind it seems that the pre-
347
optimisation of haemoglobin to improve survival following revascularisation is a relevant
348
avenue of future research.
349 350
Conclusion
351
This UK study highlights the prevalence and subsequent impact of pre-operative anaemia in
352
patients undergoing lower limb bypass surgery. Anaemia is associated with a greater
353
mortality and significantly greater rates of cardiac complication, wound infection, length of
354
hospital stay and post-operative blood transfusion. Low Haemoglobin levels as part of the
355
pre-operative work up should signal the potential for greater risks of morbidity and
356
mortality for urgent bypass patients.
357 358 359 360
Funding No funding sources to declare.
361 362
Acknowledgements The authors would like to acknowledge the contributions of the vascular consultants; Miss
363
Anne Burdess, Mr Mike Clarke, Mr Tim Lees, Mr James McCaslin, Miss Lucy Wales and Mr
364
Mike Wyatt at the Northern Vascular Centre. In addition, offer special thanks to the research
365
nurses, Deborah Amis, Martin Catterson and Noala Parr.
left ventricular
366 367 368 369 370
1. Hogan M, Klein AA, Richards T. the impact of anaemia and intravenous iron replacement therapy on outcomes in caridac surgery. European Journal Of Cardio-Thoracic Surgery 2014; 1-9.
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2. Fowler AJ, Ahmad T, Phull MK et al. Meta-analysis of the association between preoperative anaemia and mortality after surgery. British Journal Of Surgery 2015; 102. 3. Sanders J, Cooper JA, Farrar D et al. Pre-operative anaemia is associated with total morbidity burden on days 4 and 5 after cardiac surgery: a cohort study. Perioperative Medicine 2017; 6. 4. Horwich TB, Fonarow GC, Hamilton MA et al. Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure. Journal of the American College of Cardiology 2002; 39: 1780-1786. 5. Szachniewicz J, Petruk-Kowalczyk J, Majda J et al. Anaemia is an independent predictor of poor outcome in patients with chronic heart failure. International Journal of Cardiology 2003; 90: 303-308. 6. Ezekowitz Justin A, McAlister Finlay A, Armstrong Paul W. Anemia Is Common in Heart Failure and Is Associated With Poor Outcomes. Circulation 2003; 107: 223-225. 7. National Clinical Guideline C. Blood transfusion (NG24). In. 2017. 8. Leahy MF, Hofmann A, Towler S et al. Improved outcomes and reduced costs associated with a health-system-wide patient blood management program: a retrospective observational study in four major adult tertiary-care hospitals. Transfusion 2017; 57: 1347-1358. 9. Munoz M, Gomez-Ramirez S, Kozek-Langeneker S et al. 'Fit to fly': overcoming barriers to preoperative haemoglobin optimization in surgical patients. Br J Anaesth 2015; 115: 15-24. 10. Kotze A, Harris A, Baker C et al. British Committee for Standards in Haematology Guidelines on the Identification and Management of Pre-Operative Anaemia. Br J Haematol 2015; 171: 322-331. 11. Conte MS, Bradbury AW, Kolh P et al. Global Vascular Guidelines on the Management of Chronic Limb-Threatening Ischemia. Eur J Vasc Endovasc Surg 2019. 12. Desormais I, Aboyans V, Bura A et al. Anemia, an independant predictive factor for amputation and mortality in patients hospitalised for peripheral arterial disease. European Society For vascular Surgery 2014; 48. 13. Chau M, Richards T, Evans C et al. The UK cardiac and vascular surgery interventional anaemia response (CAVIAR) study: protocol for an observational cohort study to determine the impact and effect of pre-operative anaemia management in cardiac and vascular surgical patients. BMJ Open 2017; 7. 14. Rutherford RB, Baker JD, Ernst C et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997; 26: 517-538. 15. Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Annals of internal medicine 2009; 150: 604-612. 16. Al Falluji N, Lawrence-Nelson J, Kostis JB et al. Effect of anemia on 1-year mortality in patients with acute myocardial infarction. Am Heart J 2002; 144: 636-641. 17. Bodewes TCF, Pothof AB, Darling JD et al. Preoperative anemia associated with adverse outcomes after infrainguinal bypass surgery in patients with chronic limb-threatening ischemia. J Vasc Surg 2017; 66: 1775-1785 e1772.
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18. Desormais I, Aboyans V, Bura A et al. Anemia, an independent predictive factor for amputation and mortality in patients hospitalized for peripheral artery disease. Eur J Vasc Endovasc Surg 2014; 48: 202-207. 19. Velescu A, Clará A, Cladellas M et al. Anemia Increases Mortality After Open or Endovascular Treatment in Patients with Critical Limb Ischemia: A Retrospective Analysis. European Journal of Vascular and Endovascular Surgery 2016; 51: 543-549. 20. Møller A, Nielsen HB, Wetterslev J et al. Low vs. high hemoglobin trigger for Transfusion in Vascular surgery (TV): a randomized clinical feasibility trial. Blood 2019; blood-2018-2010-877530. 21. McClellan WM, Flanders WD, Langston RD et al. Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 2002; 13: 1928-1936. 22. Dunkelgrun M, Hoeks SE, Welten GM et al. Anemia as an independent predictor of perioperative and long-term cardiovascular outcome in patients scheduled for elective vascular surgery. Am J Cardiol 2008; 101: 1196-1200. 23. Goei D, Flu WJ, Hoeks SE et al. The interrelationship between preoperative anemia and N-terminal pro-B-type natriuretic peptide: the effect on predicting postoperative cardiac outcome in vascular surgery patients. Anesth Analg 2009; 109: 1403-1408. 24. Lipsic E, van der Horst IC, Voors AA et al. Hemoglobin levels and 30-day mortality in patients after myocardial infarction. Int J Cardiol 2005; 100: 289292. 25. Kannel WB. Lipids, diabetes, and coronary heart disease: insights from the Framingham Study. Am Heart J 1985; 110: 1100-1107.
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Demographics Number AGE Gender Haemoglobin Rutherford Class. 3 – Claudication (modified) 4 - Rest Pain 5 - Tissue loss (digits) 6 - Extensive tissue loss Comorbidities and Medications Diabetes Hypertension IHD Heart Failure Renal Failure COPD Antiplatelets Statins Creatinine (Mean (s.d)) Sodium (mean (s.d)) Operative Data Duration in minutes (mean (s.d)) Conduit Vein Prosthetic
Non-Anaemic 79 (64%) 67.2(9.4) M68 F11 140.9 (14.8)
Anaemic 45 (36%) 65.8(11.2) M32 F13 105.5(9.5)
0.687 0.017 (<0.001)
14 (18%) 25 (32%) 9 (11%) 31 (39%)
4 (9%) 10 (22%) 6 (13%) 25 (56%)
0.118 0.139 0.918 0.214
23 (29.1%) 52 (65.8%) 23 (29.1%) 3 (4%) 3 (4%) 17 (21.5%) 54 (68.3%) 54 (68.3%) 86.4 (47.4) 137.6 (3.5)
18 (40%) 16 (35.6%) 33 (73.3%) 3 (6.7%) 2 (4.4%) 12 (26.7%) 29 (64.4%) 33 (73.3%) 89.4 (41.7) 137.2 (3.8)
0.193 0.699 0.364 0.297 0.550 0.514 0.241 0.875 0.272 0.591
241.5 (153) 69 (87.3%) 10 (12.7%)
256.7 (180) 39 (86.7%) 6 (13.3%)
0.781 0.701
Table 1 - Baseline demographics, co-morbidity and operative data
P Value
Group
Months (Mean (s.e)) 95% Confidence Interval
Non-anaemic
37.8 (1.4)
35.9 – 39.7
Anaemic
32.9 (2.1)
28.9 – 37.0
Overall
36.1(0.99)
34.2 – 38.1
Table 1-Mean survival in months
Non-Anaemic (79)
Anaemic (45)
P-Value
Myocardial Infarction
3 (3.8%)
5 (11.1%)
0.020
Wound infection
5 (6.3%)
9 (20%)
0.036
Graft Occlusion 3m
20 (25%)
16 (35.6%)
0.229
Re-intervention (endovas. or open)
32 (40.5%)
20 (44.4%)
0.495
Limb-loss
17 (21.5%)
14 (31.1%)
0.189
14 (16)
27 (23)
0.001
1 (1.3%)
3 (6.7%)
0.106
4 (5%)
8 (17.8%)
0.037
13 (16.5%)
19 (42.2%)
0.001
2 (2-3)
2 (1-3)
0.324
Complications
Length of Stay
Mortality 30d Mortality 1-year mort
Post -operative Red Blood Cell (RBC) transfusion Number of patients receiving RBC’s Median Quantity (IQR) (in units)
Table 1 – Complications, Length of Stay and Mortality, by Group
Renal Function (eGFR (ml/kg/min))
Non-Anaemic
Anaemic
Baseline
86.5 (28.2)
77.7 (26.6)
0.098
Day 1 Post-op
89.0 (31.6)
85.0 (34.9)
0.691
Week 1 Post-op
86.3 (31.2)
80.1 (30.8)
0.361
Year 1 Post-op
103.8 (43.2)
67.7 (25.0)
0.178
Table 1 – Renal function over time, by group
P-Value
1
Significant Variable
HR
95% CI
P-value
Anaemia1
3.7
1.1 – 12.3
0.034* 0.034*
Anaemia2
3.6
1.1 – 12.1
0.037* 0.037*
Anaemia3
4.0
1.14 – 12.1
0.031* 0.031*
Antiplatelet4
0.17
0.04 – 0.67
0.011* 0.011*
2
3
4
Anaemia, Anaemia, age, gender, +Comorbidities, +Medication and RBC transfusion (*significant p-value)
Table 1 - Cox Proportional Hazard table of significant variable by model of regression analysis
Non- anaemic Anaemic
Log rank, sig p=0.017
Months 0
6
12
18
24
30
36
Not anaemic
79
77
63
42
31
26
10
Anaemic
45
42
28
24
12
9
4
Figure 1 - Kaplan-Meier Survival Analysis; (Non-Anaemic = Blue, Anaemic = Red,)
Non- anaemic Anaemic
Log rank, sig p=0.025
Months 0
6
12
18
24
30
36
Not anaemic
65
63
50
33
23
18
7
Anaemic
41
38
25
21
9
6
4
Figure 1 - Kaplan-Meier Survival Analysis for sub-group of CLTI patients; (Non-Anaemic = Blue, Anaemic = Red)
ROC for mortality
Figure 1- ROC curve for mortality and Haemoglobin (AUC= 0.749)