hip replacement ( hip - rep ) , also called total hip arthroplasty , is a common and efficacious surgical procedure . kurtz et al reported a significant increase in the primary total hip - rep rate in the united states from 47/100,000 in 1990 to 69/100,000 in 2002 ( an increase of 22/100,000 in 12 years ) . a taiwan - based cohort study revealed that the rate of primary total hip - reps and primary partial hip - reps increased from 37/100,000 in 1996 to 55/100,000 in 2004 ( an increase of 18/100,000 in 8 years ) . peripheral arterial disease ( pad ) is a manifestation of systemic atherosclerosis and is highly related to the risk of ischemic stroke ( is ) , myocardial infarction , and fatal vascular events . even without previous myocardial infarction or is , patients with pad exhibit an almost equal relative risk of death from cardiovascular causes as do patients with a history of coronary or cerebrovascular disease . regensteiner and hiatt reported that nearly 20% of adults older than 70 years have pad . claudication , atypical leg discomfort , and rest pain are common symptoms of pad ; however , most critically , as many as 50% of patients with pad are asymptomatic . the reported risk factors for developing pad include aging , diabetes mellitus ( dm ) , smoking , hypertension ( htn ) , and hyperlipidemia . in this article ,  pad denotes vascular diseases including atherosclerosis of the abdominal aorta , iliac , and extremity arteries ; extremity artery bypass graft ; arterial embolisms and thrombosis ; and unspecified disorders of the arteries and arterioles . several studies have reported that hip - rep is associated with an increased risk of pad ; however , no research has investigated this association in an asian context . thus , we conducted a nationwide retrospective cohort study to examine the risk of developing pad in patients who received a hip - rep , hypothesizing that the procedure might increase the risk of developing pad . this retrospective cohort study used data from the longitudinal health insurance database ( lhid ) . the lhid is a subset of the national health insurance research database ( nhird ) program , which was established by the taiwan bureau of nhi ( bnhi ) . the nhi program , inaugurated in 1995 , covers approximately 99% of the more than 23 million people in taiwan . by the end of 2010 , the bnhi had contracts with all hospitals and 92% of clinics nationwide . each person covered by the nhi receives a unique identification number . comprehensive information on insured patients , including demographic data , clinic visit dates , disease diagnoses , and prescription details , is included in the lhid . the diagnostic codes used were those in the international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) . this study was approved by the institutional review board of china medical university and hospital , taiwan ( cmu - rec-101012 ) . we identified 5284 patients who received a hip - rep ( icd-9-cm codes 815.1 and 815.2 ) but had no history of pad ( icd-9-cm codes 440.0 , 440.2 , 440.3 , 440.8 , 440.9 , 443 , 444.0 , 444.22 , 444.8 , 447.8 , and 447.9 ) from 2000 to 2011 . a control group was randomly selected from insured people with no hip - rep or history of pad and was matched with the hip - rep group at a ratio of approximately 4:1 according to sex , age , and year of hip - rep . the index dates of the control cohort were assigned according to days and months randomly , and the index years were the same year as those of the matched cases . in total , 5284 patients were included in the hip - rep group and 21,124 patients comprised the control group . demographic factors included sex and age ( in groups ages < 50 , 5064 , 6579 , and > 80 years ) . patients with htn ( icd-9-cm codes 401405 ) , hyperlipidemia ( icd-9-cm code 272 ) , dm ( icd-9-cm code 250 ) , ischemic stroke ( is , icd-9-cm codes 433438 ) , ischemic heart disease ( ihd , icd-9-cm codes 410414 ) , chronic obstructive pulmonary disease ( copd , icd-9-cm codes 490 , 491 , 495 , and 496 ) , or chronic kidney disease ( ckd , icd-9-cm code 585 ) diagnosed before the index date were considered to have a comorbidity . we identified a significant outcome of pad development ( icd-9-cm codes 440.0 , 440.2 , 440.3 , 440.8 , 440.9 , 443 , 444.0 , 444.22 , 444.8 , 447.8 , and 447.9 ) . patients were followed from the index date until either december 2011 , onset of pad , death , or withdrawal from the nhi . the distribution of sex , age , and comorbidities ( htn , hyperlipidemia , dm , is , ihd , copd , and ckd ) between the hip - rep and the control groups were compared . differences were examined using the chi - square tests for categorical variables and the student t test for continuous variables . follow - up time in person - years was calculated for each person from the index date until pad development . the incidence rate was calculated by dividing the number of pad diagnoses by the number of person - years . the cumulative incidence of pad was computed using the kaplan  meier method , and the difference in cumulative incidence between the groups was tested using a log - rank test . hazard ratios ( hrs ) and 95% confidence intervals ( cis ) were calculated using cox proportional hazards models to assess the association between hip - rep and pad , with sex , age , and comorbidities adjusted for . all analyses were performed using sas version 9.3 ( sas institute , cary , nc ) . this retrospective cohort study used data from the longitudinal health insurance database ( lhid ) . the lhid is a subset of the national health insurance research database ( nhird ) program , which was established by the taiwan bureau of nhi ( bnhi ) . the nhi program , inaugurated in 1995 , covers approximately 99% of the more than 23 million people in taiwan . by the end of 2010 , the bnhi had contracts with all hospitals and 92% of clinics nationwide . each person covered by the nhi receives a unique identification number . comprehensive information on insured patients , including demographic data , clinic visit dates , disease diagnoses , and prescription details , is included in the lhid . the diagnostic codes used were those in the international classification of diseases , ninth revision , clinical modification ( icd-9-cm ) . this study was approved by the institutional review board of china medical university and hospital , taiwan ( cmu - rec-101012 ) . we identified 5284 patients who received a hip - rep ( icd-9-cm codes 815.1 and 815.2 ) but had no history of pad ( icd-9-cm codes 440.0 , 440.2 , 440.3 , 440.8 , 440.9 , 443 , 444.0 , 444.22 , 444.8 , 447.8 , and 447.9 ) from 2000 to 2011 . a control group was randomly selected from insured people with no hip - rep or history of pad and was matched with the hip - rep group at a ratio of approximately 4:1 according to sex , age , and year of hip - rep . the index dates of the control cohort were assigned according to days and months randomly , and the index years were the same year as those of the matched cases . in total , 5284 patients were included in the hip - rep group and 21,124 patients comprised the control group . demographic factors included sex and age ( in groups ages < 50 , 5064 , 6579 , and > 80 years ) . patients with htn ( icd-9-cm codes 401405 ) , hyperlipidemia ( icd-9-cm code 272 ) , dm ( icd-9-cm code 250 ) , ischemic stroke ( is , icd-9-cm codes 433438 ) , ischemic heart disease ( ihd , icd-9-cm codes 410414 ) , chronic obstructive pulmonary disease ( copd , icd-9-cm codes 490 , 491 , 495 , and 496 ) , or chronic kidney disease ( ckd , icd-9-cm code 585 ) diagnosed before the index date were considered to have a comorbidity . we identified a significant outcome of pad development ( icd-9-cm codes 440.0 , 440.2 , 440.3 , 440.8 , 440.9 , 443 , 444.0 , 444.22 , 444.8 , 447.8 , and 447.9 ) . patients were followed from the index date until either december 2011 , onset of pad , death , or withdrawal from the nhi . the distribution of sex , age , and comorbidities ( htn , hyperlipidemia , dm , is , ihd , copd , and ckd ) between the hip - rep and the control groups were compared . differences were examined using the chi - square tests for categorical variables and the student t test for continuous variables . follow - up time in person - years was calculated for each person from the index date until pad development . the incidence rate was calculated by dividing the number of pad diagnoses by the number of person - years . the cumulative incidence of pad was computed using the kaplan  meier method , and the difference in cumulative incidence between the groups was tested using a log - rank test . hazard ratios ( hrs ) and 95% confidence intervals ( cis ) were calculated using cox proportional hazards models to assess the association between hip - rep and pad , with sex , age , and comorbidities adjusted for . all analyses were performed using sas version 9.3 ( sas institute , cary , nc ) . a total of 5284 patients who had received a hip - rep between 2000 and 2011 was frequency - matched according to sex , age , and year of hip - rep with 21,124 patients who had not received a hip - rep . the hip - rep group had a mean age of 67.2 years ( standard deviation [ sd ]  =  16.2 years ) and a slight female predominance ( 52.5% ) . compared with the control group , the hip - rep group exhibited a significantly higher prevalence of htn ( 58.5% vs 51.1% ) , dm ( 22.1% vs 17.4% ) , is ( 27.7% vs 19.9% ) , ihd ( 30.0% vs 26.9% ) , copd ( 32.6% vs 28.1% ) , and ckd ( 5.2% vs 2.6% ) ( table 1 ) . demographics between hip - rep and comparison group the results of kaplan  meier analysis revealed that the hip - rep group had a higher cumulative incidence rate of pad than did the control group ( log - rank test , p  =  0.001 ) ( figure 1 ) . during the follow - up period , the incidence rates of pad for the hip - rep and control groups were 7.79 and 5.79 per 1000 person - years , respectively . after adjustments for sex , age , and comorbidities , patients who received a hip - rep exhibited an increased risk of pad compared with those in the control group ( adjusted hr  =  1.24 , 95% ci  =  1.051.48 ) ( table 2 ) . compared with patients ages 50 years and younger , the adjusted hr of pad was 3.46-fold higher among those ages 5064 years , 4.61-fold higher among those ages 6579 years , and 4.87-fold higher among those ages 80 years and older . multivariate cox proportional hazards analysis revealed that pad was independently associated with htn ( adjusted hr  =  1.35 , 95% ci  =  1.121.63 ) , dm ( adjusted hr  =  1.58 , 95% ci  =  1.341.86 ) , ihd ( adjusted hr  =  1.70 , 95% ci  =  1.441.99 ) , and ckd ( adjusted hr  =  1.75 , 95% ci  =  1.292.37 ) . cumulative incidence of peripheral arterial disease in hip replacement and control cohorts . hazard ratio and 95% confidence intervals for pad and pad - associated risk factor stratified by sex , the incidence rates of pad in women and men who received a hip - rep were 9.34 and 9.17 per 1000 person - years , respectively , both higher than those in women and men in the control cohort ( 6.54 and 5.01 per 1000 person - years , respectively ) . in addition , women who received a hip - rep exhibited a 1.29-fold ( 95% ci  =  1.031.61 ) higher risk of developing pad than did women who did not receive a hip - rep . among the age groups , a significantly higher hr of pad was observed among patients who received a hip - rep while ages 65 years or younger ( adjusted hr  =  1.67 , 95% ci  =  1.182.36 ) . stratified by follow - up year , the hip - rep group exhibited a significantly higher risk than did the comparison group of developing pad within 0.5 years and 0.51 years ( adjusted hr  =  1.69 , 95% ci  =  1.032.78 and adjusted hr  =  1.63 , 95% ci  =  1.012.63 , respectively ) ( table 3 ) . hazard ratio and 95% confidence intervals for pad compared to comparison cohort stratified by gender , age , and follow - up year compared with patients without the examined diseases and hip - rep treatment , patients received hip - rep without any comorbidity had a 2.45-fold risk for pad ( 95% ci  =  1.543.89 ) . patients with only dm exhibited the highest risk of developing pad ( adjusted hr  =  3.66 , 95% ci  =  1.677.99 ) , followed by those with only is ( adjusted hr  =  3.64 , 95% ci  =  1.807.35 ) and those with only ihd ( adjusted hr  =  3.44 , 95% ci  =  1.716.94 ) compared to people with no comorbidity . among patients who received a hip - rep , those with four or more comorbidities exhibited a significantly increased risk of pad ( adjusted hr  =  6.00 , 95% ci  =  4.168.67 ) , followed by those with any three comorbidities ( adjusted hr  =  4.32 , 95% ci  =  2.846.59 ) , those with any two comorbidities ( adjusted hr  =  3.49 , 95% ci  =  2.255.43 ) , and those with one comorbidity ( adjusted hr  =  2.80 , 95% ci  =  1.744.49 ) ( table 4 ) . we conducted this nationwide population - based retrospective cohort study to elucidate the relationship between hip - rep and the risk of developing pad . after adjustments for sex , age , htn , dm , is , ihd , copd , and ckd , patients who received a hip - rep exhibited a 1.24-fold higher risk of developing pad than did patients in the control group . age , htn , dm , ihd , copd , and ckd were also significantly associated with pad . most notably , a significantly higher risk of developing pad was noted among women who received a hip - rep , patients who received a hip - rep while ages 65 years or younger , and patients who received a hip - rep within the first follow - up year . our data revealed that advanced age , rather than sex , influenced the risk of developing pad . however , this study did not demonstrate that patients with only hyperlipidemia were at increased risk of developing pad ( compared with patients without the examined diseases ) , as previous studies have shown . using more cases or longer study periods might reveal the positive association between hyperlipidemia and the risk of developing pad . this study revealed that patients who received a hip - rep had more comorbidities ( htn , dm , and ckd ) than did patients in the control group . accordingly , one possible reason for the increased risk of pad in the hip - rep group is that the patients in the group had a significantly higher prevalence of comorbidities . we did not have sufficient data on the prevalence of comorbidities in asian patients who received a hip - rep . however , a 19902004 national hospital discharge survey - based statistical analysis in the united states reported that patients who received a hip - rep had an increased likelihood of developing dm , htn , hypercholesterolemia , obesity , pulmonary disease , or cad . alternatively , the population of patients with pad identified in this study might have been underestimated because pad is frequently underdiagnosed . thus , the number of patients with pad was likely greater than that diagnosed and enrolled ; therefore , the impact of hip - rep on the risk of developing pad might have been underestimated . first , the diagnoses recorded in the national health insurance research database ( nhird ) are primarily for administrative billing purposes and were not validated for academic purposes . second , data on symptoms of pad , family medical history , lifestyle , smoking habit , bmi status , laboratory data , and imaging findings , which are all potentially relevant to this study , are not included in the nhird . third , the evidence derived from a retrospective cohort study is generally of lower methodological quality than that of prospectively randomized trials because a retrospective cohort study design is subject to numerous biases related to adjustments for confounding factors . despite our meticulous study design with the adequate control of confounding factors , a key limitation was that bias could have existed because of possible unmeasured or unknown confounders . thus , a bias such as pad patients with a mistaken diagnosis of arthrosis might occur . we could not verify the exact temporal relationship between hip - rep and pad by using the nhird data . first , the results indicated that hip - rep independently increases the risk of developing pad . because hip - rep has been reported as being associated with an increased risk of atherosclerosis and unspecified cardiovascular disease and arterial thrombosis , few studies have examined the specific relationship between hip - rep and pad or considered hip - rep an independent risk factor for developing pad . some reports suggested a positive association between hip - rep and risk of developing pad . for example , islam and blake reported a total infrarenal aortic occlusion condition after primary hip - rep , and that an aortobifemoral bypass resolved the problem . hemodynamic change , or vascular compromise , was proposed as a potential factor or an aggravated factor for developing pad . however , future prospective , large - scale research ; the second clinically notable aspect of this study is that the more comorbidities in the hip - rep group , the more risk of pad and related morbidity and mortality ; physicians should consider these conditions and treat patients accordingly . first , this study is the first to examine the relationship between hip - rep and the risk of developing pad in an asian country . second , we conducted this retrospective cohort research using nationwide population data from the nhird , which covers a highly representative sample of the general population of taiwan because the reimbursement policy is universal and operated only by the government . moreover , all insurance claims are scrutinized by peer review and medical reimbursement specialists . pad was accurately diagnosed and coded ( icd-9 codes ) by the specialists according to the standard diagnosed criteria including typical symptoms / signs , laboratory data , and imaging findings . in addition , if the doctors or hospitals make the wrong codes or diagnoses , the national health insurance administration will punish them with a lot of penalty . therefore , the diagnoses of pad in this study were highly reliable . third , the joint effect of hip - rep and different numbers of comorbidities are discussed , possibly elucidating the risk of pad among patients with multiple comorbidities . in conclusion , patients who received a hip - rep might have an increased risk of developing pad . age , htn , dm , ihd , and ckd are also crucial risk factors for developing pad . patients who receive a hip - rep and have the aforementioned comorbidities are at an even higher risk of developing pad . an increased risk of developing pad was present among women who received a hip - rep , patients who received a hip - rep while ages 65 years or younger , and patients who received a hip - rep within the first follow - up year in our study period . although hip - rep is an orthopedic procedure , it might influence the vascular system profoundly . we suggest that further research involving larger samples and a more rigorous methodology be conducted .
abstractthe correlation between hip replacement ( hip - rep ) and peripheral arterial disease ( pad ) remains uncertain . 
 thus , we investigated the relationship between hip - rep and risk of developing pad in a nationwide retrospective cohort study.national health insurance data were used to assemble a cohort of patients who were diagnosed from 2000 to 2011 . 
 patients with a history of pad were excluded . 
 a total of 5284 patients who received a hip - rep and 21,124 matched controls were enrolled . 
 we used cox proportional hazards regression model to analyze the adjusted risk of developing pad.the risk of developing pad in the hip - rep group was 1.24-fold higher ( 95% ci  =  1.051.48 ) than that in the control group . 
 the adjusted risk of developing pad increased with patient age ; compared with patients aged 50 years or younger , the risk among those ages at least 80 years was 4.87-fold higher . 
 patients with diabetes exhibited the highest risk of developing pad ( hr  =  1.58 , 95% ci  =  1.341.86 ) . compared with patients who had not received a hip - rep or reported any comorbidity , patients who received a hip - rep were 2.45-fold more likely to develop pad ( 95% ci  =  1.543.89 ) ; the risk increased with the number of comorbidities.hip-reps might be independently linked with an increased risk of developing pad . 
 the impact of hip - reps on this risk was greater in women and patients ages 65 years and younger and within the first year of follow - up .