Dysvascular lower limb amputation: incidence, survival and pathways of care
Fard, Behrouz
DOI:
10.33612/diss.134440454
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2020
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29
C
HAPTER3
–
Mortality, reamputation and pre-operative comorbidities in
patients undergoing dysvascular lower limb amputation.
Behrouz Fard1,2
Pieter U. Dijkstra1,3
NEDA Study Group†
Henricus G. J. M. Voesten1,4
Jan H. B. Geertzen2
1 University of Groningen, University Medical Center Groningen, Department of Rehabilitation Medicine, Groningen, the Netherlands.
2 Roessingh Center for Rehabilitation, Enschede, the Netherlands.
3 University of Groningen, University Medical Center Groningen, Department of Oral and Maxillofacial Surgery, Groningen, the Netherlands.
4 Nij Smellinghe Hospital, Department of Vascular Surgery, Drachten, the Netherlands.
† Members of the Northern Netherlands Epidemiology of Dysvascular Amputation (NEDA) Study Group are listen in the Acknowledgements section.
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Abstract
Background: Historically, mortality rates after major lower limb amputation (LLA) have been very
high. However, there are inconsistencies regarding the risk factors. Reamputation rate after major LLA is largely unknown. The aim of this study is to report the 30 days and 1 year mortality and 1 year reamputation rates after major LLA and to identify potential risk factors.
Methods: Observational cohort study in which all patients undergoing dysvascular major LLA in
2012-2013 in 12 hospitals in the northern region of the Netherlands are included.
Results: In total 382 patients underwent major LLA, 65% were male, the mean age (SD) was 71.9 ±
12.5 years. Peripheral arterial disease was observed in 88% and diabetes mellitus (DM) in 56% of patients. No revascularization or prior LLA on the amputated side was observed among 26%, whereas 56% had no minor or major LLA on either limb prior to the study period. The 30 days and 1 year mortality rates were 14% and 34%, respectively. Patients aged 75-84 and >85 years had 3-4 times higher odds of dying within 1 year. Transfemoral amputation (OR 2.2), history of heart failure (OR 2.3), myocardial infarction (OR 1.7), hemodialysis (OR 5.7), immunosuppressive medication (OR 2.8) and guillotine amputation (OR 5.1) were independently associated with 1 year mortality. Twenty-six percent underwent ipsilateral reamputation within 1 year, for which no risk factors were identified.
Conclusion: Mortality rate in the first year after major LLA is high, particularly among those
undergoing transfemoral amputation, which is likely to be indicative of more severe vascular disease. Higher mortality among the most elderly patients, those with more severe cardiac disease and hemodialysis reflects the frailty of this population. Interestingly DM, revascularization history and prior minor or major LLA were not associated with mortality rates.
Keywords: Amputation, peripheral arterial disease, diabetes mellitus, mortality, reamputation,
comorbidity.
Abbreviations: BL: bilateral; DM: diabetes mellitus; CABG: coronary artery bypass grafting; KD:
knee disarticulation; LLA: lower limb amputation; OR: odds ratio; PAD: peripheral arterial disease; PTA: percutaneous transluminal angioplasty, Re: reamputation, TF: transfemoral; TT: transtibial.
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Introduction
The vast majority of lower limb amputations (LLA) is related to diabetes mellitus (DM) and peripheral arterial disease (PAD). These ‘dysvascular’ amputations account for over 90% of LLA in the Western European countries1,2. LLA are differentiated in minor and major amputations (i.e., ankle disarticulation
and more proximal levels), with the latter being associated with more disability3 and higher mortality
rates4,5. Recent systematic reviews estimate the 30 day, 1 year and 5 year mortality rates for major LLA
as 4-22%6, 47%7 and 52-80%5 respectively. Several studies indicate that older age, end-stage renal
disease and more proximal levels of amputation are associated with higher mortality rates5–7. The role
of other comorbidities such as cardiovascular, pulmonary and cerebrovascular diseases remains uncertain6. For example, cerebrovascular diseases was reported as being associated with higher
mortality by some8,9, while others did not support this association and found different comorbidities as
risk factors10. DM is observed among 40-50% of patients undergoing major LLA11,12, but it remains
unclear whether DM affects mortality rates among LLA patients5. There is no consensus on whether
DM and non-DM patients undergoing LLA should be viewed as separate populations. Several recent studies report decreased incidence rates for major LLA in the general and DM-populations11–13, which
may be attributed to improved treatment of PAD and DM in the past 2 decades14. Nonetheless, some
patients undergo multiple minor and major amputations during their life-time. Few studies have reported reamputation rates after major LLA4,15, as most studies have focused on minor LLA (including
partial foot amputations)16,17 and often report on DM populations only18,19.
We hypothesize that multivariate analysis of mortality rates with a larger set of comorbid conditions will improve to the contemporary understanding of mortality risk, in the frail population that is confronted with dysvascular amputation. Also, details pertaining to revascularization attempts, previous LLA, the sequence of the performed amputations and subsequent reamputations should be taken into account. The aim of this study is to report the 30 days and 1 year mortality and 1 year reamputation rates following major LLA and to identify potential risk factors for these outcomes.
Methods
Setting and population
Data were collected retrospectively in 12 hospitals –one academic and 11 general hospitals– in the northern region of the Netherlands, with a population of 1.7 million inhabitants20. In the Netherlands,
general practitioners are tasked with providing primary medical care for residents registered in their practices. In 2012 the average pool of registered residents per general practitioner was 2350 persons20.
Patients are referred for specialist care in general hospitals or to the regional academic hospital for specialist care of higher complexity (after consultation with the general hospital). DM care is provided by the endocrinologist, who will also refer patients to appropriate specialists when complications are expected (e.g., vascular surgeon or ophthalmologist) and initiate multidisciplinary prevention and
32
treatment of diabetic foot ulcers in particular. Similarly, vascular surgeons provide surveillance and treatment for patients with or at risk of PAD. Medical insurance is mandatory for all citizens, which ensures universal medical access for both primary and specialist care. As mandated by the central government, the infrastructure and health care systems are designed as such that in 95% of all medical emergency calls, ambulance response time is within 15 minutes. In the study region (provinces of Groningen, Friesland and Drenthe) the majority of the population resides within cities with a general hospital (within 5 km radius), the median distance to a general hospital is 9.4 km20 and the maximum
distance from the most rural town to a general hospital is 38 km. Because centralized or regional medical registries are absent in the Netherlands, medical records of patients had to be accessed directly on site in each of the hospitals. Approval of the regional Medical Ethics Committee was obtained prior to data collection (M15.176087). In addition, in each of the general hospitals the local Medical Ethics Committee(s) or the Board of Directors were informed and approved the study.
Major LLA was defined as an amputation through the ankle or more proximal level6,7,21,22. All major LLA,
performed from January 2012 through December 2013, were included. The choice to include patients undergoing amputation in 2 consecutive years was in part to facilitate comparison of incidence rates over time to previous cohorts in the region in 1991-199223 and 2003-200424 respectively. Data
collection at the hospitals was performed from January 2015 through April 2017. Any major LLA among patients with a recorded diagnosis of DM and/or PAD at the time of or prior to major LLA were included as dysvascular amputations. Additional details of the search strategy and inclusion are provided in Appendix A. Amputation due to trauma, cancer, complex regional pain syndrome type-1, iatrogenic complications, intractable leg lymphedema and congenital syndromes were excluded. Sporadically, rapidly progressing Staphylococcus Aureus and Streptococcus Group-A infections in otherwise healthy adults with no prior history of PAD/DM leading to LLA were observed in the academic hospital. These patients were excluded, because they represent a separate population than dysvascular amputation patients, for whom the eventual cause of amputation may have been infection/sepsis control but the underlying disease leading to amputation had been PAD, DM and related complications.
Variables
The primary outcome variables were the 30 days and 1 year post-operative mortality rates, for which time to death was calculated as the time (days) between the first major LLA during the study period (i.e., the index amputation) and date of death as stated in patients’ medical records. The secondary outcome variable was reamputation, defined as subsequent major LLA –either revision of the stump, conversion to more proximal level or contralateral amputation– within 1 year of the index amputation. Vascular surgical history, including percutaneous transluminal angioplasty (PTA), arterial bypass grafting, endarterectomy and previous minor or major LLA, was recorded and specified for having been performed either ipsilateral, contralateral or bilateral to the side of index amputation. Planned
two-33 stage amputation among the dysvascular population is not the norm in the Netherlands, and to our knowledge have not (or very rarely) been performed in the study region in the past 10 years. Guillotine amputations are reserved for emergency situations, for example when time is of the essence for sepsis control or patients are too unstable for the longer operating time required for the standard amputation procedure. In this study, when Guillotine amputations were performed, the definitive amputations performed several days later (if patients did survive) were not considered reamputations. When multiple LLA were performed in the study period, the most proximal level was used to determine the level of LLA for the analyses of mortality rates. When major LLA were performed on both limbs in the study period (either consecutively or in a single operation) amputations were labeled as bilateral. A primary LLA was defined as no recorded history of any vascular surgical procedure (i.e., PTA, bypass or endarterectomy), minor or major LLA on the side of index amputation. Comorbidities were based on items from the Charlson Comorbidity Index25 using International Classification of Disease (ICD-9) codes,
with several additional items, which are described in detail in Appendix A. Statistical analysis
Initially we had planned a Cox regression analysis but because of violation of the proportional hazards assumption, it was deemed inappropriate. Survival was analyzed using Kaplan-Meier estimation of cumulative mortality rates, for which the data were right censored. No missing data was imputed. Differences in observed mean days of survival after amputation was analyzed using Log-rank tests. Associations between patient characteristics for the outcomes 30 days and 1 year mortality and reamputation within 1 year, were explored using χ2 tests. Variables with p < 0.2 were included in the
multiple logistic regression analyses employing backward stepwise elimination. Odds ratios (OR) with 95% Confidence Intervals (CI) were calculated for the identified associations between the predictor variables and outcomes. Age was analyzed both as a continuous variable (not shown) and recoded into age categories in order to facilitate clinical interpretation. For the main analyses statistical significance was set at α = 0.05. Microsoft Excel 2016, IBM SPSS Statistics 24 and G*Power 3.1 were used for the analyses.
Results
Patient characteristics
A total of 382 patients undergoing major LLA in 2012-2013 were identified (Table I), 65% were male. The mean age (SD) at the time of index amputation was 71.9 ± 12.5 years. At 30 days for 2 (0.5%) patients and at 1 year for 16 (4%) patients, outcome data were unavailable and dates of last documented contact were used for time to censored events. PAD was observed in 88% of patients (Table I) and DM was present in 56% of patients. Among those with PAD 52% also had DM. Among 7 (1.8%) patients the reason for amputation was an acute arterial occlusion without any prior history of either PAD or DM at the time of index amputation. Fifty-four (14%) of patients were treated in the
34
regional academic hospital, the remaining 86% were geographically distributed by place of residence in the 11 general hospitals. Fifteen (4%) guillotine amputations were performed. Hypertensive disease was the most common comorbidity and was observed in 73% of patients. Twenty-six percent had no history of any revascularization or amputation on the side of index amputation (i.e., primary LLA). Fifty-six percent had no previous minor or major LLA on either limb, whereas 34% had undergone minor and 10% had major LLA prior to the index amputation. The sequence of amputations performed in the study period is illustrated in Fig. 1.
Figure1. Sequence of performed major lower limb amputation. Percentages are relative to
included patients at baseline (N = 382). a On either side. b First LLA performed in the study period, ankle disarticulation (n = 2) and hip disarticulation (n = 1) not shown. c Ipsilateral and contralateral, when multiple reamputations occurred the most proximal level within 1 year after index amputation is presented. BL: bilateral; KD: knee disarticulation; LLA: lower limb amputation; TF: transfemoral; TT: transtibial; Re: reamputation.
Survival
Of the initial 382 patients, 54 (14%) died within 30 days and 130 (34%) within 1 year after the index amputation, the mean survival was 273 days (95% CI 259-288) (Fig. 2). Patients in the age categories 75-84 and >85 years survived the shortest and had the highest 1 year mortality rates, 48% and 50% respectively (Fig. 2B). Forty-two percent of patients with transfemoral amputation died within 1 year and had shorter mean survival days (251, 95% CI 229-273) compared to more distal levels of amputation (293, 95% CI 274-313; 291, 95% CI 237-344) (Fig. 2C). No significant differences in mean
TF n = 119 (31.2%) KD n = 33 (8.6%) TT n = 227 (59.4%)
Prior major LLA
n = 11 (2.9%)
Prior minor LLA
n = 131 (34.3%)
Prior minor and major LLA n = 28 (7.3%) Re-TT n = 2 KD n = 2 TF n = 49 BL-TT n = 8 BL-KD n = 1 Index amputationb N = 382 Prior amputationsa n = 170 Reamputation within 1 yearc n = 85 Re-KD n = 1 TF n = 9 BL-TF n = 2 BL-TF n = 2 Re-TF n = 5 BL-TF n = 4
35 survival days and 1 year mortality rates were observed between transtibial and knee disarticulation levels (Fig. 2C). Survival distributions specified by DM diagnosis (i.e., DM vs. non-DM), types of DM, bilateral LLA, prior major/minor ipsilateral or contralateral LLA were also analyzed (not shown) but no statistically significant differences in mean survival were observed.
F ig ure 2. K ap la n-M ei er a na ly si s of m or ta lit y an d m ea n da ys o f s ur vi va l b y gen de r (A ), ag e ca teg or ie s (B ) an d lev el of am pu ta tio n (C ). a M os t po st p ro xi m al lev el of a m pu ta tio n per for m ed wit hi n st udy p er iod , a nk le di sa rt ic ul at io n (n = 1 ) an d hi p di sa rt ic ul at io n (n = 1) n ot s how n. K D : k nee d is ar tic ul at io n; LL A : l owe r lim b am pu ta tio n; T F: t ra ns fem or al ; T T : tr an st ib ia l. L ev el o f L L A — TF — KD — TT A ge — 0 -54 — 75 -84 — 55 -64 — > 85 — 65 -74 G en d er — M al e — Fe m al e 10 0 0 30 20 0 30 0 0. 1 0. 2 0. 3 0. 4 Mor tal ity (c um ula tiv e r ate ) 0. 5 0. 6 0 T im e (d ay s) 36 5 10 0 0 30 20 0 30 0 0. 1 0. 2 0. 3 0. 4 Mor tal ity (c um ula tiv e r ate ) 0. 5 0. 6 0 T im e (d ay s) 36 5 10 0 0 30 20 0 30 0 0. 1 0. 2 0. 3 0. 4 Mo rta lity (c um ula tiv e r ate ) 0. 5 0. 6 0 T im e (d ay s) 36 5 A C B In d ex L L A n (% ) D ea d <1 y ea r n (% ) D ay s su rv iv al (95% C I) T o ta l 382 (100) 130 (34) 273 (259 -288) Gend er M al e 247 (65) 76 (31) 284 (267 -301) F em al e 135 (35) 54 (40) 254 (230 -280) Ag e 0 -54 42 (11) 12 (29) 311 (277 -345) 55 -64 66 (17) 14 (21) 306 (275 -336) 65 -74 96 (25) 17 (18) 320 (297 -341) 75 -84 122 (32) 59 (48) 230 (202 -257) >85 56 (15) 28 (50) 224 (185 -265) L ev el o f L L A a TT 176 (46) 49 (28) 293 (274 -313) KD 25 (7) 6 (24) 291 (237 -344) TF 179 (47) 75 (42) 251 (229 -273)
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Patient characteristics and univariate analyses leading to inclusion of variables in the regression models are presented in Table I. Results of the multivariate analyses of 30 days and 1 year mortality are presented in Table II. Only prior history of heart failure (OR 2.5, 95% CI 1.4-4.6) and guillotine amputation (OR 3.6, 95% CI 1.1-11.4) were independently associated with higher 30 days mortality rates. In line with the observations of survival distributions (Fig. 2B), multivariate analyses indicated that patients in the age categories 75-84 and >85 years had the highest 1 year mortality rates compared to patients aged 0-54 years (Table II). The 1 year mortality rates for the age groups 0-54, 55-64 and 65-74 were similar. Transfemoral amputation was associated with higher 1 year mortality rates (OR 2.2, 95% CI 1.4-3.8) compared to transtibial amputation. Several factors were also independently associated with higher 1 year mortality rates: prior history of heart failure (OR 2.3, 95% CI 1.3-4.0), myocardial infarction (OR 1.7, 95% CI 1.0-3.1), guillotine amputation (OR 5.1, 95% CI 1.4-18.0), hemodialysis (OR 5.7, 95% CI 2.1-15.2) and use of immunosuppressive medication (OR 2.8, 95% CI 1.6-5.0). Several variables of interest with regard to mortality rates (Table I) such as primary LLA, revascularization attempts, bilateral LLA, prior LLA on either limb and prior LLA on ipsilateral limb (Appendix B) were not associated with mortality rates using univariate and subsequent multivariate analyses. Additionally, analyses were performed defining the level of amputation by index amputation (instead of most proximal level), the results were similar: transfemoral amputation was associated with higher mortality rates compared to transtibial (Appendix C).
Reamputation
Of the initial 382 patients, 98 (26%) did not undergo reamputation but died before 1 year and 12 (3%) were lost to follow-up, which makes 272 patients eligible for analysis of reamputation rates. Seventy patients (26%) underwent ipsilateral reamputation within 1 year of the index amputation (Table III): 8 were revisions at the same level and 62 were performed on a more proximal level. Reasons for reamputation were: non-healing stump (n = 25), local infection of the wound (n = 28), systemic infection originating from the wound (n = 6), revision of the stump in order to facilitate prosthesis use (n = 4), PAD proximal to the stump (n = 4) or not stated (n = 3). Seventeen patients (6%) underwent reamputation contralateral to the index limb, of which two also had an ipsilateral reamputation. In total 85 (31%) underwent at least one major reamputation on either limb. Patient characteristics and univariate analyses of ipsilateral reamputations rates are presented in Table III. Logistic regression analyses did not provide independently associated risk factors for any of the variables. Additionally, analyses of reamputation risk factors were performed for the total study population, including patients who died before 1 year without undergoing reamputation (Appendix D). These analyses did not yield different results, except that the ipsilateral reamputation rate was 18% (Appendix D) in contrast to 26% (Table III) and age categories being associated with reamputation in univariate analysis, which did not remain consistently significant in the multivariate model.
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Table I. Characteristics of patients undergoing major lower limb amputation
Baseline 30 days 1 year
Alive Dead P a Alive Dead P a
Total 382 (100) 326 (85) 54 (14) 236 (62) 130 (34) Age, years (mean, SD) 71.9
(12.5) 71.6 (12.6) 73.7 (12.1) 0.25 69.4 ± 12.2 75.6 ± 12.4 <0.01 Age, categories 0-54 42 (11) 38 4 0.15 30 12 <0.01 55-64 66 (17) 56 9 50 14 65-74 96 (25) 88 8 76 17 75-84 122 (32) 97 24 56 59 >85 56 (15) 47 9 24 28 Gender (male) 247 (65) 213 32 0.39 163 76 0.04 Prior LLA(either limb)
No minor/major LLA 212 (56) 176 35 0.05 126 75 0.26 Prior minor LLA 131 (34) 120 11 89 39
Prior major LLA 39 (10) 30 8 21 16 Level of amputation b Transtibial 176 (46) 159 17 0.04 122 49 <0.01 Knee disarticulation 25 (7) 21 3 17 6 Transfemoral 179 (47) 144 34 95 75 Primary LLA c 100 (26) 80 18 0.17 51 43 0.02 Bilateral amputation 17 (5) 15 2 0.76 12 4 0.38 Guillotine amputation 15 (4) 10 5 0.03 6 8 0.09 Smoking status (ever) 289 (76) 247 40 0.79 187 89 0.02 Medical history
PAD 336 (88) 285 49 0.49 204 118 0.22
DM 216 (56) 190 26 0.54 134 77 0.38
DM type I 26 (7) 23 3 13 13
DM type II, oral
medication 74 (19) 64 10 48 22
DM type II, insulin 116 (30) 103 13 73 42
Cerebrovascular disease 104 (27) 93 11 0.21 58 39 0.26 Cardiac disease Hypertension 277 (73) 231 45 0.06 162 106 0.01 Myocardial infarction 101 (26) 86 15 0.83 24 44 0.01 CABG 82 (21) 69 12 0.87 43 35 0.05 Heart failure 102 (26) 77 24 <0.01 45 53 <0.01 Chronic pulmonary disease 112 (29) 93 18 0.47 65 41 0.42 Renal disease 128 (34) 103 25 0.03 68 58 0.01 Hemodialysis 28 (7) 21 7 0.09 10 18 <0.01 Autoimmune disease 49 (13) 42 7 0.99 25 24 0.03 Immunosuppressive medication 90 (24) 75 15 0.45 44 46 <0.01 Alcohol abuse 65 (17) 52 12 0.25 42 19 0.43 Revascularization (ipsilateral) PTA 148 (39) 125 23 0.55 95 46 0.36 Bypass graft 134 (35) 117 17 0.53 90 38 0.09 Endarterectomy 100 (26) 92 8 0.04 75 20 <0.01 Values are number of patients (%) unless indicated otherwise. CABG, coronary artery bypass grafting; DM, diabetes mellitus; LLA, lower limb amputation; PAD, peripheral arterial disease; PTA, percutaneous transluminal angioplasty.
a χ2 tests for categorical variables and t tests for age between patients alive and dead at 30 days and 1 year after
amputation.
b Most post proximal level of amputation performed within study period, ankle disarticulation (n=1) and hip
disarticulation (n=1) not included.
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Table II. Multivariate analyses of 30 days and 1 year mortality
β SE P OR (95% CI) 30 days mortality Constant -2.20 0.20 <0.001 Guillotine amputation 1.29 0.58 0.027 3.64 (1.16-11.41) Heart failure 0.95 0.30 0.002 2.59 (1.43-4.67) 1 year mortality Constant -2.44 0.48 <0.001 Age a <0.001 55-64 -0.25 0.59 0.632 0.78 (0.28-2.19) 65-74 -0.36 0.51 0.481 0.70 (0.26-1.88) 75-84 1.13 0.47 0.009 3.40 (1.36-8.55) >85 1.46 0.53 0.005 4.30 (1.54-12.05) Level of amputation b Knee disarticulation 0.17 0.57 0.760 1.19 (0.39-3.64) Transfemoral 0.81 0.27 0.003 2.25 (1.32-3.83) Guillotine amputation 1.65 0.64 0.010 5.19 (1.49-18.08) Myocardial infarction 0.58 0.29 0.046 1.78 (1.01-3.13) Heart failure 0.85 0.28 0.003 2.33 (1.35-4.04) Hemodialysis 1.74 0.49 <0.001 5.72 (2.15-15.20) Immunosuppressive medication 1.05 0.29 <0.001 2.85 (1.60-5.07) Multiple backwards logistic regression; Nagelkerke R2 30 days 0.063; Nagelkerke R2 1
year 0.323.
a Compared to 0-54 years category. b Compared to transtibial amputation.
Table III. Univariate analyses of reamputation within 1 year
Eligible Ipsilateral reamputation <1 year No Yes P a Total 272 (100) 202 (74) 70 (26) Age, mean (SD) 69.6 (12.4) 70.2 (12.6) 67.8 (11.7) 0.17 Age, categories 0-54 37 (13) 24 13 0.54 55-64 54 (20) 38 16 65-74 84 (31) 64 20 75-84 67 (25) 52 15 <85 30 (11) 24 6 Gender (male) 184 (68) 140 44 0.32 Smoking status (ever) 212 (78) 156 56 0.63 Medical history
Peripheral arterial disease 233 (86) 170 63 0.23
DM 156 (57) 83 33 0.37
DM type I 17 (6) 10 7
DM type II, oral medication 55 (20) 43 12 DM type II, insulin use 84 (31) 66 18
Renal disease 85 (31) 60 25 0.35
Hemodialysis 15 (5) 8 7 0.06
Autoimmune disease 30 (11) 21 9 0.57 Immunosuppressive medication 54 (20) 38 16 0.47 Alcohol abuse 50 (18) 37 13 0.96 Prior LLA(ipsilateral)
No minor/major LLA 162 (60) 114 48 0.18 Reamputation from minor LLA 103 (38) 83 20
Reamputation from major LLA 7 (3) 5 2
Primary LLA b 64 (23) 49 15 0.63
Revascularization (ipsilateral)
PTA 103 (38) 71 32 0.12
Bypass graft 101 (37) 69 32 0.09 Endarterectomy 79 (29) 57 22 0.61 Values are number of patients (%) unless indicated otherwise. DM, diabetes mellitus; LLA, lower limb amputation; PTA, percutaneous transluminal angioplasty.
a χ2 tests categorical variables and t tests for age between patients undergoing ipsilateral
reamputation within 1 year after index amputation.
b Patients with no ever recorded vascular surgical procedure or minor/major LLA on the side of
39
Discussion
The main finding of this study is that the post-operative and 1 year mortality rates of dysvascular major LLA is high, as 34% of patients do not survive the first year. In line with previous studies10,26,27, the most
elderly patients –those aged >75 years– had the highest mortality risk. Transfemoral amputation was associated with higher mortality rates, in line with several previous studies reported in two systematic reviews5,7. Proximal amputation is likely to be indicative of more severe disease6, when a distal level is
not an option (due to poor vascularization or local infection) or has already been performed. Bilateral amputations have been reported to be associated with both worse28 and better survival rates4,29,
whereas no differences were observed in our study. These discrepancies may be explained by aggregation of different combinations of anatomic levels among bilateral LLAs, that is: transtibial-transtibial, transfemoral-transtibial-transtibial, transfemoral-transfemoral, et cetera. Consistent with our observations, we therefore propose that the eventual anatomic level of LLA is more predictive of survival rather than the distinction between unilateral or bilateral LLA. Patients with first ever LLA may be expected to have better odds of survival, as they are likely to be in better physical condition and have less severe disease compared to those who have already undergone an amputation6. However,
this assumption was not confirmed in our study: no differences in mortality rates were found with regard to patients having any, minor or major LLA prior to the index amputation. Unsurprisingly, guillotine amputations were associated with high mortality30, which is to be expected as the procedure
is performed when the situation is already life-threatening for patients.
A systematic review concluded that diffuse cardiovascular disease is associated with the high mortality among LLA patients7. Our results suggest that more severe cardiac disease such as heart failure
contributes to the risk of death after LLA26,31. Similar to our study, end-stage renal disease in which
hemodialysis is needed was found to be associated with higher mortality rates among LLA patients28,30.
Although other studies indicate that this association might be the case for renal disease in general26,32,
our findings do not support that renal disease is an independent risk factor. Inclusion of immunosuppressive medication in our study as potential risk factor was based on clinical observations and the expected inherent side effects such as interference with glycemic control and susceptibility to infections33. To our knowledge this is the first study identifying use of immunosuppressive medication
as a potential risk factor of 1 year mortality: two previous studies found steroid use to be associated with higher 30 day mortality34,35. A systematic review found DM associated with higher mortality in 7
out of 13 studies, whereas 6 out of 13 studies did not support this conclusion5. In this study, no
differences in mortality rates were observed between DM and non-DM patients undergoing major LLA. Reamputation after either minor or major LLA is to be avoided as much as possible because of subsequent perioperative risks with each operation and decrease in mobility and physical condition
40
with each hospital admission. Systematic reviews estimate that 20%19 of ray amputations and 28%36 of
transmetatarsal amputations will require reamputation at a more proximal level. It is therefore alarming that among 26% of patients, ipsilateral reamputations were observed in the first year after undergoing major LLA. Previous studies report 9-20%4 and 7%15 ipsilateral reamputation after major
LLA. We argue that it is more appropriate that deceased non-reamputated patients are subtracted from the denominator: since those patients do not complete the first year without reamputation, their inclusion underestimates the rate of reamputation by inflating the observed numbers of non-reamputated cases. Based on clinical observation, we had expected to observe higher reamputation rates among DM patients and those with prior revascularization or LLA on the index limb, however no risk factors for reamputation in the first year after LLA were identified.
Historically, mortality rates after major LLA have been ‘notoriously’ high5–7, which has been argued by
some to be attributable to the population comprising of elderly and medically frail patients at the time of major LLA7,37,38. Whereas others regard LLA as failure of the health care system39 and question
whether it should be regarded as lifesaving considering the high mortality rates40. An opposing view is
that delay of amputation in favor of (repeated) revascularization attempts may be detrimental for chances of survival38,41,42. One-third mortality rate within 1 year after major LLA may indeed be
regarded as alarmingly high, considering that for the overall Dutch population aged 75-84 years in 2013, the 1 year risk of death was estimated as 2.5-7.3%20. Illustrative of the frailty of the LLA population is
that survival after major LLA is more in line with heart failure which has a 5 year mortality rate of 44%43
in the Netherlands, and hemodialysis which has 1 year mortality up to 25%44. The decision-making
process for surgeons and patients may be seen as a continuum: on one side there are clear indications to perform an amputation (e.g., life-threatening situations or uncontrollable pain), while on the other side of the spectrum there are the situations in which patients and surgeons continue to avoid an amputation through revascularization attempts. Based on the current literature it remains unclear when to ‘call it quits’ prior to opting for an amputation5. We propose that the high mortality rates and
the identified risk factors should not deter from performing an amputation, but may be taken into consideration by surgeons and patients for whom a major LLA might be impending, especially for the most elderly patients with pronounced cardiovascular disease.
Strengths and limitations
The main strength of this study is that by accessing and reviewing the medical records of patients in 12 hospitals, we were able to collect data in more detail pertaining to the patient characteristics for a substantial cohort of major LLA. Initially we aimed to categorize the indication for LLA, we were unable to do so objectively because of the heterogeneity in the clinical decision making. For example, a majority of patients had both DM and PAD, which made it a subjective matter to distinguish which of the two diseases ultimately was the cause of amputation. Unfortunately, in a majority of cases we could
41 not determine the pre-amputation nutritional and ambulatory status of patients with certainty and thus were unable to assess whether these were predictive of survival5,7,31. The relatively small sample
size may have led to limited power for the multivariate analyses. Post-hoc analyses of the minimum detectable effect sizes given the study sample size and assuming a 0.8 power were performed for several variables for which no association was observed in 1 year mortality rates. The minimum detectable OR were respectively: prior LLA OR 1.69 (observed OR 1.18); bilateral LLA OR 3.56 (observed OR 1.69) and DM OR 1.62 (observed OR 1.09). We suspect that analysis of reamputation risk factors has suffered the most from the sample size. Assuming that approximately 25% of all patients undergo reamputation within 1 year and that a certain characteristic (for example DM) is associated with OR 1.25 for reamputation: future research cohorts would likely detect this difference when the sample size is at least N=1250. The medical ethical permissions allowed us only to store the data relevant to the study population (i.e., dysvascular LLA), because of this we were unable to provide an overview of the excluded patients (i.e., LLA due to other causes).
Conclusion
In this multicenter retrospective cohort study the 30 days mortality after major LLA was 14% and the 1 year mortality was 34%. Forty-two percent of transfemoral amputees did not survive the first year, which was a higher rate than those with transtibial or knee disarticulation amputations. Patients aged >75 years at the time of major LLA had 3-4 times higher odds of death within 1 year. Also, history of heart failure, myocardial infarction, hemodialysis, immunosuppressive medication use and amputations performed in emergency setting (guillotine) were independently associated with higher 1 year mortality. Twenty-six percent of patients underwent ipsilateral reamputation within 1 year, for which no risk factors were identified.
Acknowledgements
The authors are very grateful to the vascular surgeons in the participating hospital for permission and cooperation in accessing the patient records for data collection. Northern Netherlands Epidemiology of Dysvascular Amputation (NEDA) Study Group: M. Van den Berg (Treant Hospitals, Emmen & Hoogeveen), J.C. Breek† (Martini Hospital, Groningen), J.J.A.M Van den Dungen (University Medical Center Groningen, Groningen), P. Klinkert (Tjongerschans Hospital, Heerenveen), L.A. Van Walraven (Antonius Hospital, Sneek), A.K. Jahrome (Medical Center Leeuwarden, Leeuwarden), M.J. Van der Laan (Ommelander Hospital Group, Scheemda), J.L. Van Wanroij (Isala Diaconessenhuis, Meppel) and B.P. Vierhout (Wilhelmina Hospital, Assen).
42
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44
Supplemental information: Appendices A-D
A ppen dix A. D et ai ls f or sear ch s tr at eg y, i n cl u si on /e xc lu si on an d de fin it io n of co m or bi di ty v ar iab le s. In clu sio n IC D -9 C o mo rb idi ty IC D -9 A m pu tat io n Ce re br ov asc u lar d is ease d D isar ti cu la ti on o f an kl e 8 4 .1 3 S u bar ach n oi da l h em or rh ag e 430 D isar ti cu la ti on o f an kl e th ro u gh m al le ol i of t ib ia an d fi bu la 8 4 .1 4 In tr acer eb ral h em or rh ag e 431 O th er am pu ta ti on b el ow k n ee 8 4 .1 5 Tr an sci en t cer eb ral i sch em ia 435 D isar ti cu la ti on o f kn ee 8 4 .1 6 O th er i nt racr an ia l he m or rh ag e 432 A m pu tat io n ab ov e kn ee 8 4 .1 7 O ccl u si on an d st en os is of p re ce re br al ar te ri es 433 D isar ti cu la ti on o f hi p 8 4 .1 8 O ccl u si on o f cer eb ra l ar te ri es 434 Lo we r lim b am pu tat io n , n ot sp ec if ie d 8 4 .1 0 R en al d isease d Per ip h er al ar te ri al d isease ( PA D ) A cu te g lo m er ul on ep h ri ti s 580 A th er oscl er os is of t he e xt re m it ie s, n ot s pe ci fi ed 4 4 0 .2 0 N ep h ro ti c sy n dr om e 581 A th er oscl er os is of t he e xt re m it ie s w it h c la u di cat io n 4 4 0 .2 1 Ch ro n ic g lo m er ul on ep h ri ti s 582 A th er oscl er os is of t he e xt re m it ie s w it h r est p ai n 4 4 0 .2 2 N ep h ri ti s an d n ep h ro pat h y, n ot sp ec ifi ed 583 A th er oscl er os is of t he e xt re m it ie s w it h u lcer at io n 4 4 0 .2 3 A cu te r en al f ai lu re 584 A th er oscl er os is of t he e xt re m it ie s w it h g an gr en e 4 4 0 .2 4 Ch ro n ic r en al f ai lu re 585 O th er p er ip h er al v asc ul ar d is ease 4 4 3 .x x R en al f ai lu re , un sp ec if ie d 586 D iab et es M el lit u s (D M ) 250 A u to im m un e di sease d D M t yp e I (o r ju ve ni le o n set ) a,b R eu m at oi d ar th ri ti s 714 D M t yp e II (o r ad ul t on se t) a,b Ps or ias is an d si m ilar d iso rd er s 696 In su lin t re at m en t (s h or t an d lo n g act in g) b In fl am m at or y bo we l di sease 5 5 5 .0 -9 A n ky lo si n g sp on dy lit is an d in fl am m at or y sp on dy lar th ro pat hi es 7 2 0 .0 -9 E x clu sio n S yst em ic l u pu s er yt h em at osu s 7 1 0 .0 -9 M al ig n an t n eo pl asm o f bo n e an d ar ti cu la r car ti lag e 1 7 0 .x x H em od ia ly si s a,b M al ig n an t n eo pl asm o f co n ne ct iv e an d ot h er so ft t iss u e 1 7 1 .x x Pu lm on ar y di se ase d M al ig n an t m el an om a of sk in 1 7 2 .x x Ch ro n ic o bst ru ct iv e pu lm on ar y di se ase 491 Tr au m at ic am pu ta ti on o f le g( s) 8 9 7 .x x A st h m a 493 Cr u sh in g in ju ry o f lo we r lim b 9 2 8 .x x E m ph ys em a 492 R ef le x sy m pat he ti c dy st ro ph y of t h e lo w er li m b 3 3 7 .2 2 A lco h ol ab u se 3 5 0 .0 -3 Ce rt ai n co n ge ni ta l m u scu lo sk el et al d ef or m it ie s 7 5 4 .x x Pu m on ar y di sease d O th er co n ge ni ta l m u scu lo sk el et al an om al ie s 7 5 6 .x x Ch ro n ic o bst ru ct iv e pu lm on ar y di se ase 491 A st h m a 493 Imm u n o su pr e ss iv e me dic a tio n c,d E m ph ys em a 492 Pr ed n iso n e Car di ac di seas e D M A R D s (i .e ., M et h ot re xat e, A zat hi op ri ne , S ul fasa laz in e) H yp er te n si ve d isease 402 B io lo gi ca l D M A R D s (i .e ., In fli xi m ab , A dal im u m ab , E tan er cept , R it u xi m ab ) M yo car di al in far ct io n 4 1 0 .x x Cal ci n eu ri n in hi bi to rs (i .e ., T acr ol im u s, Cl yc lo sp or in e) Co ro n ar y ar te ri al b y-pass g raf t a M yco ph en ol at e M ot ef il H ear t fa ilu re 4 2 8 .x x N ot e. F ir st , ex te n si ve s ear ch t er m s we re ap pl ie d in cl u di n g IC D -9 co de s, l ocal ly u sed op er at io n/ pr ocedu re co de s an d fr ee t ex t to i de n ti fy a ll am pu ta ti on s w it hi n t he ti m e fr am e 2 0 1 2 , Jan u ar y – 2 0 13 , D ec em be r. S eco n d, t h e ex cl u si on cr it er ia w er e ap pl ie d. T hi rd , sp or ad ic cas es c le ar ly n ot r el at ed t o PA D o r D M ( e. g. , fu lm in an t in fe ct io n in o th er w ise h ea lt h y ad ul ts ) we re ad di ti on al ly e xc lu de d. a N o ICD co de s, u si n g fr ee t ex t in p at ie n ts’ r eco rd s on ly . b A t th e ti m e of in de x am pu tat io n . c In t he p ast 1 y ear p ri or t o th e in de x am pu tat io n . d D ich ot om iz ed as ye s/ n o if an y of t he u n de rl yi n g di ag n oses we re p re sen t.
45
Appendix B. Additional patient characteristics and univariate analyses of 30 days and 1 year mortality.
Baseline 30 days 1 year
Alive Dead P a Alive Dead P a
Total 382 (100) 326 (85) 54 (14) 236 (62) 130 (34) Prior LLA(either limb) b
No minor/major LLA 212 (56) 176 35 0.05 126 75 0.26 Prior minor LLA 131 (34) 120 11 89 39
Prior major LLA 39 (10) 30 8 21 16 Prior LLA (ipsilateral limb) c
No prior minor/major LLA 235 (61) 196 37 0.40 137 84 0.29 Prior minor LLA 136 (36) 121 15 93 41
Prior major LLA 11 (3) 9 2 6 5
Level of amputation (most proximal) b
Transtibial 176 (46) 159 17 0.04 122 49 <0.01 Knee disarticulation 25 (7) 21 3 17 6
Transfemoral 179 (47) 144 34 95 75 Level of amputation (index) c
Transtibial 227 (59) 205 22 <0.01 148 72 0.07 Knee disarticulation 33 (9) 27 5 23 8
Transfemoral 119 (31) 91 27 63 49
Note. Values are number of patients (%) unless indicated otherwise. Ankle disarticulation (n=2) and hip
disarticulation (n=1) not included.
a χ2 tests for categorical variables between patients alive and dead at 30 days and 1 year after index amputation. b For comparison: already presented in Table II.
c Additional data in order to analyse the robustness of the results.
LLA, lower limb amputation.
Appendix C. Additional multivariate analysis of 1 year mortality, using index level of amputation.
β SE P OR (95% CI) Constant -2.42 0.49 <0.001 Age a <0.001 55-64 -0.05 0.51 0.929 0.95 (0.32-2.8) 65-74 -0.28 0.53 0.597 0.75 (0.26-2.15) 75-84 1.45 0.49 0.004 4.27 (1.61-11.35) >85 1.86 0.56 0.001 6.44 (2.15-19.28) Level of amputation (index) b
Knee disarticulation 0.28 0.58 0.635 1.32 (0.42-4.14) Transfemoral 0.76 0.28 0.007 2.13 (1.23-3.70) Guillotine amputation 1.56 0.68 0.022 4.78 (1.26-18.15) Heart failure 0.80 0.29 0.005 2.24 (1.27-3.94) Hemodialysis 1.86 0.50 <0.001 6.42 (2.42-17.03) Immunosuppressive medication 0.99 0.30 <0.001 2.71 (1.50-4.89)
Note. Additional analyses of 1 year mortality, using index level of amputation instead of most
proximal level as presented in Table II. Multiple backwards logistic regression; Nagelkerke R2 0.333. a Compared to 0-54 years category.
46
Appendix D. Additional analyses of reamputation within 1 year, using the total study population.
Baseline Ipsilateral reamputation <1 year No Yes P a Total 382 (100) 312 (82) 70 (18) Age, categories 0-54 42 (11) 29 13 0.02 55-64 66 (17) 50 16 65-74 96 (25) 76 20 75-84 122 (32) 107 15 <85 56 (15) 50 6 Gender (male) 247 (65) 203 44 0.73 Smoking status (ever) 289 (76) 233 56 0.35 Medical history
Peripheral arterial disease 336 (88) 273 63 0.56
DM 216 (56) 179 37 0.49
DM type I 26 (7) 19 7 0.49
DM type II, oral medication 74 (19) 62 12 DM type II, insulin use 116 (30) 98 18
Renal disease 128 (34) 103 25 0.66
Hemodialysis 28 (7) 21 7 0.34
Autoimmune disease 49 (13) 40 9 0.93 Immunosuppressive medication 90 (24) 74 16 0.88 Alcohol abuse 65 (17) 52 13 0.70 Prior LLA(ipsilateral)
No minor/major LLA 235 (61) 187 48 0.39 Reamputation from minor LLA 136 (36) 116 20
Reamputation from major LLA 11 (3) 9 2
Primary LLA b 100 (26) 85 15 0.31
Revascularisation (ipsilateral)
PTA 148 (39) 116 32 0.19
Bypass graft 134 (35) 103 32 0.04 Endarterectomy 100 (26) 78 22 0.27
Note. Additional univariate analyses of reamputation, in contrast to data presented in Table III,
patients who died before 1 year but did not undergo reamputation are not excluded from the denominators. Values are number of patients (%) unless indicated otherwise.
a χ2 tests categorical variables between patients undergoing ipsilateral reamputation within 1 year
after index amputation.
b Patients with no ever recorded vascular surgical procedure or minor/major LLA on the side of index
amputation.
