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Risk of major limb amputation in diabetic foot ulcer and accompanying disease: A meta-analysis
Accepted Manuscript Risk of Major Limb Amputation in diabetic foot ulcer and accompanying disease: A meta-analysis Jin Yong Shin, MD, Si-Gyun Roh, MD, Basel Sharaf, MD, D.D.S, Nae-Ho Lee, MD, PhD PII:
S1748-6815(17)30324-8
DOI:
10.1016/j.bjps.2017.07.015
Reference:
PRAS 5416
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received Date: 6 April 2017 Revised Date:
9 July 2017
Accepted Date: 26 July 2017
Please cite this article as: Shin JY, Roh S-G, Sharaf B, Lee N-H, Risk of Major Limb Amputation in diabetic foot ulcer and accompanying disease: A meta-analysis, British Journal of Plastic Surgery (2017), doi: 10.1016/j.bjps.2017.07.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Risk of Major Limb Amputation in diabetic foot ulcer and accompanying disease
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: A meta-analysis
Jin Yong Shin1,2, MD, Si-Gyun Roh1,2,3, MD, Basel Sharaf3, MD, D.D.S, Nae-Ho Lee1,2, MD, PhD
Department of Plastic and Reconstructive Surgery, Medical School of Chonbuk National
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1
University, Jeonju, Republic of Korea
Research Institute of Clinical Medicine-Biomedical Research Institute of Chonbuk National
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2
University Hospital, Jeonju, Republic of Korea
Division, of Plastic surgery, Department of Surgery, Mayo Clinic, Rochester, MN
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3
*
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Short running title: Risk of major amputation rates in diabetic patients
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Corresponding author: Si-Gyun Roh, MD, Department of Plastic and Reconstructive Surgery,
Chonbuk National University Hospital, 20, Geonji-ro, Deokjin-Gu, Jeonju-si, Chonbuk, 561712, Republic of Korea, Tel: +82 632501860; Fax: +82 632501866 E-mail address: [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Limb amputation in diabetic patients raises important issues regarding lower quality of life and survival rates. This meta-analysis is aimed to identify predictive factors
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accompanying diseases with high major amputation rates in diabetic patients. Methods: A systematic literature review and meta-analysis were performed using MEDLINE, EMBASE and Cochrane databases. Eight variables were extracted from the included studies
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utilized to assess the quality of the studies.
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and evaluated based on major amputation rates. The Newcastle-Ottawa scale (NOS) was
Results: The search strategy identified 101 publications. After screening, 10 articles were selected for review. Hypertension, ischemic heart disease, cerebrovascular disease and peripheral vascular disease were identified as predictive variables of higher major amputation
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rate.
Conclusions: Although further investigation of long-term and prospective studies is needed, we identified four variables as predisposing factors for higher major amputation in diabetic
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patients through meta-analysis.
Abbreviation DM IHD
Diabetes mellitus Ischemic heart disease
CVD
Cerebrovascular disease
PAD
Peripheral arterial disease
NOS
Newcastle–Ottawa scale
ACCEPTED MANUSCRIPT Introduction Diabetes Mellitus (DM) is a global epidemic with dramatically increasing prevalence.1 Diabetic foot ulcerations are multifactorial in nature and lead to various
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complications preceding amputation, which is associated with significant morbidity and mortality in this patient population.2 The 5-year survival rate in major lower extremity amputation (such as above the ankle amputation) is estimated at less than 50% in published 3,4
and comparable to survival rates in patients with serious health conditions,
Emphasis
on
diabetes
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as cancer and congestive heart failure.5,6 education,
such
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studies
improved
medical
management
and
multidisciplinary foot care continue to improve limb salvage and outcomes in this patient population. However, the socioeconomic burden, disability, and financial costs to the medical system are too heavy. A recent audit of 2.5 million inpatient diabetic foot ulcers treated in the
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United States between 2001 and 2010 reported a 16.5% incidence of amputation and an average treatment cost of $100,000.7 Many previous studies were performed for clarifying risk factor of amputation and the results showed that conditions such as peripheral neuropathy,
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12
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vascular disease, and poor glycemic control were associated with a high risk of amputation.8-
In our meta-analysis, we analyzed the relationship between the risk of major
amputation in patients with diabetic foot and accompanying diseases. Health care workers should recognize the need for a multidisciplinary and professional approach and this will provide an opportunity to understand the pathogenic mechanism of major amputation.
ACCEPTED MANUSCRIPT Methods Data Sources and Searches Searches were conducted in the PubMed, EMBASE, and Cochrane databases to
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identify all eligible articles published before January 2017, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.13 The purpose of these literature searches was to evaluate the relationship between the risk of amputation in patients
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with diabetic foot and accompanying disease. The search terms included “diabetic”,
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“diabetes”, “foot”, “lower leg or extremities”, “amputation”, and “risk or predisposing”. Only human studies were included and relevant articles were examined for references to additional eligible studies.
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Study Selection
The inclusion criteria were as follows: (1) full-length articles that provided sufficient data to enable the estimation of the major amputation rate; (2) articles that provided a brief
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description of patient information and medical records; (3) prospective or retrospective trials; and (4) articles that provided a brief explanation of outcome variables (definition of major
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amputation). Studies were excluded for the following reasons: (1) incomplete or interim data; (2) written in languages other than English; (3) no information on amputation in patients with diabetic foot; (4) case report, letter, or review article; and (5) the articles had the same authors and evaluated overlapping patients. Two of the authors (JYS and SGR) independently evaluated the eligibility of all studies identified by the literature search according to the predetermined selection criteria. The abstracts of all the studies were reviewed to exclude articles according to our exclusion
ACCEPTED MANUSCRIPT criteria. Full-text reviews were performed to determine whether the remaining studies satisfied the inclusion criteria. Disagreements between the two evaluators were resolved by a
Data Extraction and Quality Assessment
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third author (NHL).
Two of the authors (JYS and SGR) independently extracted the data from the
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included studies. The predictor variables (accompanying disease) were hypertension, ischemic heart disease (IHD), cerebrovascular disease (CVD), peripheral arterial disease
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(PAD), dyslipidemia, nephropathy, retinopathy, and neuropathy. Additionally, myocardial infarction, dialysis, and history of revascularization were also investigated; however, these could not be analyzed because of insufficient data. The outcome variable was major amputation rate. A major amputation was defined as an amputation above the ankle.
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The methodological quality of the studies was assessed using the Newcastle–Ottawa scale (NOS) for nonrandomized studies. NOS parameters comprise three categories, including selection of the study population, comparability of the groups, and ascertainment of
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the exposure or outcomes. Each parameter consists of subcategorized questions based on selection, comparability, and exposure or outcomes.14,15 If the methodology of a study was
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rated as having the highest quality, then the study was awarded a maximum of nine stars. Two authors independently evaluated the methodological quality of all the studies.
Data Synthesis and Analysis We used the Comprehensive Meta-Analysis software (version 3.3.070, Biostat Inc.) for this meta-analysis. We calculated the major amputation rate, and assessed the heterogeneity of each study using the I2 test, which measures the percentage of heterogeneity
ACCEPTED MANUSCRIPT across studies.16 I2 was calculated as follows: I2 (%) = 100 × (Q-df)/Q, where Q is Cochrane’s heterogeneity statistic and df is the degrees of freedom. I2 statistics with values of 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively. We then
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computed the 95% confidence interval of each treatment modality using random- and fixedeffects models. We confirmed the results using an I2 test, with significance set at a p-value
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less than 0.05. We provided forest plots to describe the study outcomes.
Identification of Relevant Studies
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Results
Figure 1 shows a flow diagram of how eligible studies were evaluated. The database searches identified 1485 publications that potentially met the study criteria. Duplicate records
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of 897 studies were excluded. Review of the titles and abstracts of the remaining 588 studies resulted in exclusion of an additional 487 studies. A total of 101 full text articles were further reviewed for eligibility by. An additional 92 studies were excluded due to incomplete data (n
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= 81), letter (n = 8), or case report (n = 2). The remaining 10 nonrandomized studies were
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included in the final analysis.10,17-25
Characteristics of Studies Included in the Final Analysis Among the 10 studies, we identified a total of 51,034 patients with diabetic feet. In the included studies, a total 654 patients underwent major amputation and were investigated. The clinical data and pooled analysis of the included studies are shown in Tables 1 and 2. (already mentioned earlier)In nonrandomized studies, the mean value awarded for quality was 7.8 (Table 3).
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Meta-analysis of Enrolled Studies: Major Amputation Rate in Diabetic Patients According to Various Accompanying Diseases
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We analyzed the relationship between the major amputation rate in diabetic patients and eight accompanying diseases. The significant variables related to a higher major amputation rate were hypertension, IHD, CVD, and PAD; however, dyslipidemia,
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nephropathy, retinopathy, and neuropathy showed no significant relationship. The overall effect of the major amputation rate was 2.078 (p = 0.038) for hypertension compared with no
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hypertension (Fig. 2), and the overall effect was estimated to be 1.971 (p = 0.049) for IHD compared with no IHD (Fig. 3). Additionally, statistically significant differences were identified for CVD and PAD (overall effect: 2.242, p = 0.025; overall effect: 2.004, p = 0.045, respectively; Figs 4 and 5). Dyslipidemia, nephropathy, retinopathy, and neuropathy showed
Discussion
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no statistically significant difference (Supplemental Figs 1, 2, 3, and 4).
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Our meta-analysis highlighted statistically significant associations of PAD, IHD,
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CVD and hypertension with higher major amputation risk in diabetic patients. PAD is known to be a definite risk factor for amputation in patients with diabetic foot and our meta-analysis regarding major amputation is consistent with this result. PAD is associated with with increased risk of foot infections.26 Lavery et al. propectively evaluated 1666 patients over a 2 year period and reported the amputation rate with ischemic infection to be 154 greater than that with non-ischemic infection.26 IHD and CVD were also found to be risk factors for major amputation. IHD is known to be a main cause of death in diabetic patients, and thus it must be an important accompanying disease that requires special care.4,27
ACCEPTED MANUSCRIPT The present study clarified that hypertension has significant association with higher major amputation rate in diabetic patients. Although there are some controversy defining hypertension as risk factor of amputation,28-30 the proper blood pressure control may be
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understood by effective treatment for slowing progression of nephropathy and retinopathy. Dyslipidemia has been proven to be a risk factor for cardiovascular disease and worse outcomes in diabetic patients.31,32 On the other hand, lower lipid levels maybe a
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manifestation of malnutrition and can be associated with long duration of diabetic ulcers. , our present study identified that dyslipidemia did not have a significant association with
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major amputation in diabetic patients.
Neuropathy has also been reported to be a risk factor of amputation in previous studies. On the other hand, other studies failed to show neuropathy as a significant factor in predicting limb loss.10,19,24 Our meta-analysis corroborated the lack of significant association
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between neuropathy and limb amputation. Possible explanations for this could be its high association with the duration of diabetes mellitus and dependence on other risk factors such as infection or ischemia.11
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Nephropathy is a marker of PAD33 and recent studies also demonstrated that diabetic foot ulcers are more frequent in patients with nephropathy.34 However, there was no
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significant association with major amputation in our present study. Similarly, retinopathy was not associated with major amputation rates, the microangiopathy is no longer predictive factor of higher major amputation in diabetic patients. Our meta-analysis has some limitations. First, because of the lack of prospective
studies on this subject, large-scale long-term follow-up studies are needed to verify the most definitive risk factors of major amputation in diabetic patients. Second, these results are based on univariate analyses, and we did not verify the complexity of each variable. In fact, because major amputation for diabetic foot is thought to occur in relation to various factors, a
ACCEPTED MANUSCRIPT more comprehensive analysis is thus needed. Despite these limitations, the current metaanalysis highlights the relationship between diabetes related comorbidities and major amputation rates. In addition to that, we have analyzed only major amputation excluding
associated with lower life quality and survival rate.
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minor amputation due to reduce heterogeneity. The major amputation has been known to be
In conclusion, after evaluating multiple accompanying diseases, we identified four
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comorbidities that were significantly related to a high rate of major amputation in diabetic patients. Based on our findings, we consider diabetic patients with PAD, IHD, CVD or
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hypertension should warrant attention because of their high possibility for major amputation. These factors may also be helpful for physicians to assess which patients need hospitalization and expedient treatment. Future large-scale prospective studies are necessary to validate our
Acknowledgments
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findings.
The authors of this manuscript thank the authors of the original cited studies for providing the
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Funding
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information.
No external funding was received.
Conflict of Interest
No potential conflicts of interest relevant to this article were reported.
Author contribution J.Y.S. and S.G.R. undertook the literature search and reviewed the abstracts and full articles.
ACCEPTED MANUSCRIPT J.Y.S. wrote the manuscript. N.H.L. and B.S. performed and supervised the review and statistical analysis. All authors designed the study and contributed to the discussion.
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No prior presentation has been performed.
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Prior presentation
ACCEPTED MANUSCRIPT References 1.
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Yusof NM, Rahman JA, Zulkifly AH, et al. Predictors of major lower limb amputation among type II diabetic patients admitted for diabetic foot problems. Singapore Med J. 2015;56:626-31.
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Sun JH, Tsai JS, Huang CH, et al. Risk factors for lower extremity amputation in diabetic foot disease categorized by Wagner classification. Diabetes Res Clin Pract. 2012;95:358-63. Gershater MA, Londahl M, Nyberg P, et al. Complexity of factors related to outcome
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amputations in diabetic foot infections. Diabet Foot Ankle. 2011;2. Miyajima S, Shirai A, Yamamoto S, Okada N, Matsushita T. Risk factors for major limb amputations in diabetic foot gangrene patients. Diabetes Res Clin Pract.
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Faglia E, Favales F, Morabito A. New ulceration, new major amputation, and survival
rates in diabetic subjects hospitalized for foot ulceration from 1990 to 1993: a 6.5year follow-up. Diabetes Care. 2001;24:78-83.
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Reiber GE, Pecoraro RE, Koepsell TD. Risk factors for amputation in patients with
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Pradeepa R, Anjana RM, Unnikrishnan R, Ganesan A, Mohan V, Rema M. Risk factors for microvascular complications of diabetes among South Indian subjects with
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patients with type 2 diabetes. J Diabetes Complications. 2014;28:124-29.
ACCEPTED MANUSCRIPT Figure Legends
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Fig. 1. Flow diagram for identification of relevant studies
Fig. 2. Forest plot of major amputation rate by hypertension. The diamond shape indicates the
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summary estimate of pooled studies. CI, confidence interval
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Fig. 3. Forest plot of major amputation rate by ischemic heart disease. The diamond shape indicates the summary estimate of pooled studies. CI, confidence interval
Fig. 4. Forest plot of major amputation rate by cerebrovascular disease. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
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Fig. 5. Forest plot of major amputation rate by peripheral arterial disease. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Figure Legends
ACCEPTED MANUSCRIPT Supplemental Fig. 1. Forest plot of major amputation rate by dyslipidemia. The diamond shape indicates the summary estimate of pooled studies. CI, confidence interval
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Supplemental Fig. 2. Forest plot of major amputation rate by nephropathy. The diamond
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shape indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Fig. 3. Forest plot of major amputation rate by retinopathy. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Fig. 4. Forest plot of major amputation rate by neuropathy. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
ACCEPTED MANUSCRIPT
Table 1. Clinical data from included studies Study design
Major
Mean age (years☆
Location
amputation No. / Total
No.
of
patients 5
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Studies
Retrospective
15 / 696
64.0
China
Bruun (2014☆6
Retrospective
32 / 1058
*
Denmark
Yusof (2015☆7
Retrospective
31 / 218
61.0
Malaysia
Retrospective
157 / 789
67.2
Taiwan
Prospective
55 / 202
*
Gershater (2009☆
Prospective
193 / 2480
68.0
Lai (2015☆11
Retrospective
86 / 45087
*
Retrospective
12 / 194
*
Retrospective
28 / 100
59.8
Singapore
Retrospective
45 / 210
64.2
Japan
Nather (2008☆10 9
12
Wang (2014☆ Aziz (2011☆13
14
Miyajima (2006☆
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*Data was not extractable, was unclear, or unavailable.
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Sun (2012☆
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Jiang (2015☆
Singapore Sweden
Taiwan
China
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Table 2. Major amputation rate in the included studies analyzed according to accompanying disease Studies Hypertension
IHD
CVD
PAD
Dyslipidemia
Nephropathy
Retinopathy
neuropathy
1.560 (0.573☆
1.689 (0.413☆
1.152 (0.839☆
0.928
*
2.574 (0.166☆
0.792 (0.704☆
0.734 (0.601☆
*
*
*
0.306 (0.034☆
0.700 (0.437☆
123.520
(0.886☆ 6
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Jiang (2015☆5
Accompanying diseases (Odds ratio, p value☆
1.312 (0.496☆
*
*
*
*
Yusof (2015☆7
0.765 (0.590☆
0.082 (0.015☆
0.177 (0.232☆
0.796
1.275 (0.475☆
(0.580☆ 1.506 (0.029☆
1.022 (0.936☆
1.480 (0.093☆
*
Nather (2008☆10
1.650 (0.119☆
2.351 (0.008☆
2.700 (0.043☆
9.281
(0.001☆
*
*
*
1.408 (0.140☆
1.650 (0.119☆
3.458 (0.000☆
0.977 (0.941☆
*
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Sun (2012☆8
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Bruun (2014☆
(0.000☆
Gershater (2009☆9 11
Lai (2015☆
1.059 (0.703☆
1.600 (0.002☆
1.283 (0.140☆
*
*
1.107 (0.536☆
1.072 (0.648☆
0.985 (0.956☆
1.095 (0.692☆
1.382 (0.156☆
3.390 (0.000☆
3.832
0.338 (0.000☆
1.344 (0.454☆
3.018 (0.017☆
2.406 (0.005☆
Wang (2014☆
*
*
*
*
*
*
2.439 (0.157☆
1.714 (0.392☆
Aziz (2011☆13
*
*
*
*
*
*
*
1.836 (0.374☆
Miyajima (2006☆14
*
5.765 (0.000☆
*
19.0944
*
4.418 (0.007☆
13.393
27.343
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(0.000☆
12
(0.004☆
(0.012☆
(0.021☆
1.265 (0.206☆
1.181 (0.238☆
2.078 (0.038☆
1.971 (0.049☆
2.242 (0.025☆
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Meta-analysis
*Data was not extractable, was unclear, or unavailable.
2.004 (0.045☆
-0.248 (0.804☆
1.411 (0.158☆
ACCEPTED MANUSCRIPT
Selection
Comparability
Exposure or outcome
Jiang (2015☆5
Total 8
6
Bruun (2014☆
9
Yusof (2015☆7
7
Sun (2012☆8
7 10
7
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Nather (2008☆
Gershater (2009☆9
9
11
Lai (2015☆
7
Wang (2014☆12
8
13
8
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Aziz (2011☆
Miyajima (2006☆14
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Studies
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Table 3. Methodological quality of included studies measured by the Newcastle–Ottawa scale
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S1748-6815(17)30324-8
DOI:
10.1016/j.bjps.2017.07.015
Reference:
PRAS 5416
To appear in:
Journal of Plastic, Reconstructive & Aesthetic Surgery
Received Date: 6 April 2017 Revised Date:
9 July 2017
Accepted Date: 26 July 2017
Please cite this article as: Shin JY, Roh S-G, Sharaf B, Lee N-H, Risk of Major Limb Amputation in diabetic foot ulcer and accompanying disease: A meta-analysis, British Journal of Plastic Surgery (2017), doi: 10.1016/j.bjps.2017.07.015. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. 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.
ACCEPTED MANUSCRIPT Risk of Major Limb Amputation in diabetic foot ulcer and accompanying disease
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: A meta-analysis
Jin Yong Shin1,2, MD, Si-Gyun Roh1,2,3, MD, Basel Sharaf3, MD, D.D.S, Nae-Ho Lee1,2, MD, PhD
Department of Plastic and Reconstructive Surgery, Medical School of Chonbuk National
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1
University, Jeonju, Republic of Korea
Research Institute of Clinical Medicine-Biomedical Research Institute of Chonbuk National
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2
University Hospital, Jeonju, Republic of Korea
Division, of Plastic surgery, Department of Surgery, Mayo Clinic, Rochester, MN
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Short running title: Risk of major amputation rates in diabetic patients
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Corresponding author: Si-Gyun Roh, MD, Department of Plastic and Reconstructive Surgery,
Chonbuk National University Hospital, 20, Geonji-ro, Deokjin-Gu, Jeonju-si, Chonbuk, 561712, Republic of Korea, Tel: +82 632501860; Fax: +82 632501866 E-mail address: [email protected]
ACCEPTED MANUSCRIPT Abstract Background: Limb amputation in diabetic patients raises important issues regarding lower quality of life and survival rates. This meta-analysis is aimed to identify predictive factors
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accompanying diseases with high major amputation rates in diabetic patients. Methods: A systematic literature review and meta-analysis were performed using MEDLINE, EMBASE and Cochrane databases. Eight variables were extracted from the included studies
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utilized to assess the quality of the studies.
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and evaluated based on major amputation rates. The Newcastle-Ottawa scale (NOS) was
Results: The search strategy identified 101 publications. After screening, 10 articles were selected for review. Hypertension, ischemic heart disease, cerebrovascular disease and peripheral vascular disease were identified as predictive variables of higher major amputation
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rate.
Conclusions: Although further investigation of long-term and prospective studies is needed, we identified four variables as predisposing factors for higher major amputation in diabetic
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patients through meta-analysis.
Abbreviation DM IHD
Diabetes mellitus Ischemic heart disease
CVD
Cerebrovascular disease
PAD
Peripheral arterial disease
NOS
Newcastle–Ottawa scale
ACCEPTED MANUSCRIPT Introduction Diabetes Mellitus (DM) is a global epidemic with dramatically increasing prevalence.1 Diabetic foot ulcerations are multifactorial in nature and lead to various
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complications preceding amputation, which is associated with significant morbidity and mortality in this patient population.2 The 5-year survival rate in major lower extremity amputation (such as above the ankle amputation) is estimated at less than 50% in published 3,4
and comparable to survival rates in patients with serious health conditions,
Emphasis
on
diabetes
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as cancer and congestive heart failure.5,6 education,
such
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studies
improved
medical
management
and
multidisciplinary foot care continue to improve limb salvage and outcomes in this patient population. However, the socioeconomic burden, disability, and financial costs to the medical system are too heavy. A recent audit of 2.5 million inpatient diabetic foot ulcers treated in the
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United States between 2001 and 2010 reported a 16.5% incidence of amputation and an average treatment cost of $100,000.7 Many previous studies were performed for clarifying risk factor of amputation and the results showed that conditions such as peripheral neuropathy,
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vascular disease, and poor glycemic control were associated with a high risk of amputation.8-
In our meta-analysis, we analyzed the relationship between the risk of major
amputation in patients with diabetic foot and accompanying diseases. Health care workers should recognize the need for a multidisciplinary and professional approach and this will provide an opportunity to understand the pathogenic mechanism of major amputation.
ACCEPTED MANUSCRIPT Methods Data Sources and Searches Searches were conducted in the PubMed, EMBASE, and Cochrane databases to
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identify all eligible articles published before January 2017, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist.13 The purpose of these literature searches was to evaluate the relationship between the risk of amputation in patients
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with diabetic foot and accompanying disease. The search terms included “diabetic”,
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“diabetes”, “foot”, “lower leg or extremities”, “amputation”, and “risk or predisposing”. Only human studies were included and relevant articles were examined for references to additional eligible studies.
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Study Selection
The inclusion criteria were as follows: (1) full-length articles that provided sufficient data to enable the estimation of the major amputation rate; (2) articles that provided a brief
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description of patient information and medical records; (3) prospective or retrospective trials; and (4) articles that provided a brief explanation of outcome variables (definition of major
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amputation). Studies were excluded for the following reasons: (1) incomplete or interim data; (2) written in languages other than English; (3) no information on amputation in patients with diabetic foot; (4) case report, letter, or review article; and (5) the articles had the same authors and evaluated overlapping patients. Two of the authors (JYS and SGR) independently evaluated the eligibility of all studies identified by the literature search according to the predetermined selection criteria. The abstracts of all the studies were reviewed to exclude articles according to our exclusion
ACCEPTED MANUSCRIPT criteria. Full-text reviews were performed to determine whether the remaining studies satisfied the inclusion criteria. Disagreements between the two evaluators were resolved by a
Data Extraction and Quality Assessment
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third author (NHL).
Two of the authors (JYS and SGR) independently extracted the data from the
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included studies. The predictor variables (accompanying disease) were hypertension, ischemic heart disease (IHD), cerebrovascular disease (CVD), peripheral arterial disease
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(PAD), dyslipidemia, nephropathy, retinopathy, and neuropathy. Additionally, myocardial infarction, dialysis, and history of revascularization were also investigated; however, these could not be analyzed because of insufficient data. The outcome variable was major amputation rate. A major amputation was defined as an amputation above the ankle.
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The methodological quality of the studies was assessed using the Newcastle–Ottawa scale (NOS) for nonrandomized studies. NOS parameters comprise three categories, including selection of the study population, comparability of the groups, and ascertainment of
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the exposure or outcomes. Each parameter consists of subcategorized questions based on selection, comparability, and exposure or outcomes.14,15 If the methodology of a study was
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rated as having the highest quality, then the study was awarded a maximum of nine stars. Two authors independently evaluated the methodological quality of all the studies.
Data Synthesis and Analysis We used the Comprehensive Meta-Analysis software (version 3.3.070, Biostat Inc.) for this meta-analysis. We calculated the major amputation rate, and assessed the heterogeneity of each study using the I2 test, which measures the percentage of heterogeneity
ACCEPTED MANUSCRIPT across studies.16 I2 was calculated as follows: I2 (%) = 100 × (Q-df)/Q, where Q is Cochrane’s heterogeneity statistic and df is the degrees of freedom. I2 statistics with values of 25%, 50%, and 75% correspond to low, moderate, and high heterogeneity, respectively. We then
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computed the 95% confidence interval of each treatment modality using random- and fixedeffects models. We confirmed the results using an I2 test, with significance set at a p-value
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less than 0.05. We provided forest plots to describe the study outcomes.
Identification of Relevant Studies
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Results
Figure 1 shows a flow diagram of how eligible studies were evaluated. The database searches identified 1485 publications that potentially met the study criteria. Duplicate records
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of 897 studies were excluded. Review of the titles and abstracts of the remaining 588 studies resulted in exclusion of an additional 487 studies. A total of 101 full text articles were further reviewed for eligibility by. An additional 92 studies were excluded due to incomplete data (n
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= 81), letter (n = 8), or case report (n = 2). The remaining 10 nonrandomized studies were
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included in the final analysis.10,17-25
Characteristics of Studies Included in the Final Analysis Among the 10 studies, we identified a total of 51,034 patients with diabetic feet. In the included studies, a total 654 patients underwent major amputation and were investigated. The clinical data and pooled analysis of the included studies are shown in Tables 1 and 2. (already mentioned earlier)In nonrandomized studies, the mean value awarded for quality was 7.8 (Table 3).
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Meta-analysis of Enrolled Studies: Major Amputation Rate in Diabetic Patients According to Various Accompanying Diseases
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We analyzed the relationship between the major amputation rate in diabetic patients and eight accompanying diseases. The significant variables related to a higher major amputation rate were hypertension, IHD, CVD, and PAD; however, dyslipidemia,
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nephropathy, retinopathy, and neuropathy showed no significant relationship. The overall effect of the major amputation rate was 2.078 (p = 0.038) for hypertension compared with no
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hypertension (Fig. 2), and the overall effect was estimated to be 1.971 (p = 0.049) for IHD compared with no IHD (Fig. 3). Additionally, statistically significant differences were identified for CVD and PAD (overall effect: 2.242, p = 0.025; overall effect: 2.004, p = 0.045, respectively; Figs 4 and 5). Dyslipidemia, nephropathy, retinopathy, and neuropathy showed
Discussion
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no statistically significant difference (Supplemental Figs 1, 2, 3, and 4).
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Our meta-analysis highlighted statistically significant associations of PAD, IHD,
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CVD and hypertension with higher major amputation risk in diabetic patients. PAD is known to be a definite risk factor for amputation in patients with diabetic foot and our meta-analysis regarding major amputation is consistent with this result. PAD is associated with with increased risk of foot infections.26 Lavery et al. propectively evaluated 1666 patients over a 2 year period and reported the amputation rate with ischemic infection to be 154 greater than that with non-ischemic infection.26 IHD and CVD were also found to be risk factors for major amputation. IHD is known to be a main cause of death in diabetic patients, and thus it must be an important accompanying disease that requires special care.4,27
ACCEPTED MANUSCRIPT The present study clarified that hypertension has significant association with higher major amputation rate in diabetic patients. Although there are some controversy defining hypertension as risk factor of amputation,28-30 the proper blood pressure control may be
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understood by effective treatment for slowing progression of nephropathy and retinopathy. Dyslipidemia has been proven to be a risk factor for cardiovascular disease and worse outcomes in diabetic patients.31,32 On the other hand, lower lipid levels maybe a
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manifestation of malnutrition and can be associated with long duration of diabetic ulcers. , our present study identified that dyslipidemia did not have a significant association with
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major amputation in diabetic patients.
Neuropathy has also been reported to be a risk factor of amputation in previous studies. On the other hand, other studies failed to show neuropathy as a significant factor in predicting limb loss.10,19,24 Our meta-analysis corroborated the lack of significant association
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between neuropathy and limb amputation. Possible explanations for this could be its high association with the duration of diabetes mellitus and dependence on other risk factors such as infection or ischemia.11
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Nephropathy is a marker of PAD33 and recent studies also demonstrated that diabetic foot ulcers are more frequent in patients with nephropathy.34 However, there was no
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significant association with major amputation in our present study. Similarly, retinopathy was not associated with major amputation rates, the microangiopathy is no longer predictive factor of higher major amputation in diabetic patients. Our meta-analysis has some limitations. First, because of the lack of prospective
studies on this subject, large-scale long-term follow-up studies are needed to verify the most definitive risk factors of major amputation in diabetic patients. Second, these results are based on univariate analyses, and we did not verify the complexity of each variable. In fact, because major amputation for diabetic foot is thought to occur in relation to various factors, a
ACCEPTED MANUSCRIPT more comprehensive analysis is thus needed. Despite these limitations, the current metaanalysis highlights the relationship between diabetes related comorbidities and major amputation rates. In addition to that, we have analyzed only major amputation excluding
associated with lower life quality and survival rate.
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minor amputation due to reduce heterogeneity. The major amputation has been known to be
In conclusion, after evaluating multiple accompanying diseases, we identified four
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comorbidities that were significantly related to a high rate of major amputation in diabetic patients. Based on our findings, we consider diabetic patients with PAD, IHD, CVD or
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hypertension should warrant attention because of their high possibility for major amputation. These factors may also be helpful for physicians to assess which patients need hospitalization and expedient treatment. Future large-scale prospective studies are necessary to validate our
Acknowledgments
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findings.
The authors of this manuscript thank the authors of the original cited studies for providing the
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Funding
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information.
No external funding was received.
Conflict of Interest
No potential conflicts of interest relevant to this article were reported.
Author contribution J.Y.S. and S.G.R. undertook the literature search and reviewed the abstracts and full articles.
ACCEPTED MANUSCRIPT J.Y.S. wrote the manuscript. N.H.L. and B.S. performed and supervised the review and statistical analysis. All authors designed the study and contributed to the discussion.
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No prior presentation has been performed.
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Prior presentation
ACCEPTED MANUSCRIPT References 1.
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Yusof NM, Rahman JA, Zulkifly AH, et al. Predictors of major lower limb amputation among type II diabetic patients admitted for diabetic foot problems. Singapore Med J. 2015;56:626-31.
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Sun JH, Tsai JS, Huang CH, et al. Risk factors for lower extremity amputation in diabetic foot disease categorized by Wagner classification. Diabetes Res Clin Pract. 2012;95:358-63. Gershater MA, Londahl M, Nyberg P, et al. Complexity of factors related to outcome
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ACCEPTED MANUSCRIPT Figure Legends
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Fig. 1. Flow diagram for identification of relevant studies
Fig. 2. Forest plot of major amputation rate by hypertension. The diamond shape indicates the
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summary estimate of pooled studies. CI, confidence interval
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Fig. 3. Forest plot of major amputation rate by ischemic heart disease. The diamond shape indicates the summary estimate of pooled studies. CI, confidence interval
Fig. 4. Forest plot of major amputation rate by cerebrovascular disease. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
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Fig. 5. Forest plot of major amputation rate by peripheral arterial disease. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Figure Legends
ACCEPTED MANUSCRIPT Supplemental Fig. 1. Forest plot of major amputation rate by dyslipidemia. The diamond shape indicates the summary estimate of pooled studies. CI, confidence interval
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Supplemental Fig. 2. Forest plot of major amputation rate by nephropathy. The diamond
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shape indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Fig. 3. Forest plot of major amputation rate by retinopathy. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
Supplemental Fig. 4. Forest plot of major amputation rate by neuropathy. The diamond shape
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indicates the summary estimate of pooled studies. CI, confidence interval
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Table 1. Clinical data from included studies Study design
Major
Mean age (years☆
Location
amputation No. / Total
No.
of
patients 5
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Studies
Retrospective
15 / 696
64.0
China
Bruun (2014☆6
Retrospective
32 / 1058
*
Denmark
Yusof (2015☆7
Retrospective
31 / 218
61.0
Malaysia
Retrospective
157 / 789
67.2
Taiwan
Prospective
55 / 202
*
Gershater (2009☆
Prospective
193 / 2480
68.0
Lai (2015☆11
Retrospective
86 / 45087
*
Retrospective
12 / 194
*
Retrospective
28 / 100
59.8
Singapore
Retrospective
45 / 210
64.2
Japan
Nather (2008☆10 9
12
Wang (2014☆ Aziz (2011☆13
14
Miyajima (2006☆
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*Data was not extractable, was unclear, or unavailable.
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Sun (2012☆
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Jiang (2015☆
Singapore Sweden
Taiwan
China
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Table 2. Major amputation rate in the included studies analyzed according to accompanying disease Studies Hypertension
IHD
CVD
PAD
Dyslipidemia
Nephropathy
Retinopathy
neuropathy
1.560 (0.573☆
1.689 (0.413☆
1.152 (0.839☆
0.928
*
2.574 (0.166☆
0.792 (0.704☆
0.734 (0.601☆
*
*
*
0.306 (0.034☆
0.700 (0.437☆
123.520
(0.886☆ 6
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Jiang (2015☆5
Accompanying diseases (Odds ratio, p value☆
1.312 (0.496☆
*
*
*
*
Yusof (2015☆7
0.765 (0.590☆
0.082 (0.015☆
0.177 (0.232☆
0.796
1.275 (0.475☆
(0.580☆ 1.506 (0.029☆
1.022 (0.936☆
1.480 (0.093☆
*
Nather (2008☆10
1.650 (0.119☆
2.351 (0.008☆
2.700 (0.043☆
9.281
(0.001☆
*
*
*
1.408 (0.140☆
1.650 (0.119☆
3.458 (0.000☆
0.977 (0.941☆
*
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Sun (2012☆8
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Bruun (2014☆
(0.000☆
Gershater (2009☆9 11
Lai (2015☆
1.059 (0.703☆
1.600 (0.002☆
1.283 (0.140☆
*
*
1.107 (0.536☆
1.072 (0.648☆
0.985 (0.956☆
1.095 (0.692☆
1.382 (0.156☆
3.390 (0.000☆
3.832
0.338 (0.000☆
1.344 (0.454☆
3.018 (0.017☆
2.406 (0.005☆
Wang (2014☆
*
*
*
*
*
*
2.439 (0.157☆
1.714 (0.392☆
Aziz (2011☆13
*
*
*
*
*
*
*
1.836 (0.374☆
Miyajima (2006☆14
*
5.765 (0.000☆
*
19.0944
*
4.418 (0.007☆
13.393
27.343
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(0.000☆
12
(0.004☆
(0.012☆
(0.021☆
1.265 (0.206☆
1.181 (0.238☆
2.078 (0.038☆
1.971 (0.049☆
2.242 (0.025☆
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*Data was not extractable, was unclear, or unavailable.
2.004 (0.045☆
-0.248 (0.804☆
1.411 (0.158☆
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Selection
Comparability
Exposure or outcome
Jiang (2015☆5
Total 8
6
Bruun (2014☆
9
Yusof (2015☆7
7
Sun (2012☆8
7 10
7
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Nather (2008☆
Gershater (2009☆9
9
11
Lai (2015☆
7
Wang (2014☆12
8
13
8
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Aziz (2011☆
Miyajima (2006☆14
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Table 3. Methodological quality of included studies measured by the Newcastle–Ottawa scale
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