though many patients suffer from peripheral arterial occlusive disease ( paod ) , diagnosis is often delayed . if paod is not diagnosed and treated immediately , it is highly probable that the disease will progress to critical limb ischemia ( cli ) . although treatment options , especially endovascular treatment modalities , have improved in recent decades , mortality and amputation rates remain high . various scoring systems have been established to identify patients at high risk for cardiovascular disease . the most renowned is the framingham risk score , which distinguishes individuals at low , moderate , and high risk for coronary heart disease . this score includes clinical ( eg , blood pressure ) and laboratory parameters ( eg , high density lipoprotein cholesterol ) . recently , the procam score was published to evaluate the 10-year myocardial infarction ( mi ) risk to identify patients who might profit from more intense prevention and cardiovascular risk factor management . this score includes laboratory parameters ( eg , cholesterol ) , clinical parameters ( eg , blood pressure ) , and concomitant medication ( antihypertensives ) . although cli is a common disorder , there is still no risk score to evaluate the cli risk in paod patients . we therefore evaluated cli risk factors in our paod cohort and developed a risk score , the graz cli score , which is easy to use with paod patients . for our cross - sectional study , we formed a first cohort of 1000 patients with paod treated at our department between 2003 and 2007 to identify cli risk factors and to develop our scoring model . we validated our scoring system with a second cohort , consisting of 1124 paod patients we treated between 2007 and 2011 . the inclusion criterion for our study was treatment at our institution for paod during the given time period ; there were no exclusion criteria . the study was approved by the institutional review board of the medical university of graz , austria ( irb number 24 - 506 ex 11/12 ) . as this was a retrospective analysis of blinded data , the board agreed that neither written nor verbal consent would be required . paod was diagnosed and graded in our outpatient clinic on the basis of clinical evaluation , ankle brachial index , and duplex scan according to the tasc ii criteria . successive paod patients presenting at our outpatient angiology clinic were scheduled for admission to our ward for further treatment of their atherosclerotic disease . cli was defined as paod presenting with ischemic rest pain and/or skin ulceration / gangrene in accordance with current guidelines and corresponding to fontaine classes 3 and 4 . upon hospital admission , the patient 's medical records were analyzed systematically for cardiovascular risk factors , comorbidities , and medication . groups were compared with the  test for categorical values , the t test for normally distributed continuous variables , and the mann univariate regression analysis was used to assess the influence of individual demographic data and comedication parameters on cli . variables exhibiting a significance level of p  <  0.05 on univariate analysis were then entered into a multivariate binary logistic regression model . for all tests , the threshold p value for significance was p    0.05 . terpstra test performed to detect any statistical trend indicating that cli rates increase with the cli risk score . groups were compared with the  test for categorical values , the t test for normally distributed continuous variables , and the mann univariate regression analysis was used to assess the influence of individual demographic data and comedication parameters on cli . variables exhibiting a significance level of p  <  0.05 on univariate analysis were then entered into a multivariate binary logistic regression model . for all tests , the threshold p value for significance was p    0.05 . terpstra test performed to detect any statistical trend indicating that cli rates increase with the cli risk score . there were statistically significant differences between cohort 1 and cohort 2 with respect to the incidence of coronary artery disease ( cad ; 326 [ 32.6% ] vs 420 [ 37.4% ] , p  =  0.03 ) and atrial fibrillation ( 149 [ 14.9% ] vs 219 [ 19.4% ] , p  =  0.01 ) . with regard to concomitant medication we found differences in antiplatelet therapy ( aspirin : 414 [ 41.4% ] vs 379 [ 33.7% ] , p  =  0.001 ) and clopidogrel ( 152 [ 15.2% ] vs 287 [ 25.5% ] , p  =  0.001 ) . this might be because of the differences in the time periods when patients presented at our outpatient clinic , where cohort 1 was treated between 2004 and 2007 and cohort 2 was treated between 2007 and 2011 . during the latter period , patients were increasingly treated with clopidogrel . furthermore , cad frequency differed significantly between groups also leading to a difference in concomitant medication ( angiotensin receptor blocker and -blocker : 112 [ 11.2% ] vs 171 [ 15.2% ] , p  =  0.01 , and 381 [ 38.1% ] vs 495 [ 44% ] , p  =  0.01 ) . patients characteristics of peripheral arterial occlusive disease patients included in the study ( cohort 1 and cohort 2 ) parameters of medical history and concomitant medication were first evaluated in a univariate regression analysis for the occurrence of cli in cohort 1 ( table 2 ) . variables exhibiting a significance level of p  <  0.05 on univariate analysis were then entered into a multivariate binary logistic regression model . in cohort 1 , the strongest risk factors for cli in the multivariate regression model were age > 75 years ( or 2.0 [ 95% confidence interval [ ci ] 1.33.0 ] , p  <  0.001 ) , type 2 diabetes ( or 3.1 [ 95% ci 2.24.4 ] , p  <  0.001 ) , prior mi ( or 2.5 [ 95% ci 1.15.5 ] , p  =  0.03 ) , and therapy with low molecular weight heparin ( lmwh ) ( 2.8 [ 95% ci 1.74.4 ] , p  <  0.001 ) . for those conditions we scored 2 points each . one point was given for age between 65 and 75 years ( or 1.6 [ 95% ci 1.12.5 ] , p  =  0.03 ) as well as for use of cardiac glycosides ( or 1.9 [ 95% ci 1.33.4 ] , p  =  0.003 ) or loop diuretics ( or 1.5 [ 95% ci 1.12.1 ] , p  =  0.01 ) . as statin therapy was associated with an or of 0.5 ( 95% ci 0.40.8 , p  <  0.001 ) , we subtracted 1 point for those patients ( table 3 ) . risk factors for critical limb ischemia in peripheral arterial occlusive disease patients ( cohort 1 ) in univariate regression analysis adjusted risk factors for critical limb ischemia in peripheral arterial occlusive disease patients ( cohort 1 ) in the second group of patients , we could prove that the frequency of cli was significantly higher in patients with a high cli score ( table 4 ) . the high - risk group ( score 610 ) was very small and we actually were not able to show a linear progression for cli in these patients , but we nonetheless were able to define 3 different risk groups ( low cli risk : score 1 to 1 , n  =  434 ; intermediate cli risk : score 24 , n  =  569 ; and high cli risk : score 510 , n  =  121 ) according to the number of score points ( table 1 ) . the cli rate was significantly higher in patients with a higher score , especially those with a score of > 4 points ( figure 1 ) . the statistical trend we saw for the increase in the cli rate with increasing score points was statistically significant ( p  <  0.001 ) . critical limb ischemia patients according to the critical limb ischemia risk score in cohort 2 percentage of patients with critical limb ischemia stratified by critical limb ischemia risk score . data in the figure are % ( cli patients / all patients in the group ) . we analyzed the correlation of the graz cli score with the inflammatory parameters that reflect the activity of the underlying atherosclerotic disease . we calculated pearson 's correlation and spearman 's  for the correlation of c - reactive protein ( crp ) and fibrinogen with the cli score and found a highly significant statistical correlation for both parameters ( for crp : pearson 's r  =  0.3 ; spearman 's   =  0.4 ; for fibrinogen : pearson 's r  =  0.2 ; spearman 's   =  0.3 ; p value for all calculations < 0.001 ) . this study demonstrated that the risk for cli in paod patients can be determined easily on the basis of their clinical parameters and concomitant medication . our score correlates well with inflammatory parameters that reflect the activity of atherosclerosis in these patients . in general , scoring systems can be useful for identifying patients at high risk for vascular endpoints . the framingham risk score can be used to highlight patients at high risk for cardiovascular disease and those with a high - risk score might profit from intense management of their vascular risk factors , as might those with a high graz cli score . we hypothesize that those paod patients should be treated immediately as their elevated inflammatory parameters suggest a more aggressive atherosclerosis . with our score , age and diabetes were among the most aggressive risk factors , with an or of 2.0 and 3.1 , respectively . we were able to show that an elevated cha2ds2-vasc score is associated with an elevated cli risk . with this scoring system , there are signs of chronic inflammation in both , diabetes and insulin resistance , a typical feature of type 2 diabetes . concerning age there are similar data on age - related inflammation increase in atherosclerotic patients . the reason for this age - related systemic chronic inflammation is mainly attributed to the progressive activation of immune cells over time . when the graz cli score was analyzed , much research has been conducted to evaluate the protective effect of statin therapy , especially in cli patients . westin et al recently showed that statins were associated with lower mortality , a reduction in major adverse cardiovascular and cerebrovascular events , and longer amputation - free survival in cli patients . even in patients who have undergone endovascular treatment , statin therapy is associated with superior clinical outcome . especially in combination with angiotensin - converting enzyme inhibitors , statins may have even reduced mortality in diabetic cli patients during a 2-year follow - up . the beneficial findings of statins in cli patients were further underlined in large databases , like the reach registry . a recent publication on symptomatic paod patients revealed that among them , statin use was associated with an 18% lower rate of adverse limb outcomes , including worsening of symptoms , peripheral revascularization , and ischemic amputations . statin therapy should by all means be initiated for all paod patients , especially those with diabetes . these recommendations are also reflected in current guidelines , although adherence to them is rather poor . as this medication is mainly given to patients with congestive heart failure , their low cardiac output causes hemodynamic alterations that include a low flow state , increased peripheral resistance , endothelial cell dysfunction , and vascular smooth muscle cell dysfunction that could exacerbate ischemic symptoms . we already know that patients with paod have a higher risk of fatal and nonfatal cardiovascular events than do patients with symptomatic atherosclerosis in other vascular beds such as the coronary , carotid , and cerebral arteries . the higher values for inflammatory parameters with higher cli scores might reflect a more active underlying atherosclerosis that in turn could increase their mi rate . in elderly patients , diurectics are often prescribed for the many geriatric patients who suffer from congestive heart failure , and loop diuretics were implicated as a further cli risk factor in our cohort . dehydration reduces peripheral perfusion , leading to vascular occlusion and more severe paod symptoms , reflected in a higher cli rate . antiplatelet therapy is mandatory for atherosclerosis patients , especially after endovascular treatment , but for some patients , such as those with atrial fibrillation , vitamin k antagonist ( vka ) is indicated . when vka therapy is contraindicated because of a high bleeding risk , lmwh is an alternative . this therapy was a risk factor for cli in our cohort with an or of 2.8 . one explanation is that these patients might tend to be multimorbid , with highly active underlying atherosclerosis leading to a high cli rate . this activation of platelets might explain the increase in vascular endpoints including the development of cli . furthermore , there were statistically significant differences between cohort 1 and cohort 2 concerning incidence of cad , atrial fibrillation , and comedication ( clopidogrel , angiotensin receptor blocker , and -blocker therapy ) . as clopidogrel is beneficial especially in pad patients , at least some impact on our results can not be excluded . with the graz cli score , we have developed a simple risk stratification scheme on the basis of information that can be easily acquired from the medical history , without any laboratory parameters . this score proved to be a promising tool to identify paod patients at high risk for cli and should be further evaluated in an upcoming prospective study .