between june 1998 and december 1999 , a total of 247 patients with new diabetic foot ulcers and without previous major amputation presented to the study center .
they were included in this prospective study and followed up until 31 may 2011 , or until death .
seventy - nine patients ( 32.0% ) were treated by the diabetes team of the study center for the whole observation period or until death , while the remaining patients received foot care in various other institutions .
patients who were cared for at the study center continuously were invited for control at least every 3 months and treated by the same interdisciplinary team both as inpatients and outpatients when they had any new foot lesion .
patients who continued their treatment at external institutions were contacted by the study center at least once yearly .
they agreed to be contacted personally or allowed the investigators to obtain information on their outcomes from their relatives or their family physicians .
a diabetologist and a diabetic care nurse assessed all patients initially and performed the follow - up visits .
patient history included data on demographic characteristics , type and duration of diabetes , microvascular and macrovascular comorbidities , and smoking habits .
the physical examination included objective evaluation for peripheral neuropathy and peripheral arterial disease ( pad ) .
protective sensation was assessed separately for each leg with the calibrated rydel - seiffer tuning fork and the 5.07 monofilament .
loss of protective sensation as a result of neuropathy was presumed in the presence of insensitivity to the 5.07 monofilament or a vibration perception of 4/8 or below .
pad was defined by an ankle - brachial pressure index ( abi ) < 0.9 with additional investigation by means of duplex ultrasonography or angiography .
degree of severity of pad was subdivided according to measured abi and classified as mild ( abi , 0.70.9 ) , moderate ( abi , 0.410.69 ) , or severe ( abi , 0.4 ) ( 9,10 ) . patients with noncompressible arteries as a result of medial arterial calcification ( abi , 1.31 ) in whom pad had been diagnosed by imaging techniques were analyzed as having  not classified pad . 
ischemic heart disease was defined as the presence of a history of angina pectoris or myocardial infarction , any positive cardiac stress test result , or pathological signs on coronary angiography .
history of stroke was assumed to be present with any event of neurologic deficiency , whether persistent or resolved .
full definitions and related references have been published elsewhere ( 11 ) . in accordance with an earlier publication from the same center , we defined chronic renal insufficiency ( cri ) by a serum creatinine concentration 1.5 mg / dl and dialysis as the continuous need for renal replacement therapy ( advanced renal disease ) ( 12 ) .
clinical and demographic data , as well as outcome data ( healing , amputation , ulcer recurrence , death ) , were collected continuously according to a preset standardized protocol and sampled in a study database . the reported data concerned first major amputation and mortality rates among the studied individuals .
the cause of death was established from clinical findings before death , from death certificates , or by autopsy .
baseline variables were described depending on their distributions by means , sds , ranges , or frequency tables .
time from study entry to first major limb amputation and time from study entry to death were evaluated separately as censored event times by kaplan - meier curves .
patient data were censored at last observation . in case of the outcome first major amputation , death without major amputation
potential risk factors or confounders for both outcomes were analyzed by fitting cox multiple regression models .
the assumption of proportional hazards was assessed graphically by stratified kaplan - meier curves ( not all shown ) . the following factors were included in the analysis as possible predictors or confounders : sex , age , smoking , living in a nursing home , living alone , diabetes type , diabetes duration , insulin treatment ( yes vs. no ) , neuropathy , charcot foot syndrome , history of coronary heart disease , history of stroke , cri , dialysis , pad , minor amputation before inclusion , and first - ever foot lesion ( yes vs. no ) . at first ,
with stepwise and backward variable selection ( significance level for entry,10% ; significance level for remaining , 15% ) , the most relevant factors were selected . finally , two resulting main cox multiple regression models were fitted . instead of pad yes or no ,
the effect of nonselected covariates from above was estimated in some few cases by including this factor additionally in the final model , and interactions between pad and cri were investigated .
all statistical tests were performed two - sided at a significance level of 5% if not stated otherwise .
statistical analyses were calculated by the sas statistical software package ( version 9.3 ; sas institute inc . , cary , nc ) .
a diabetologist and a diabetic care nurse assessed all patients initially and performed the follow - up visits .
patient history included data on demographic characteristics , type and duration of diabetes , microvascular and macrovascular comorbidities , and smoking habits .
the physical examination included objective evaluation for peripheral neuropathy and peripheral arterial disease ( pad ) .
protective sensation was assessed separately for each leg with the calibrated rydel - seiffer tuning fork and the 5.07 monofilament .
loss of protective sensation as a result of neuropathy was presumed in the presence of insensitivity to the 5.07 monofilament or a vibration perception of 4/8 or below .
pad was defined by an ankle - brachial pressure index ( abi ) < 0.9 with additional investigation by means of duplex ultrasonography or angiography .
degree of severity of pad was subdivided according to measured abi and classified as mild ( abi , 0.70.9 ) , moderate ( abi , 0.410.69 ) , or severe ( abi , 0.4 ) ( 9,10 ) . patients with noncompressible arteries as a result of medial arterial calcification ( abi , 1.31 ) in whom pad had been diagnosed by imaging techniques were analyzed as having  not classified pad .  ischemic heart disease was defined as the presence of a history of angina pectoris or myocardial infarction , any positive cardiac stress test result , or pathological signs on coronary angiography .
history of stroke was assumed to be present with any event of neurologic deficiency , whether persistent or resolved .
full definitions and related references have been published elsewhere ( 11 ) . in accordance with an earlier publication from the same center , we defined chronic renal insufficiency ( cri ) by a serum creatinine concentration 1.5 mg / dl and dialysis as the continuous need for renal replacement therapy ( advanced renal disease ) ( 12 ) .
clinical and demographic data , as well as outcome data ( healing , amputation , ulcer recurrence , death ) , were collected continuously according to a preset standardized protocol and sampled in a study database . the reported data concerned first major amputation and mortality rates among the studied individuals .
the cause of death was established from clinical findings before death , from death certificates , or by autopsy .
baseline variables were described depending on their distributions by means , sds , ranges , or frequency tables .
time from study entry to first major limb amputation and time from study entry to death were evaluated separately as censored event times by kaplan - meier curves .
patient data were censored at last observation . in case of the outcome first major amputation , death without major amputation
potential risk factors or confounders for both outcomes were analyzed by fitting cox multiple regression models .
the assumption of proportional hazards was assessed graphically by stratified kaplan - meier curves ( not all shown ) .
the following factors were included in the analysis as possible predictors or confounders : sex , age , smoking , living in a nursing home , living alone , diabetes type , diabetes duration , insulin treatment ( yes vs. no ) , neuropathy , charcot foot syndrome , history of coronary heart disease , history of stroke , cri , dialysis , pad , minor amputation before inclusion , and first - ever foot lesion ( yes vs. no ) . at first , each factor was included as independent variable in an univariate model . with stepwise and backward variable selection ( significance level for entry,10% ; significance level for remaining , 15% ) , the most relevant factors were selected .
finally , two resulting main cox multiple regression models were fitted . instead of pad yes or no ,
the effect of nonselected covariates from above was estimated in some few cases by including this factor additionally in the final model , and interactions between pad and cri were investigated .
all statistical tests were performed two - sided at a significance level of 5% if not stated otherwise .
statistical analyses were calculated by the sas statistical software package ( version 9.3 ; sas institute inc . , cary , nc ) .
mean patient age at study inclusion was 68.8  10.9 years ( range , 2591 years ) , mean diabetes duration was 15.7  10.5 years ( range , 053 years ) , 58.7% of the patients were male , and the majority had type 2 diabetes ( 87.5% ) .
neuropathy and pad were present at study initiation in 86.2% and 55.5% of the patients , respectively .
forty - eight patients with pad ( 37.2% ) met the definition for a severe stage of the disease in at least one leg . in 40 patients ( 16.2% ) , arteries were noncompressible as a result of medial arterial calcification . in eight patients with medial arterial calcification , pad could not be classified on the basis of abi . in nine patients ( 3.6% )
twenty - nine patients ( 11.7% ) had evidence of active or inactive charcot foot syndrome at the time of inclusion .
fifty - eight patients ( 23.5% ) fulfilled the criteria for cri or were receiving renal replacement therapy .
fifty - two patients ( 21.1% ) were active smokers ( 26.9% of the male patients and 12.8% of the female patients ) , and 94 patients ( 38.1% ) were former smokers ( 51.7% of the male patients and 18.6% of the female patients ) .
histories of a coronary event or stroke were reported by 51 ( 20.7% ) and 54 ( 21.9% ) of the subjects , respectively , without major differences by sex .
demographic data , risk factors , and comorbidities of the study population the mean follow - up period was 5.7  4.4 years ( range , 0.00313.2 years ) , including both survivors and patients who died during the study period .
thirty - eight patients had a first major amputation during the follow - up period .
the cumulative probabilities of a first major amputation were 8.7% ( 5.112.4% ) , 12.5% ( 8.016.9% ) , 15.9% ( 10.721.0% ) , and 22.3% ( 15.329.2% ) at years 1 , 3 , 5 , and 10 , respectively ( table 2 ) .
all except one of the affected patients had evidence of pad at inclusion in the study , and 51.4% had evidence of severe pad in the concerned extremity
. in separate univariate cox regression models , age , dialysis , and pad were significant risk increasing factors , and neuropathy was a significant preventive factor ( table 3 ) .
after taking pad into the model as the second variable , however , neuropathy no longer remained significant ( hazard ratio [ hr ] , 0.62 ; p = 0.218 ) .
thus the seemingly protective effect of neuropathy was almost fully explained by the absence of pad .
age , pad , dialysis , and smoking were selected by stepwise and backward selection in cox regression .
age ( hr per year , 1.05 [ 95% ci , 1.011.10 ] ; p = 0.023 ) , being on dialysis at baseline ( hr , 3.51 [ 95% ci , 1.0212.07 ] ; p = 0.046 ) and pad at baseline ( 35.34 [ 4.81259.79 ] ; p < 0.001 ) were the independent predictive variables for a first major limb amputation during follow - up ( table 3 , model 1 ) .
presence of mild pad at baseline increased the risk of a first major amputation 20-fold , moderate pad 34-fold , and severe pad 62-fold ( table 3 , model 2 ) relative to no pad .
the hr between severe and mild pad was 3.13 ( 1.118.79 ; p = 0.03 ) , and that between severe and moderate pad was 1.80 ( 0.843.86 ; p = 0.13 ) .
models including an additional interaction variable between pad and dialysis did not yield valid results because of the low number of dialysis cases .
kaplan - meier curves corresponding to cumulative probabilities of the first major amputation stratified by pad classes present a visual representation of these results ( fig .
cumulative probabilities ( with 95% ci ) of first major limb amputation or death univariate analysis and cox multiple regression models of association between variables and major amputation or death a : relevance of the presence and severity of pad for the cumulative probability of a first major limb amputation . to avoid complexity , pad
not classified because of medial arterial calcification is not shown ( n = 8 ; only 1 event of first major limb amputation ) .
the highest curve represents no pad , the second curve represents mild pad , the third curve represents moderate pad , and the lowest curve represents severe pad .
b : relevance of the presence or absence of pad , advanced renal disease , or both combined for the cumulative probability of death .
the highest curve represents no pad and no renal disease , the second curve represents renal disease and no pad , the third curve represents pad and no renal disease , and the lowest curve represents pad and renal disease .
there was no statistical difference in the risk of a first major amputation during the follow - up period between patients who had undergone a minor amputation before inclusion in the study when this factor was included as an additional covariate ( hr , 1.21 [ 95% ci , 0.562.59 ] ; p = 0.630 ) in model 1 of table 3 . by 31 may 2011 , a total of 174 of the subjects had died , including 83 ( 47.7% ) from cardiac diseases , 17 ( 9.8% ) after stroke , 18 ( 10.3% ) from malignancies , 23 ( 13.2% ) from renal complications , and 24 ( 13.8% ) as a result of septic conditions .
septic conditions as cause of death were more prevalent among patients who had cri or were receiving renal replacement therapy than among patients without obvious renal impairment ( 21.3 vs. 11.0% ) .
the cumulative mortalities for the whole cohort at years 1 , 3 , 5 , and 10 were 15.4% ( 10.920.0% ) , 33.1% ( 27.139.1% ) , 45.8% ( 39.452.2% ) , and 70.4% ( 64.576.4% ) , respectively . for patients with pad at baseline ,
the corresponding numbers were 21.9% ( 14.89.0% ) , 44.1% ( 35.552.7% ) , 58.8% ( 50.267.4% ) , and 81.0 ( 74.188.0 ) , respectively ( table 2 ) . in separate univariate cox regression models , age , living in a nursing home , type 2 diabetes , history of coronary heart disease , history of stroke , cri , dialysis , and pad
were significant risk increasing factors , the presence of charcot foot syndrome a significant preventive factor ( table 3 ) .
age , sex , pad , cri , dialysis , and history of stroke were selected by stepwise and backward selection in cox regression .
living in a nursing home was selected only by backward selection , was not significant ( p = 0.116 ) , and was not included in the final model .
independent predictive variables for death were age ( hr per year , 1.08 [ 95% ci 1.061.10 ] ; p < 0.001 ) , male sex ( 1.65 [ 1.182.32 ] ; p = 0.004 ) , cri ( 1.83 [ 1.252.66 ] ; p = 0.002 ) , dialysis ( 6.43 [ 3.1413.16 ] ; p < 0.001 ) , and pad ( 1.44 [ 1.051.98 ] ; p = 0.023 ) ( table 3 , model 3 ) .
when the classified pad variable was used , severe pad dominated the significant association of pad with the risk of death ; however , the overall p value for the class variable was not significant ( p = 0.065 ) . a significant interaction ( p = 0.023 ) between pad ( yes or no ) and cri
was concluded by adding an interaction variable in model 3 of table 3 ( changed hrs [ 95% cis ] of the main variables , pad , 1.72 [ 1.201.44 ] ; cri , 3.25 [ 1.805.85 ] ; and interaction of pad and cri , 0.42 [ 0.200.89 ] ) .
this means higher hrs of the pad - only and cri - only patients but lower hr than the corresponding product hr for patients with pad and cri ( reference , no pad and no cri ) .
kaplan - meier survival curves stratified by pad and renal disease are presented in fig .
patients who had undergone a minor amputation for a previous foot lesion had no significant increase in probability of death during follow - up ( hr , 1.25 [ 95% ci , 0.851.83 ] ; p = 0.258 ) ( additional covariable in model 3 of table 3 ) .
mean patient age at study inclusion was 68.8  10.9 years ( range , 2591 years ) , mean diabetes duration was 15.7  10.5 years ( range , 053 years ) , 58.7% of the patients were male , and the majority had type 2 diabetes ( 87.5% ) .
neuropathy and pad were present at study initiation in 86.2% and 55.5% of the patients , respectively .
forty - eight patients with pad ( 37.2% ) met the definition for a severe stage of the disease in at least one leg . in 40 patients ( 16.2% ) , arteries were noncompressible as a result of medial arterial calcification . in eight patients with medial arterial calcification , pad could not be classified on the basis of abi . in nine patients ( 3.6% )
twenty - nine patients ( 11.7% ) had evidence of active or inactive charcot foot syndrome at the time of inclusion .
fifty - eight patients ( 23.5% ) fulfilled the criteria for cri or were receiving renal replacement therapy .
fifty - two patients ( 21.1% ) were active smokers ( 26.9% of the male patients and 12.8% of the female patients ) , and 94 patients ( 38.1% ) were former smokers ( 51.7% of the male patients and 18.6% of the female patients ) .
histories of a coronary event or stroke were reported by 51 ( 20.7% ) and 54 ( 21.9% ) of the subjects , respectively , without major differences by sex .
demographic data , risk factors , and comorbidities of the study population the mean follow - up period was 5.7  4.4 years ( range , 0.00313.2 years ) , including both survivors and patients who died during the study period .
thirty - eight patients had a first major amputation during the follow - up period .
the cumulative probabilities of a first major amputation were 8.7% ( 5.112.4% ) , 12.5% ( 8.016.9% ) , 15.9% ( 10.721.0% ) , and 22.3% ( 15.329.2% ) at years 1 , 3 , 5 , and 10 , respectively ( table 2 ) .
all except one of the affected patients had evidence of pad at inclusion in the study , and 51.4% had evidence of severe pad in the concerned extremity
. in separate univariate cox regression models , age , dialysis , and pad were significant risk increasing factors , and neuropathy was a significant preventive factor ( table 3 ) .
after taking pad into the model as the second variable , however , neuropathy no longer remained significant ( hazard ratio [ hr ] , 0.62 ; p = 0.218 ) .
thus the seemingly protective effect of neuropathy was almost fully explained by the absence of pad .
age , pad , dialysis , and smoking were selected by stepwise and backward selection in cox regression .
age ( hr per year , 1.05 [ 95% ci , 1.011.10 ] ; p = 0.023 ) , being on dialysis at baseline ( hr , 3.51 [ 95% ci , 1.0212.07 ] ; p = 0.046 ) and pad at baseline ( 35.34 [ 4.81259.79 ] ; p <
0.001 ) were the independent predictive variables for a first major limb amputation during follow - up ( table 3 , model 1 ) .
presence of mild pad at baseline increased the risk of a first major amputation 20-fold , moderate pad 34-fold , and severe pad 62-fold ( table 3 , model 2 ) relative to no pad .
the hr between severe and mild pad was 3.13 ( 1.118.79 ; p = 0.03 ) , and that between severe and moderate pad was 1.80 ( 0.843.86 ; p = 0.13 ) .
models including an additional interaction variable between pad and dialysis did not yield valid results because of the low number of dialysis cases .
kaplan - meier curves corresponding to cumulative probabilities of the first major amputation stratified by pad classes present a visual representation of these results ( fig .
cumulative probabilities ( with 95% ci ) of first major limb amputation or death univariate analysis and cox multiple regression models of association between variables and major amputation or death a : relevance of the presence and severity of pad for the cumulative probability of a first major limb amputation . to avoid complexity , pad
not classified because of medial arterial calcification is not shown ( n = 8 ; only 1 event of first major limb amputation ) .
the highest curve represents no pad , the second curve represents mild pad , the third curve represents moderate pad , and the lowest curve represents severe pad .
b : relevance of the presence or absence of pad , advanced renal disease , or both combined for the cumulative probability of death .
the highest curve represents no pad and no renal disease , the second curve represents renal disease and no pad , the third curve represents pad and no renal disease , and the lowest curve represents pad and renal disease .
there was no statistical difference in the risk of a first major amputation during the follow - up period between patients who had undergone a minor amputation before inclusion in the study when this factor was included as an additional covariate ( hr , 1.21 [ 95% ci , 0.562.59 ] ; p = 0.630 ) in model 1 of table 3 .
by 31 may 2011 , a total of 174 of the subjects had died , including 83 ( 47.7% ) from cardiac diseases , 17 ( 9.8% ) after stroke , 18 ( 10.3% ) from malignancies , 23 ( 13.2% ) from renal complications , and 24 ( 13.8% ) as a result of septic conditions .
septic conditions as cause of death were more prevalent among patients who had cri or were receiving renal replacement therapy than among patients without obvious renal impairment ( 21.3 vs. 11.0% ) .
the cumulative mortalities for the whole cohort at years 1 , 3 , 5 , and 10 were 15.4% ( 10.920.0% ) , 33.1% ( 27.139.1% ) , 45.8% ( 39.452.2% ) , and 70.4% ( 64.576.4% ) , respectively . for patients with pad at baseline ,
the corresponding numbers were 21.9% ( 14.89.0% ) , 44.1% ( 35.552.7% ) , 58.8% ( 50.267.4% ) , and 81.0 ( 74.188.0 ) , respectively ( table 2 ) .
in separate univariate cox regression models , age , living in a nursing home , type 2 diabetes , history of coronary heart disease , history of stroke , cri , dialysis , and pad were significant risk increasing factors , the presence of charcot foot syndrome a significant preventive factor ( table 3 ) .
age , sex , pad , cri , dialysis , and history of stroke were selected by stepwise and backward selection in cox regression .
living in a nursing home was selected only by backward selection , was not significant ( p = 0.116 ) , and was not included in the final model .
independent predictive variables for death were age ( hr per year , 1.08 [ 95% ci 1.061.10 ] ; p < 0.001 ) , male sex ( 1.65 [ 1.182.32 ] ; p = 0.004 ) , cri ( 1.83 [ 1.252.66 ] ; p = 0.002 ) , dialysis ( 6.43 [ 3.1413.16 ] ; p < 0.001 ) , and pad ( 1.44 [ 1.051.98 ] ; p = 0.023 ) ( table 3 , model 3 ) . when the classified pad variable was used , severe pad dominated the significant association of pad with the risk of death ; however , the overall p value for the class variable was not significant ( p = 0.065 ) . a significant interaction ( p = 0.023 ) between pad ( yes or no ) and
cri was concluded by adding an interaction variable in model 3 of table 3 ( changed hrs [ 95% cis ] of the main variables , pad , 1.72 [ 1.201.44 ] ; cri , 3.25 [ 1.805.85 ] ; and interaction of pad and cri , 0.42 [ 0.200.89 ] ) .
this means higher hrs of the pad - only and cri - only patients but lower hr than the corresponding product hr for patients with pad and cri ( reference , no pad and no cri ) .
kaplan - meier survival curves stratified by pad and renal disease are presented in fig .
patients who had undergone a minor amputation for a previous foot lesion had no significant increase in probability of death during follow - up ( hr , 1.25 [ 95% ci , 0.851.83 ] ; p = 0.258 ) ( additional covariable in model 3 of table 3 ) .
the results of this study suggest that although long - term limb salvage in a modern series of diabetic foot patients is favorable , long - term patient survival still appears to be poor , especially among patients with pad , renal insufficiency , or the combination of both . to our knowledge , this is the first report in the medical literature that has examined both risk for major amputation and mortality in a primary data set of patients followed up for more than a decade .
our cohort was remarkably similar in patient age and high prevalence of pad to other european cohorts studied for outcomes of diabetic foot disease over shorter ( 1315 ) or longer ( 5 years ) ( 25,16 ) observation periods .
in accordance with other studies , we observed a predominance of male patients in our cohort ( 58.7% ) ; however , it was less pronounced than in some studies ( 35,13,1618 ) . among the patients in our study ,
limb loss was observed almost exclusively in patients who had evidence of pad at study initiation .
an independent association between pad and amputation has been found in other long - term studies as well ( 35 ) ; however , all those studies combined minor and major amputations rather than analyzing major amputation exclusively . in a study investigating a large cohort of diabetic foot patients ( n = 1,088 ) treated at centers of excellence in 10 different european countries , the major amputation rate among patients with pad during a 12-month follow - up was 8% , compared with 2% among patients without pad ( p < 0.001 ) ( 13 ) .
more than 50% of the individuals in our study who had a first major amputation had evidence of severe pad at baseline .
the cumulative probability of a first major amputation was strongly linked to the severity of preexisting pad .
none of the other three long - term studies provided clear stratification of severity of pad .
( 5 ) , who followed 84 of 95 hospitalized diabetic foot ulcer patients ( 95% ) for 6.5 years after hospital release , popliteal stenosis as a potential marker for more distal and probably more severe peripheral vascular disease ( 19 ) was the only independent predictor of amputation ( relative risk , 2.67 [ 95% ci , 1.3410.07 ] ; p  0.01 ) . in two other recent publications , severe pad
( ankle pressure 50 mm hg or toe pressure 30 mm hg ) was a predictor of increased major amputation risk in diabetic patients with neuroischemic or ischemic foot ulcers ( 14,20 ) .
being on renal replacement therapy at the time of inclusion ( hr , 3.51 [ 95% ci , 1.0212.07 ] ; p = 0.046 ) was an independent predictive variable for a first major amputation during follow - up in our study . in the eurodiale ( european study group on diabetes and the lower extremity ) study , the presence of end - stage renal disease ( defined as dependency on hemodialysis or peritoneal dialysis or a previous renal transplant procedure ) was an independent predictor of lack of healing ( odds ratio , 2.51 [ 95% ci , 1.414.48 ] ; p = 0.002 ) , and that was true for patients with and without pad ( 13 ) ; however , major amputation in that analysis was not a specifically analyzed end point .
( 14 ) , uremia was significantly associated with major amputation among patients with neuroischemic and ischemic ulcers ( 2.43 [ 1.334.45 ] ; p = 0.004 ) as well as with minor or major amputation among patients with neuropathic ulcers ( 2.62 [ 1.394.96 ] ; p = 0.003 ) .
( 5 ) among 62 patients without previous amputation after multivariate analysis , only diabetic nephropathy remained as an independent predictor of first amputation ( relative risk , 6.00 [ 95% ci , 1.6222.21 ] ; p < 0.01 ) .
authors of the other long - term studies either did not explore renal impairment as an influential factor for major amputation ( 4 ) or decided that a possible association with baseline variables would not be significant because of the small numbers of major amputation events in the study ( 3 ) . excess mortality among patients with diabetic foot disease over observation periods of variable duration has been reported repeatedly during recent decades ( 25,7,8,1317,20,21 ) .
the published results are somewhat difficult to compare , however , because some studies describe death without healing of a distinct diabetic foot lesion as the end point ( 13,14,18 ) , while others report cumulative mortality 1 , 3 , or 5 years after patient inclusion in the study ( 2,4,1618 ) .
death before healing of the initial ulcer occurred in 5.8% of our cases , which is almost identical to the results reported from the eurodiale study ( 6.0% ) ( 13 ) .
somewhat higher frequencies were reported from sweden ( 14 ) and from the uk ( 18 ) .
( 14 ) included patients who died with unhealed stumps after major amputation , however , while our study and the eurodiale consortium considered the major amputation event to be the definite end point .
our 1-year mortality was in the same range as the data reported from nottingham ( 18 ) ( 15.9 and 16.7% , respectively ) , whereas our 5-year mortality was comparable to the reports of moulik et al .
mortality data during a 10-year follow - up period have only been published in two medical reports so far .
izumi et al . ( 7 ) studied 277 patients receiving amputations between 1993 and 1997 , following them up for as long as 10 years ( through 2003 ) .
they reported cerebrovascular , cardiovascular , and end - stage renal diseases as being strongly associated with death in those receiving distal amputations .
for those receiving high - level amputations , only coronary artery disease was associated with increased mortality risk .
additionally , people with high - level amputations were at greater risk of death than were those receiving low - level amputations .
these results confirm the observation of poor survival after major amputation in patients with and without diabetes reported from studies with shorter follow - up periods ( 2224 ) ; however , the izumi et al .
study ( 7 ) exclusively followed up patients who had received a lower limb amputation , not all patients had the opportunity to complete ten years of follow - up , and 10-year mortality was not stated .
( 8) used 19951997 data from the nord - trndelag health study ( hunt 2 ) to evaluate mortality among people with diabetes who did or did not have a diabetic foot ulcer .
people with a diabetic foot ulcer ( n = 155 ) had a 2.3-fold greater risk for death relative to nondiabetic patients during the 10-year follow - up period ( 49.0% vs. 35.2% ) , with age , male sex , and smoking as significant covariate factors .
the extent of mortality excess equals that observed after 3 years of follow - up in swedish primary healed diabetic foot ulcer patients ( 2.35-fold ) but is considerably lower than the 3-year value for those with amputation in the same study ( 3.94-fold ) ( 2 ) .
the 10-year cumulative mortality reported from the study of iversen et al ( 8) is also substantially lower than the number from our study ( 70.4% ) .
the difference could be due to a possible underestimation of the mortality risk in hunt 2 explained by its design .
it was stated by the authors that diabetic individuals who did not respond to the questionnaire on foot ulcers reported otherwise more advanced disease .
in addition , recruitment procedures in that study made it difficult for housebound or institutionalized individuals to participate , which probably led to a reduced number of elderly people with a history of foot ulcers or amputation in that study relative to other studies ( 2,21 ) .
in addition to age ( hr per year , 1.08 ) , male sex ( hr , 1.65 [ 95% ci , 1.182.32 ] ; p = 0.004 ) , cri ( hr , 1.83 ) , being on dialysis ( 6.43 ) , and pad ( 1.44 ) were independent predictive variables for death in our study .
concerning cri , this result is in agreement with those of two other long - term studies that analyzed this variable : ghanassia et al .
( 5 ) found renal impairment ( relative risk , 4.57 [ 95% ci , 1.119.4 ] ; p < 0.05 ) to be the only independent predictor of mortality in a multivariate analysis ( 5 ) , and in the work of faglia et al .
( 3 ) renal impairment was a predictor of death in the univariate analysis ( hr , 2.57 [ 95% ci , 1.225.41 ] ; p = 0.013 ) but was not confirmed in the multivariate analysis .
( 5 ) did not report a statistical relevance of pad as a predictor of death , whereas faglia found the independent association of an abi 0.5 ( 2.29 [ 1.294.08 ] ; p = 0.005 ) confirmed by multivariate analysis .
this fits nicely with our finding , that severe pad ( abi 0.4 ) dominates the significant association of pad with the risk of death when using the classified pad variables .
the increased risk among death of patients with a history of diabetic foot ulcers and its association with a low abi has recently also been described for an asian population ( 25 ) . in concordance with our own study ,
male sex was a significant predictor in the 10-year study done by iversen et al .
although three of the other long - term studies did not report significant sex differences concerning mortality ( 2,4,5 ) , faglia et al .
( 3 ) found female sex to be independently associated with death ( hr , 1.96 [ 95% ci , 1.083.56 ] ; p = 0.027 ) . because the discrepancy in age between male and female patients in that study was comparable to that among our patients ( 62.0 vs. 67.2 years and 66.5 vs. 72.0 years , respectively ) , this conflicting age - adjusted observation remains unexplained for the moment .
more than half of the deaths in our study were from cardio- and cerebrovascular events .
this observation is in full agreement with the information given in other european studies with long - term follow - up ( 25,8,16 ) . in contrast , studies on mortality of diabetic foot ulcer patients in developing and newly developed countries report a substantially higher proportion of deaths from septic conditions ( 26 ) .
neuropathy in and of itself is known to be highly associated with cardiovascular mortality ( 2729 ) .
this could be explained most plausibly by two factors : 1 ) nearly all of our patients had clinically significant neuropathy on entry into the cohort , and 2 ) we did not specifically investigate cardiovascular mortality but rather all - cause mortality .
the main strength of the study is the almost complete follow - up over a long observation period , as long as 13.2 years .
only 20 patients ( 8.1% ) were unavailable for follow - up before death or the end of the observation period .
the comparability with other studies investigating the outcome of diabetic foot disease with regard to relevant demographic variables and risk factors may be a further advantage .
a potential negative selection bias always has to be considered when cohorts from specialized diabetic foot care centers are analyzed .
it is to be expected that a number of more superficial ulcers of neuropathic origin are treated successfully in primary health care without being seen by a specialized diabetic foot center .
therefore our cohort should be typical for high - risk patients in specialized centers but not for the entire diabetic population .
in addition , male predominance was less pronounced in our cohort than in some other reported studies . in conclusion , data from this long - term study suggest strongly that limb preservation today is the rule rather than the exception , even in high - risk patients with diabetes .
long - term survival remains poor , however , probably because of myriad comorbid conditions for patients whose first presentation to an interdisciplinary clinic is with a diabetic foot ulcer .
efforts to assess and capture these patients earlier in such a clinic may ultimately prove beneficial not only in preventing amputation but also in tangentially prolonging life .
 objectivethere is a dearth of long - term data regarding patient and limb survival in patients with diabetic foot ulcers ( dfus ) . 
 the purpose of our study was therefore to prospectively investigate the limb and person survival of dfu patients during a follow - up period of more than 10 years.research design and methodstwo hundred forty - seven patients with dfus and without previous major amputation consecutively presenting to a single diabetes center between june 1998 and december 1999 were included in this study and followed up until may 2011 . 
 mean patient age was 68.8  10.9 years , 58.7% were male , and 55.5% had peripheral arterial disease ( pad ) . 
 times to first major amputation and to death were analyzed with kaplan - meier curves and cox multiple regression.resultsa first major amputation occurred in 38 patients ( 15.4% ) during follow - up . 
 all but one of these patients had evidence of pad at inclusion in the study , and 51.4% had severe pad [ ankle - brachial pressure index 0.4 ] ) . 
 age ( hazard ratio [ hr ] per year , 1.05 [ 95% ci , 1.011.10 ] ) , being on dialysis ( 3.51 [ 1.0212.07 ] ) , and pad ( 35.34 [ 4.81259.79 ] ) were significant predictors for first major amputation . 
 cumulative mortalities at years 1 , 3 , 5 , and 10 were 15.4 , 33.1 , 45.8 , and 70.4% , respectively . 
 significant predictors for death were age ( hr per year , 1.08 [ 95% ci , 1.061.10 ] ) , male sex ( [ 1.182.32 ] ) , chronic renal insufficiency ( 1.83 [ 1.252.66 ] ) , dialysis ( 6.43 [ 3.1413.16 ] ) , and pad ( 1.44 [ 1.051.98]).conclusionsalthough long - term limb salvage in this modern series of diabetic foot patients is favorable , long - term survival remains poor , especially among patients with pad or renal insufficiency . 
RESEARCH DESIGN AND METHODS
Data assessment
Statistical analysis
RESULTS
Study population
First major amputation in the study population
Mortality in the study population
CONCLUSIONS