Risk of peripheral artery occlusive disease in patients with lower leg fracture who received fixation and non-fixation treatments: A population cohort study.

BACKGROUND: The risk of peripheral artery occlusive disease (PAOD) in patients with lower leg fracture who underwent fixation procedures is not yet completely understood. Therefore, the current study aimed to examine the risk of subsequent PAOD in patients with lower leg fracture who received fixation and non-fixation treatments.
METHODS: We included 6538 patients with lower leg fracture who received non-fixation treatment and a matched cohort comprising 26152 patients who received fixation treatment from the National Health Insurance Database. Patients were frequency matched according to age, sex, and index year. The incidence and risk of PAOD in patients with lower leg fracture who received fixation and non-fixation treatments were evaluated via the stratification of different characteristics and comorbidities.
RESULTS: Non-fixation treatment, male sex, older age (≥ 50 years old), diabetes mellitus, and gout were associated with a significantly higher risk of lower extremity PAOD compare to each comparison group, respectively. Moreover, there was a significant correlation between fixation treatment and a lower risk of lower extremity PAOD in women (adjusted hazard ratio [aHR] = 0.58, 95% confidence interval [CI] = 0.38-0.90), women aged > 50 years (aHR = 0.61, 95% CI = 0.38-0.96), and patients with coronary artery disease (aHR = 0.43, 95% CI = (0.23-0.81). Further, patients with fixation treatment had a significantly lower risk of lower extremity PAOD within 2 years after trauma (aHR = 0.57, 95% CI = 0.34-0.97). The Kaplan-Meier analysis showed that the cumulative incidence of PAOD was significantly higher in the non-fixation treatment group than in the fixation treatment group at the end of the 10-year follow-up period (log-rank test: P = 0.022).
CONCLUSION: Patients with lower leg fracture who received non-fixation treatment had a significantly higher risk of PAOD than those who received fixation treatment. Moreover, the risk of PAOD was higher in women aged > 50 years, as well as in coronary artery disease patients who received non-fixation treatment than in those who received fixation treatment. Therefore, regular assessment of vessel patency are recommended for these patients. Nevertheless, further studies must be conducted to validate the results of our study.

Introduction

The prevalence of peripheral artery occlusive disease (PAOD) is about 10% in the population aged > 60 years. The risk factors may include smoking, physical inactivity, overweight, hypertension, hyperlipidemia, and hyperglycemia [1]. The signs and symptoms are intermittent claudication, ischemic pain at rest, skin ulcer, and gangrene [2]. In addition to open or endovascular revascularization, the current treatments include antiplatelet or anticoagulant therapy [3].

Lower leg fracture is managed with fixation and non-fixation procedures. In patients with stable tibial fractures and well-aligned tibial component, fracture can be successfully treated with closed reduction and cast immobilization as well as cautious maintenance of alignment during follow-up [4]. In patients with comminuted tibial fracture who present with component instability or misalignment, open reduction with internal or external fixation is commonly indicated to restore alignment. Moreover, it may be associated with a shorter hospital stay, faster pain relief, and lower risk of complications [5].

A previous study showed that 1.04% of patients with lower extremity blunt fracture present with acute artery injury [6]. Further, patients with open tibial fracture commonly develop chronic PAOD [7]. Hence, emerging evidence has shown that PAOD is associated with lower leg fracture [6, 7]. Although the mechanism underlying PAOD is not fully elucidated, it might be caused by mechanical or biochemical factors [8]. Some case studies have revealed that patients with comminuted fracture have a greater risk of PAOD, which might be attributed to a high energy impact and vessel damage [8, 9].

Therefore, the current study aimed to examine the risk of subsequent PAOD in patients with lower leg fracture who received fixation and non-fixation treatments.

Materials and methods

Data source

Taiwan established the National Health Insurance Program, which enrolled nearly 99% of residents. Since 1995, comprehensive health claimed data have been stored in the National Health Insurance Research Database (NHIRD). This database contains information about prescription, treatment, medical costs, and other medical services for both inpatients and outpatients. The current research used data from the population-based hospitalization database. To protect the privacy of each participant, the identification numbers were already encrypted before data were released by the government. The diagnoses in the Taiwan NHI are defined according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM). This study was approved by the research ethics committee of China Medical University and Hospital in Taiwan [CMUH-104-REC2-115-CR6].

Definition of fixation treatment

Fixation treatment was defined as internal or external fixation and non-fixation treatment as short leg casting.

Study population

To validate the association between fixation treatment and the risk of arterial embolism and thrombosis in the lower extremity (lower extremity PAOD) in patients with tibial and fibula fracture, we identified patients with newly diagnosed tibial and fibula fracture (ICD-9-CM: 823) from 2000 to 2012 who received internal or external fixation treatment (ICD-9-OP: 78.17, 78.57, 79.16, and 79.36). These patients were then assigned to the fixation treatment group, and those who did not receive internal or external fixation treatment to the non-fixation treatment group (ICD-9-OP: 79.06, and 79.26). The index date was set as the fixation date. Patients diagnosed with lower extremity PAOD (ICD-9-CM: 444.22) before the index date or those aged < 18 years (calculated until the index date) were excluded from the study.

Baseline comorbidity and outcome

Comorbidities were important confounding factors, and those observed before the index date included diabetes (ICD-9-CM: 250) [10], hypertension (ICD-9-CM: 401–405) [11], gout (ICD-9-CM: 274) [12], hyperlipidemia (ICD-9-CM: 272) [13], mental disorder (ICD-9-CM: 290, 294–298, 311) [14], stroke (ICD-9-CM: 430–438) [15], Parkinson disease (ICD-9-CM: 332) [16], coronary artery disease (ICD-9-CM: 410–414) [17], heart failure (ICD-9-CM: 428) [17], chronic obstructive pulmonary disease (COPD) (ICD-9-CM: 491, 492, 496) [18], liver disease (ICD-9-CM: 571, 572) [19], and end-stage renal disease (ESRD) (ICD-9-CM: 585) [20]

All participants were followed-up until the occurrence of lower extremity PAOD, death, and withdrawal from the NHIRD program or until December 31, 2013.

Statistical analysis

We performed propensity score matching. Then, to assess probabilities, which were used to assign four fixation-treated patients to each non-treated participant, the propensity score was calculated via a logistic regression analysis. The matched variables included sex, age, index year of fixation treatment, diabetes, hypertension, and gout.

The baseline demographic characteristics and comorbidities were identified. The difference between the two cohorts was assessed using standardized mean difference (SMD). Results showed a negligible difference, with a SMD of ≤ 0.1 [21]. The incidence of lower extremity PAOD was calculated as the number of newly occurred lower extremity PAOD divided by the following period (per 10,000 person-year). The Kaplan–Meier method was applied to calculate the cumulative incidence of lower extremity PAOD, and the difference between two survival curves were assessed using the log-rank test. Furthermore, the potential risk factors of lower extremity PAOD were assessed, and stratified analyses were conducted using the Cox proportional hazard model. Results were presented as hazard ratio, adjusted hazard ratio (aHR) (for demographic factors and comorbidities), and 95% confidence interval (95% CI). All statistical analyses were performed using the SAS statistical software version 9.4 (SAS Institute Inc., Cary, NC). The cumulative incidence curve was plotted using the R software. A two-sided p-value of < 0.05 was considered statistically significant.

Results

In total, 32690 participants with lower leg fracture, including 26152 with fixation treatment and 6538 with non-fixation treatment, were enrolled in this study.

In the fixation group, there were 10913 (41.7%) women and 15239 (58.3%) men. Moreover, 4736 (18.1%) patients were aged 20–29 years; 3732 (14.3%) patients were aged 30–39 years; 4644 (17.8%) patients were aged 40–49 years; 4747 (18.2%) patients were aged 50–59 years; 3944 (15.1%) patients were aged 60–69 years; 3230 (12.4%) patients were aged 70–79 years, and 1119 (4.3%) ≥ 80 years.

In the non-fixation group, there were 2770 (42.4%) women and 3768 (57.6%) men. Further, 1175 (18.0%) patients were aged 20–29 years; 948 (14.5%) patients were aged 30–39 years; 1196 (18.3%) patients were aged 40–49 years; 1157 (17.7%) patients were aged 50–59 years; 941 (14.4%) patients were aged 60–69 years; 744 (11.4%) patients were aged 70–79 years, and 377 (5.8%) ≥ 80 years.

There were no significant differences in terms of sex, age, and baseline comorbidities between the two groups (SMD of < 0.1) (Table 1).

Table 1

Demographic characteristics and comorbidities of patients newly diagnosed fracture of tibia and fibula in Taiwan during 2000–2012.

Characteristics	Total	Fracture of tibia and fibula		SMD
		With internal or external fixation N = 26152	Without internal or external fixation N = 6538
Gender				0.013
Female	13683	10913 (41.7)	2770 (42.4)
Male	19007	15239 (58.3)	3768 (57.6)
Age, mean (SD)		49.8 (18.3)	50.0 (18.6)	0.011
20–29	5911	4736 (18.1)	1175 (18)
30–39	4680	3732 (14.3)	948 (14.5)
40–49	5840	4644 (17.8)	1196 (18.3)
50–59	5904	4747 (18.2)	1157 (17.7)
60–69	4885	3944 (15.1)	941 (14.4)
70–79	3974	3230 (12.4)	744 (11.4)
>=80	1496	1119 (4.3)	377 (5.8)
Baseline comorbidity
Hypertension	3181	2471 (9.4)	710 (10.9)	0.047
Diabetes mellitus	2543	1999 (7.6)	544 (8.3)	0.025
Gout	547	412 (1.6)	135 (2.1)	0.037
Hyperlipidemia	948	721 (2.8)	227 (3.5)	0.041
Mental disorder	648	495 (1.9)	153 (2.3)	0.031
Stroke	1271	992 (3.8)	279 (4.3)	0.024
Parkinson disease	129	106 (0.4)	23 (0.4)	0.009
Coronary artery disease	1474	1141 (4.4)	333 (5.1)	0.034
Heart failure	546	425 (1.6)	121 (1.9)	0.017
COPD	846	663 (2.5)	183 (2.8)	0.016
Liver disease	1617	1243 (4.8)	374 (5.7)	0.043
ESRD	170	132 (0.5)	38 (0.6)	0.010

§A standardized mean difference of ≤0.1 indicates a negligible difference

Table 2 depicts the incidence and risk factors of lower extremity PAOD. After adjusting for age, sex, and all comorbidities, male sex (aHR = 1.49, 95% CI = 1.14–1.96), older age (≥50 years, aHR = 4.03, 95% CI = 2.73–5.95), diabetes mellitus (aHR = 4.06, 95% CI = (2.95–5.59), gout (aHR = 2.08, 95% CI = (1.25–3.46), coronary artery disease (aHR = 1.63, 95% CI = (1.10–2.40), and ESRD (aHR = 4.88, 95% CI = (2.39–10.00) were found to be associated with a significantly higher risk of lower extremity PAOD compare to each comparison group, respectively. The fixation treatment group (aHR = 0.71, 95% CI = (0.53–0.95) had a significantly lower risk of PAOD than the non-fixation treatment group.

Table 2

Cox model measured hazard ratio and 95% confidence intervals of arterial embolism and thrombosis of lower extremity associated with and without internal or external fixation among Fracture of tibia and fibula patients.

Characteristics	Event	Crude		Adjusted
	(n = 233)	HR (95% CI)	p value	HR (95% CI)	p value
Internal or external fixation
No	59	Ref.		Ref.
Yes	174	0.71 (0.53–0.95)	0.023	0.71 (0.53–0.95)	0.023
Gender
Female	97	Ref.		Ref.
Male	136	1.00 (0.77–1.30)	1.000	1.49 (1.14–1.96)	0.004
Age at baseline
<50	35	Ref.		Ref.
≥50	198	7.73 (5.08–10.43)	<0.001	4.03 (2.73–5.95)	<0.001
Baseline comorbidity
Hypertension	74	6.76 (5.11–8.94)	<0.001	1.13 (0.79–1.62)	0.500
Diabetes mellitus	85	10.68 (8.15–14.00)	<0.001	4.06 (2.95–5.59)	<0.001
Gout	19	8.22 (5.13–13.17)	<0.001	2.08 (1.25–3.46)	0.005
Hyperlipidemia	28	6.22 (4.19–9.25)	<0.001	1.28 (0.81–2.01)	0.294
Mental disorder	5	1.54 (0.63–3.73)	0.3419	0.66 (0.27–1.63)	0.369
Stroke	30	5.80 (3.94–8.53)	<0.001	1.09 (0.71–1.68)	0.685
Parkinson disease	2	3.88 (0.96–15.61)	0.057	0.99 (0.24–4.06)	0.985
Coronary artery disease	45	7.31 (5.28–10.14)	<0.001	1.63 (1.10–2.40)	0.014
Heart failure	16	7.89 (4.73–13.14)	<0.001	1.13 (0.64–2.00)	0.667
COPD	17	4.52 (2.76–7.42)	<0.001	0.83 (0.49–1.40)	0.489
Liver disease	33	4.33 (2.99–6.27)	<0.001	1.39 (0.94–2.07)	0.102
ESRD	9	16.61 (8.49–32.50)	<0.001	4.88 (2.39–10.00)	<0.001

*Abbreviation: HR, hazard ratio; CI, confidence interval.

*Adjusted HR: adjusted for gender, age, and comorbidities in Cox proportional hazards regression.

Table 3 shows the findings of the univariate and multivariate stratified analyses. Results showed a significant association between fixation treatment and a reduced risk of lower extremity PAOD among women (aHR = 0.58, 95% CI = (0.38–0.90) and women aged > 50 years (aHR = 0.61, 95% CI = (0.38–0.96), and patients with coronary artery disease (aHR = 0.43, 95% CI = (0.23–0.81).

Table 3

Incidence rates, hazard ratio and confidence intervals of arterial embolism and thrombosis of lower extremity in different stratification.

Variables	With internal or external fixation			Without internal or external fixation			Compared to without internal or external fixation
	n = 26152			n = 6538			Crude HR	p-value	Adjusted HR	p-value
	Event	Person years	IR	Event	Person years	IR	(95% CI)		(95% CI)
Gender
Female	67	86482	7.75	30	20945	14.32	0.54 (0.35–0.83)	0.005	0.58 (0.38–0.90)	0.014
<50	5	39246	1.27	3	9706	3.09	0.41 (0.10–1.71)	0.222	0.53 (0.11–2.50)	0.420
≥50	62	47237	13.13	27	11238	24.02	0.55 (0.35–0.86)	0.009	0.61 (0.38–0.96)	0.032
Male	107	120665	8.87	29	28983	10.01	0.88 (0.59–1.33)	0.556	0.83 (0.55–1.25)	0.825
Age at baseline
<50	23	113753	2.02	12	28292	4.24	0.48 (0.24–0.95)	0.037	0.53 (0.26–1.07)	0.078
≥50	151	93395	16.17	47	21636	21.72	0.74 (0.53–1.03)	0.071	0.74 (0.53–1.03)	0.073
Baseline comorbidity
Hypertension	55	13928	39.49	19	3643	52.16	0.74 (0.44–1.25)	0.267	0.69 (0.41–1.16)	0.161
Diabetes mellitus	62	11121	55.75	23	2929	78.54	0.71 (0.44–1.15)	0.163	0.70 (0.43–1.13)	0.146
Gout	13	2164	60.08	6	705	85.07	0.72 (0.27–1.90)	0.507	0.52 (0.18–1.52)	0.234
Hyperlipidemia	20	4321	46.28	8	1382	57.91	0.80 (0.35–1.83)	0.602	0.69 (0.30–1.58)	0.373
Mental disorder	3	2919	10.28	2	827	24.20	0.43 (0.07–2.60)	0.360	0.50 (0.05–4.89)	0.551
Stroke	23	5274	43.61	7	1403	49.89	0.88 (0.38–2.06)	0.772	0.81 (0.34–1.91)	0.622
Parkinson disease	1	493	20.28	1	104	96.07	0.22 (0.01–3.52)	0.284	-	-
Coronary artery disease	29	6619	43.81	16	1787	89.52	0.49 (0.26–0.90)	0.021	0.43 (0.23–0.81)	0.008
Heart failure	11	1996	55.12	5	449	111.31	0.49 (0.17–1.41)	0.186	0.39 (0.12–1.24)	0.109
COPD	14	3681	38.04	3	860	34.87	1.07 (0.31–3.75)	0.911	0.87 (0.24–3.20)	0.832
Liver disease	24	7471	32.13	9	2139	42.07	0.74 (0.34–1.60)	0.443	0.67 (0.31–1.46)	0.314
ESRD	6	518	115.83	3	129	232.35	0.52 (0.13–2.07)	0.352	0.43 (0.06–2.86)	0.380

*Abbreviation: IR, incidence rates, per 10,000 person-years; HR, hazard ratio; CI, confidence interval.

*Adjusted HR: adjusted for gender, age, and comorbidities in Cox proportional hazards regression.

After stratifying follow-up years into < 2, 2–5, and > 5 years, patients with fixation treatment had a significantly lower risk of lower extremity PAOD in the 2-year follow-up (aHR = 0.57, 95% CI = 0.34–0.97) (Table 4).

Table 4

Incidence rates, hazard ratio and confidence intervals of arterial embolism and thrombosis of lower extremity in different follow-up stratification.

Variables	With internal or external fixation			Without internal or external fixation			Compared to without internal or external fixation
	n = 26152			n = 6538			Crude HR	p-value	Adjusted HR	p-value
	Event	Person years	IR	Event	Person years	IR	(95% CI)		(95% CI)
Follow-up years
<2	45	50617	8.89	21	12442	16.88	0.53 (0.32–0.89)	0.016	0.57 (0.34–0.97)	0.036
2–5	36	66060	5.45	10	16065	6.22	0.88 (0.43–1.76)	0.709	0.86 (0.42–1.73)	0.663
>5	93	90470	10.28	28	21421	13.07	0.79 (0.52–1.20)	0.262	0.74 (0.48–1.13)	0.164

*Abbreviation: IR, incidence rates, per 10,000 person-years; HR, hazard ratio; CI, confidence interval.

*Adjusted HR: adjusted for gender, age, and comorbidities in Cox proportional hazards regression.

Fig 1 shows that the fixation treatment group had a significantly lower cumulative incidence of lower extremity PAOD than the non-fixation treatment group in the 10-year follow-up (log-rank test, P = 0.022).

Fig 1

Cumulative incidence curves of peripheral artery disease in patients with lower leg fracture who received fixation treatment and those who did not.

Discussion

Our study showed that female patients aged > 50 years who received fixation treatment had a significantly lower risk of PAOD than those who received non-fixation treatment. However, there was no significant difference among male patients (Table 3).

After stratification according to different follow-up periods, patients with fixation treatment had a significantly lower risk of lower extremity PAOD within 2 years after trauma than those with non-fixation treatment.

Previous studies have shown that patients with hip trauma are at risk of PAOD [22, 23]. To prevent misinterpretation, patients with hip fracture (ICD codes: 835, 9240, and 9280) were excluded from this research. Therefore, the term lower leg fracture refers to tibial, fibular, or tibiofibular fracture.

It is rational to conclude that patients with fixation treatment had a higher risk of PAOD than those without due to a more severe tissue damage. Nevertheless, our results showed that the non-fixation treatment group had a higher risk of PAOD than the fixation treatment group (Table 2). This could be explained by the fact that patients with lower leg fracture who did not undergo fixation surgery commonly had cast immobilization, which may increase the risk of PAOD. By contrast, some studies have revealed that prolonged lower leg immobilization after fracture was associated with venous thrombosis formation [24, 25]. However, whether this finding is true for artery compromise such as that in PAOD patients with lower leg fracture must be further investigated. Taken together, we believe that a high energy impact in lower leg comminuted fracture can not only damage bone alignment but also affect vessel patency [26, 27]. Hence, patients with this condition should receive fixation treatment [28]. Since only few studies have focused on the association between PAOD and immobilization after lower leg fracture, further investigations should be performed.

Women aged > 50 years who received non-fixation treatment had a higher risk of PAOD than those who received fixation treatment (Table 3). Moreover, they often present with menopause, which is associated with a higher risk of osteoporosis and fracture [29]. Therefore, osteoporosis can enhance the need for a longer immobilization after fracture in aging women with non-fixation treatment, thereby resulting in a higher risk for PAOD. Although osteoporosis may increase the risk of lower leg fracture, fixation may decrease the need for immobilization, which can reduce the incidence of PAOD in older female patients who underwent surgery (Table 3).

There was a significant association between fixation treatment and a reduced risk of lower extremity PAOD in patients with coronary artery disease (Table 3). It has been reported that there are close relations between coronary artery disease and PAOD [17, 30, 31]. Yet, due to limited patient number, further studies are required to identify whether coronary artery disease patients with lower leg fracture are proposed to receive fixation treatment.

Some studies have shown that chronic artery insufficiency presents as nonunion of fracture during the 2-year follow-up in patients with lower leg fracture [7, 32, 33]. In this study, compared with the fixation group, the non-fixation treatment group had a higher risk of PAOD within 2 years after trauma, and there were no differences in terms of risk after 2 years (Table 4). A time period of 2 years might be required to progressively establish collateral blood circulation after trauma. However, further studies must be performed to validate this result.

To the best of our knowledge, this is the first large-scale study with a long-term follow-up about the subsequent risk of PAOD in patients with lower leg fracture who received fixation and non-fixation treatments. In the current series, the cumulative incidence of PAOD was significantly higher in the non-fixation treatment group than in the fixation treatment group (Fig 1). In addition, women aged > 50 years, as well as coronary artery disease patients with lower leg fracture who received non-fixation treatment had a higher risk of PAOD than those who received fixation treatment (Table 3). Therefore, regular assessment of vessel patency via ultrasonography and treatment with prophylactic anticoagulation drugs are recommended for these patients.

Limitations

With reliable diagnoses and a high rate of follow-up, the assessment of PAOD risk in patients with lower leg fracture who received fixation and non-fixation treatments is strengthened by the inclusion of a large number of patients and as well as longitudinal assessments and subgroup analyses. However, the current research had several limitations. First, data about lifestyles factors, such as smoking, dietary habits, drinking, and socioeconomic status, and genetic factors were not obtained for the adjustment of PAOD risk. Moreover, a stratified analysis of patients with simple and compound (comminuted) lower leg fracture was not performed because of databank limitation. Second, PAOD was diagnosed based on admission diagnoses and codes. Thus, an extremely accurate analysis was not performed, and there was no accessible information regarding fracture severity/grade. Similarly, owing to database limitation, it would be very difficult to differentiate and analyze the fixation methods separately for internal and external fixation, as well as measure the proportion of minimally invasive plate osteosynthesis among the internal fixations population. Third, because all data were anonymized, relevant clinical variables, such as surgical findings, imaging results, and laboratory data, were not available. Fourth, biases could have existed due to the retrospective nature of the study. Nevertheless, data regarding lower leg fracture, surgery, and PAOD diagnosis were highly reliable.

Conclusion

Patients with lower leg fracture who received non-fixation treatment had a significantly higher risk of PAOD than those who received fixation treatment. Moreover, the risk of PAOD was higher in women aged > 50 years, as well as in coronary artery disease patients who received non-fixation treatment than in those who received fixation treatment. Nevertheless, further studies should be conducted to validate our results.

30 Mar 2022

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I think it is a very significant paper to improve the quality of trauma care for functional and long-term prognosis. Please correct the following two points.

Major revision

Soft tissue damage and fixation period are thought to influence vessel patency, but if this is the case, it would be better to analyze the fixation methods separately for internal and external fixation. Also, what was the proportion of minimally invasive plate osteosynthesis among the internal fixations? It would be good to at least mention that in the limitation.

Minor revision

In the preface to “Results”, the numerical notation is separated by every three digits, but not thereafter. Please unify either.

Reviewer #2: Comments to authors:

1.

In Table 1, the authors need to include more history of diseases or coexisting medical conditions, such as hyperlipidemia, mental disorders, stroke, Parkinson’s disease, ischemic heart disease, heart failure, COPD, liver cirrhosis, and renal dialysis. In addition, the use of medical care service also should be considered in this study.

2.

In Table 1, the age should be divided as 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, >=80.

3.

The immortal time bias is very important to this study and the authors need to consider this point in the study design and statistical analysis.

4.

The IRB number seems very old. The authors need to provide the real ethical approval from the Intuitional Review Board.

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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2 Jun 2022

Response to Reviewers’ comments

PONE-D-22-00911

Risk of Peripheral Artery Occlusive Disease in Patients with Lower Leg Fracture Who Received Fixation and Non-fixation Treatments: A Population Cohort Study

PLOS ONE

Dear Prof. Rudolf Kirchmair and reviewers of PLOS ONE,

Thank you very much for the Letter with the Reviewers’ comments about our manuscript. We greatly appreciate reviewers’ helpful suggestions and the opportunity to revise our manuscript. Efforts have been made to address each comment/concern.

Please find attached revision of the manuscript and see below for our response to the reviewers’ comments.

We look forward to your response.

Yours Sincerely,

Dr. Shih-Chi Wu

Trauma and Emergency Center

China Medical University Hospital

Taichung, Taiwan

Tel: 886-4-22052121 ext 2933

E-mail: rw114@mail.cmuh.org.tw

Response to Reviewers’ comments

Reviewer #1: I think it is a very significant paper to improve the quality of trauma care for functional and long-term prognosis. Please correct the following two points.

Major revision

Soft tissue damage and fixation period are thought to influence vessel patency, but if this is the case, it would be better to analyze the fixation methods separately for internal and external fixation.

Response: Thank you very much. We completely agree your comment and greatly appreciate this very crucial point. Yet, owing to database limitation, it would be very difficult to differentiate and analyze the fixation methods separately for internal and external fixation. Therefore, we have added related description in the section of “Limitation”

Also, what was the proportion of minimally invasive plate osteosynthesis among the internal fixations? It would be good to at least mention that in the limitation.

Response: Similar to the above comment. It would be very difficult to measure the proportion of minimally invasive plate osteosynthesis among the internal fixations population. Thank you very much for this point, we have added related description in the section of “Limitation”

Minor revision

In the preface to “Results”, the numerical notation is separated by every three digits, but not thereafter. Please unify either.

Response: Thank you very much, we have made correction.

Reviewer #2:

1. In Table 1, the authors need to include more history of diseases or coexisting medical conditions, such as hyperlipidemia, mental disorders, stroke, Parkinson’s disease, ischemic heart disease, heart failure, COPD, liver cirrhosis, and renal dialysis.

Response: Thank you very much for this point. We greatly appreciate this very crucial comment. We have performed a new analysis following your comment, and added references in the section of “Materials and Methods’. Please refer to the newly revised Table 1-4.

Additionally, we found that there was a significant association between fixation treatment and a reduced risk of lower extremity PAOD in patients with coronary artery disease (Table 3). Therefore, we have added description in the section of “Discussion”

Table 1. Demographic characteristics and comorbidities of patients newly diagnosed Fracture of tibia and fibula in Taiwan during 2000-2012

Characteristics Total Fracture of tibia and fibula SMD

With internal or external fixation

N=26152 Without internal or external fixation

N=6538

Gender 0.013

Female 13683 10913 (41.7) 2770 (42.4)

Male 19007 15239 (58.3) 3768 (57.6)

Age, mean (SD) 49.8 (18.3) 50.0 (18.6) 0.011

20-29 5911 4736 (18.1) 1175 (18)

30-39 4680 3732 (14.3) 948 (14.5)

40-49 5840 4644 (17.8) 1196 (18.3)

50-59 5904 4747 (18.2) 1157 (17.7)

60-69 4885 3944 (15.1) 941 (14.4)

70-79 3974 3230 (12.4) 744 (11.4)

>=80 1496 1119 (4.3) 377 (5.8)

Baseline comorbidity

Hypertension 3181 2471 (9.4) 710 (10.9) 0.047

Diabetes mellitus 2543 1999 (7.6) 544 (8.3) 0.025

Gout 547 412 (1.6) 135 (2.1) 0.037

Hyperlipidemia 948 721 (2.8) 227 (3.5) 0.041

Mental disorder 648 495 (1.9) 153 (2.3) 0.031

Stroke 1271 992 (3.8) 279 (4.3) 0.024

Parkinson disease 129 106 (0.4) 23 (0.4) 0.009

Coronary artery disease 1474 1141 (4.4) 333 (5.1) 0.034

Heart failure 546 425 (1.6) 121 (1.9) 0.017

COPD 846 663 (2.5) 183 (2.8) 0.016

Liver disease 1617 1243 (4.8) 374 (5.7) 0.043

ESRD 170 132 (0.5) 38 (0.6) 0.010

In addition, the use of medical care service also should be considered in this study.

Response: Many thanks for this point. The use of medical care service could be considered equal in Taiwan. Please refer to the following description.

“Taiwan has established the National Health Insurance Program. Inhabitants of Taiwan are obligated to join this health program, which enrolled nearly 99% of residents. Therefore, patients in Taiwan shared almost the same medical care service.

In addition, since 1995, comprehensive health claimed data have been stored in the National Health Insurance Research Database (NHIRD). The NHIRD covered more than 99% of the population in Taiwan. In addition, there were validation studies on this registry which showed that NHIRD is a large, powerful data source for biomedical research.”

References:

1. Hsing AW, Ioannidis JP. Nationwide Population Science: Lessons From the Taiwan National Health Insurance Research Database. JAMA Intern Med. 2015 Sep; 175(9):1527-9.

2. Lin LY, Warren-Gash C, Smeeth L, et al. Data resource profile: the National Health Insurance Research Database (NHIRD). Epidemiol Health. 2018;40:e2018062.

3. Hsieh CY, Su CC, Shao SC, et al. Taiwan's National Health Insurance Research Database: past and future. Clin Epidemiol. 2019; 11:349–358.

2. In Table 1, the age should be divided as 20-29, 30-39, 40-49, 50-59, 60-69, 70-79, >=80.

Response: Thanks a lot for this comment. We have performed a new analysis following your comment. Please refer to the newly revised Table 1.

Table 1. Demographic characteristics and comorbidities of patients newly diagnosed Fracture of tibia and fibula in Taiwan during 2000-2012

Characteristics Total Fracture of tibia and fibula SMD

With internal or external fixation

N=26152 Without internal or external fixation

N=6538

Gender 0.013

Female 13683 10913 (41.7) 2770 (42.4)

Male 19007 15239 (58.3) 3768 (57.6)

Age, mean (SD) 49.8 (18.3) 50.0 (18.6) 0.011

20-29 5911 4736 (18.1) 1175 (18)

30-39 4680 3732 (14.3) 948 (14.5)

40-49 5840 4644 (17.8) 1196 (18.3)

50-59 5904 4747 (18.2) 1157 (17.7)

60-69 4885 3944 (15.1) 941 (14.4)

70-79 3974 3230 (12.4) 744 (11.4)

>=80 1496 1119 (4.3) 377 (5.8)

Occupation 0.013

Office workers 15109 12092 (46.2) 3017 (46.1)

Manual workers 13833 11043 (42.2) 2790 (42.7)

Others 3748 3017 (11.5) 731 (11.2)

Baseline comorbidity

Hypertension 3181 2471 (9.4) 710 (10.9) 0.047

Diabetes mellitus 2543 1999 (7.6) 544 (8.3) 0.025

Gout 547 412 (1.6) 135 (2.1) 0.037

Hyperlipidemia 948 721 (2.8) 227 (3.5) 0.041

Mental disorder 648 495 (1.9) 153 (2.3) 0.031

Stroke 1271 992 (3.8) 279 (4.3) 0.024

Parkinson disease 129 106 (0.4) 23 (0.4) 0.009

Coronary artery disease 1474 1141 (4.4) 333 (5.1) 0.034

Heart failure 546 425 (1.6) 121 (1.9) 0.017

COPD 846 663 (2.5) 183 (2.8) 0.016

Liver disease 1617 1243 (4.8) 374 (5.7) 0.043

ESRD 170 132 (0.5) 38 (0.6) 0.010

3. The immortal time bias is very important to this study and the authors need to consider this point in the study design and statistical analysis.

Response: Many thanks for this important comment.

All the patient data in this study came from the population-based hospitalization database, whereas the diagnosis (tibia or fibular fracture) was coded immediately after admission, and the index date initiated in the treatment and non-treatment group. Due to the policy of Diagnosis Related Groups (DRG) in extremity fracture in our National Health Insurance (i.e. package fee for single case with extremity fracture), patients in the treatment group (internal or external fixation) received surgery soon after diagnosis. Therefore, the duration from established diagnosis to treatment was short (within very few days) while the immortal time bias could be neglected.

4. The IRB number seems very old. The authors need to provide the real ethical approval from the Intuitional Review Board.

Response: Thank you very much for this important point.

Please refer to the following IRB certificate.

Submitted filename: 1 st- Response to Reviewers PAOD plos one .docx

Click here for additional data file.

13 Jul 2022

Risk of Peripheral Artery Occlusive Disease in Patients with Lower Leg Fracture Who Received Fixation and Non-fixation Treatments: A Population Cohort Study

PONE-D-22-00911R1

Dear Dr. Wu ,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Rudolf Kirchmair

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: You have responded and replied appropriately to my review comment. I wish you luck in further developing your series study by collecting data on risk factors, severity of disease, and impact of treatment and other factors.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

26 Jul 2022

PONE-D-22-00911R1

Risk of Peripheral Artery Occlusive Disease in Patients with Lower Leg Fracture Who Received Fixation and Non-fixation Treatments: A Population Cohort Study

Dear Dr. Wu:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Prof Rudolf Kirchmair

Academic Editor

PLOS ONE