Eur J Vasc Endovasc Surg (2015)
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COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease G. Hackl a b
a,*
, K. Belaj a, T. Gary a, P. Rief a, H. Deutschmann b, G. Seinost a, M. Brodmann a, F. Hafner
a
Department of Internal Medicine, Division of Angiology, Medical University Graz, Graz, Austria Department of Radiology, Division of Interventional Radiology, Medical University Graz, Graz, Austria
WHAT THIS PAPER ADDS There are very few validated scores for assessing mortality risk in peripheral arterial occlusive disease (PAOD) patients. The present study uses the COhorte de Patients ARTériopathes (COPART) Risk Score in PAOD patients suffering from intermittent claudication with regard to their mortality rate in a long-term observation study. The COPART score is a suitable tool to highlight patients with a high all-cause and cardiovascular mortality risk.
Objectives: The COhorte de Patients ARTériopathes (COPART) Risk Score is a risk score assessing the 1 year outcome of patients who received inpatient treatment because of their peripheral arterial occlusive disease (PAOD). The COPART Risk Score consists of six variables each of which is allocated a different number of points (age, history of myocardial infarction, C-reactive protein, ankleebrachial index, estimated glomerular filtration rate, medication with antiplatelet agents, statins and renineangiotensin system inhibitors). Methods: 129 consecutive claudicants were included in a prospective trial with an average follow up of 8.8 ( 0.7) years. All patients were hospitalized for their first endovascular procedure to the pelvic and/or femoropopliteal arteries. The endpoints were all cause mortality and cardiovascular (CV) death. The COPART Risk Score was calculated for the three patient cohorts (low risk: 52 patients [40.3%]; medium risk: 41 patients [31.8%]; high risk: 36 patients [27.9%]). Results: During the follow up period 23.1% (n ¼ 12) of patients in the low risk group, 34.1% (n ¼ 14) of patients in the medium risk group, and 63.9% (n ¼ 23) of patients in the high risk group died. CV death occurred in 11.5% in the low, 22.0% in the medium, and 41.7% in the high risk groups. The three groups differed significantly with regard to all cause and CV mortality (p < .0001 and p ¼ .001). Conclusions: The COPART Risk Score is a suitable instrument to predict long-term all cause and CV mortality in claudicants preceding their first peripheral intervention. Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 2 September 2014, Accepted 9 April 2015, Available online XXX Keywords: COPART Risk Score, Peripheral arterial occlusive disease, Mortality, Endovascular
INTRODUCTION Chronic peripheral arterial occlusive disease (PAOD) as a manifestation of atherosclerosis in the pelvic and leg arteries has become common enough to be regarded as a pandemic.1,2 Patients predominantly die as a consequence of atherosclerotic events of the cerebral and coronary vessels.3 There are very few validated scores assessing the mortality risk of PAOD patients.4,5 The COhorte de Patients ARTériopathes (COPART) Risk Score is a well defined and * Corresponding author. Division of Angiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail address: [email protected] (G. Hackl). 1078-5884/Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2015.04.009
simple to calculate score developed in France that assesses the mortality and CV event risk (low risk [LR], medium risk [MR], high risk [HR], very high risk [VHR]) of patients who had to receive inpatient treatment for their symptomatic PAOD during a 1 year follow up period.6 Unlike other scoring systems available for PAOD patients, during the creation of this score only patients who had to be hospitalized because of the severity of their disease were included. The COPART Risk Score consists of six variables (age, history of myocardial infarction, C-reactive protein [CRP], ankleebrachial index [ABI], estimated glomerular filtration rate [eGFR], medication with antiplatelet agents, statins, and renineangiotensin system [RAS] inhibitors), which are assigned a variable number of points.7 As claudicants have a 1 year mortality of 3%, observations over a longer period of time are of particular interest.8 Therefore the COPART Risk Score for prediction of CV events and long-term mortality in claudicants prior to their first endovascular procedure were evaluated. The decision
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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to use the score for claudicants exclusively was made because intermittent claudication is the most prominent lead symptom of the disease. Additionally, the presence of this symptom is frequently the point in time when the first contact with a vascular specialist takes place. Furthermore, it was believed it to be of interest to investigate how applicable this scoring system is in a highly selected patient cohort (Rutherford Stages 2 and 3). MATERIALS AND METHODS
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the same survey. If the patient had died or could not be reached by phone, the primary care physician was contacted. The required mortality and CV event data and current medication (antiplatelet agents, coumarins, statins, and antihypertensive drugs in particular) were collected. In a final step, data collection was completed by a review of all medical files in all public Styrian hospitals including their emergency rooms as well as divisions of pathology. The study was approved by the Institutional Review Board of the Medical University Graz, Austria (EK 23-038 ex 10/11).
Study design and patient cohort Between March 2002 and November 2004, 129 consecutive patients were included in a prospective observational study of death or a CV event (myocardial infarction, stroke, amputation). Patients presented at the outpatient clinic of the Division of Angiology, Graz with intermittent claudication (Rutherford Stages 2e3), and those who had to undergo their first endovascular procedure of the pelvic and/ or femoropopliteal arteries (including the P3 segment of the popliteal artery) were included in this study. All interventions were carried out via the common femoral artery by either antegrade or retrograde access. As intermittent claudication is not an indication for endovascular recanalization of below knee (BTK) arteries, these patients were not included in this series.9 If there was no therapy with antiplatelet agents preceding the endovascular intervention, therapy with acetylsalicylic acid (ASA) 100 mg per day was started. Patients who already received other antiplatelet agents prior to the endovascular intervention because of their known coronary artery disease (CAD) were not changed to ASA. Patients who were suffering from unstable angina pectoris or the consequences of a stroke at the time of enrollment were excluded. Furthermore, patients with malignant arterial hypertension, decompensated heart failure, life expectancy of less than a year, wound infections, and contraindications to anticoagulants and/or antiplatelet agents were also excluded. All patients gave their written informed consent after being accurately informed about the clinical trial. Data collection The baseline characteristics of the patients were assessed on the day of the endovascular intervention. All blood samples were taken on the day before the intervention. This also applied to ABI measurements. In total, four follow up visits were conducted after 1, 3, 6, and 12 months. The patients’ concomitant medication and the occurrence of CV events were noted at each study visit. Between October 2010 and May 2011 the final examination was undertaken. In the course of the final examination, the occurrence of CV events was established. For this purpose, patients were invited to an outpatient examination/survey, in which they answered questions about their PAOD symptoms, medical history, and current medication. Patients who could not attend the examination were interviewed by phone using
COPART Risk Score The COPART Risk Score was calculated using the following parameters: age 75e84 years, þ 2 points; age 85, þ 3 points; history of myocardial infarction, þ 1 point; CRP 70 mg/L, þ 2 points; ABI < 0.3, þ 2 points; ABI 0.3e0.49, þ 1.5 points; ABI 1.3, þ 2 points; eGFR, > 30e60 mL/min/ 1.73 m2, þ 1 point; eGFR 30 mL/min/1.73 m2, þ 1.5 points; medication with antiplatelet agents and statins and RAS inhibitors, e 1.5 points. Medication assessment was made at the end of the follow up period. Unlike the original COPART Risk Score with a division into four groups (LR: 0 points, MR: 0.5e2 points, HR: 2.5e4 points, VHR: 4.5 points), the present study only distinguished three groups: LR ( 0 points), MR (0.5e2 points), HR ( 2.5 points). These groupings were chosen because no therapeutic consequences of the long-term influence of the prognosis between HR and VHR patients were to be expected in clinical practice. Moreover, risk stratification in LR, MR, HR has been a reliable method for other medical conditions.10,11 The division into only three risk groups was also chosen because a VHR group would have consisted of only eight patients, and consequently a statistically relevant comparison could not have been drawn. Statistics For continuous variables, patient characteristics were described as mean ( standard deviation). Skewed data were expressed as median and interquartile range. Categorical variables were expressed as frequency and percentages. The normal distribution was examined via KolmogoroveSmirnov and ShapiroeWilk test. For parametric distribution the three groups were compared by analysis of variance (ANOVA). For non-parametric data, a KruskaleWallis test was used. A Jonckheere Terpstra test was used for the comparison of the COPART Risk Score variables among the three groups and for trend statistics. Survival analysis was assessed by KaplaneMeier curves and Log-rank statistics. Statistical significance was set at p < .05. Statistical analyses were performed using SPSS version 20.0. RESULTS 129 patients were included in the study. The majority of patients were male (n ¼ 92; 71.3%). At the time of enrollment the median age was 66 years (min. 39; max. 86), and the average body mass index (BMI) was 26.2 ( 3.2)
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
COPART Risk Score Predicts Long-term Mortality
kg/m2. The average follow up was 8.8 years ( 0.7). Patient characteristics are shown in Table 1. Procedural details are shown in Table 2. The median COPART Risk Score was 1 point. Fifty two patients (40.3%) were assigned to the LR group, 41 patients (31.8%) to the MR, and 36 patients (27.9%) to the HR group. The distribution in relation to the variables and a comparison of the variables among the three groups is shown in Table 3. CRP and medication with antiplatelet agents, statins and RAS inhibitors were not significantly different among the three groups.
Table 1. Patient characteristics. n 129 Men, n (%) 92 (71.3) Age (yrs), median 66 (60e76) (25the75th percentile) BMI kg/m2, mean 26.2 ( 3.2) ( standard derivation) Observation time years, 8.8 ( 0.7) mean ( standard derivation) Previous history, n (%) Myocardial infarction 12 (9.3) Cerebrovascular disease 9 (7) (stroke, TIA) Diabetes mellitus 40 (31) Arterial hypertension 101 (78.3) Smoking 96 (74.4) Current 52 (40.3) Ex 44 (34.1) Hypercholesterolaemia 67 (51.9) Kidney function eGFR mL/min/1.73 m2, median 64 (51e85.5) (25the75th percentile) Creatinine mg/dL, median 1.1 (1.0e1.3) (25the75th percentile) ABI, median (25the75th percentile) 0.68 (0.55e0.89) Drug therapies at discharge, n (%) Antiplatelet agents 113 (87.6) Beta blockers 36 (27.9) ACE inhibitors or ARBs 71 (55) Statins 58 (45) Hemoglobin g/dL, median 14.05 (13e15.1) (25the75th percentile) Platelets g/L, median 237 (198e272) (25the75th percentile) CRP mg/L, median 4 (3e9.5) (25the75th percentile) Lipids mg/dL, median (25the75th percentile) LDL 118 (94.5e148) HDL 47 (40e59.5) Triglycerides 141 (102e195) Lipoprotein (a) 12 (9.5e47.1) HbA1c %, median (25the75th percentile) 5.8 (5.4e6.4) BMI ¼ body mass index; TIA ¼ transient ischemic attack; eGFR ¼ estimated glomerular filtration rate; ABI ¼ ankle brachial index; ACE ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; CRP ¼ C-reactive protein; LDL ¼ low density lipoproteins; HDL ¼ high density lipoprotein; HbA1c ¼ hemoglobin A1c.
3 Table 2. Procedural details. Revascularization, n (%) PTA PTA þ stent Lesions treated, n (%) One Two Three Treated vessels, n (%) Iliac artery Common femoral artery Superficial femoral artery Popliteal artery Infrapopliteal arteries Median stenosis treated % (25the75th percentile) PTA ¼ percutaneous transluminal angioplasty.
100 (77.5) 29 (22.5) 99 (76.7) 25 (19.4) 5 (3.9) 30 0 81 18 0 85
(23.2) (0) (62.8) (14.0) (0) (80e95)
During the follow up period, 23 patients (17.8%) suffered myocardial infarction, 22 patients (17.1%) had a stroke, and 14 patients (10.9%) underwent amputation of the initially treated lower extremity. The average time to myocardial infarction was 42.3 22.3 months. The average time to stroke was 48.7 28.6 months. The three risk groups differed significantly with regards to CV events (p ¼ .035). Fig. 1 shows the comparison of CV events among the three groups. Forty nine patients (38%) died during the observation period, and 30 (23.3%) suffered CV death. There were no deaths within 30 days of the procedure. The average survival was 47.8 25.5 months. In the LR group, 23.1% (n ¼ 12) had died by the end of follow up, 11.5% due to CV disease (mean survival 96.7 4.1 months). In the MR group 34.1% (n ¼ 14) died during follow up (mean survival Table 3. Scoring model for each variable. Variable
Frequency, n (%)
p between the groups*
Age 75e84 years (þ 2 points) 37 (28.7) 0.0001 85 (þ 3 points) 2 (1.6) 0.074 History of myocardial 12 (9.3) 0.048 infarction (þ 1 point) CRP 70 mg/L (þ 2 points) 2 (1.6) 0.5 ABI < 0.3 (þ 2 points) 6 (4.7) 0.007 0.3e0.49 (þ 1.5 points) 15 (11.6) 0.003 1.3 þ (2 points) 13 (10.1) 0.008 eGFR 30e60 mL/min/1.73 m2 49 (38.0) 0.0001 (þ 1 point) 30 mL/min/1.73 m2 6 (4.7) 0.007 (þ 1.5 points) Medication with antiplatelet 24 (18.6) 0.2 agents, statins and RAS inhibitors during follow up (e 1.5 points) CRP ¼ C-reactive protein; ABI ¼ ankleebrachial index; eGFR ¼ estimated glomerular filtration rate; RAS ¼ renin angiotensin system. *p values were calculated using the JonchkheereeTerpstra test.
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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93.9 4.3 months) whereas 63.9% (n ¼ 23) of the HR group patients died (mean survival 66.9 3.1 months). 22% of MR group and 41.7% of HR group patients suffered a CV death. The three groups differed significantly with regards to both, overall mortality and CV mortality (p < .0001 and p ¼ .001). Figs. 2 and 3 show the chronological sequence for the endpoints, overall survival and CV death, between the three groups with KaplaneMeier curves. Further analyses were done omitting the non-statistically significant variables CRP and medication between the three groups. It was shown that the mortality results were not substantially influenced by omitting these parameters (overall mortality p ¼ .002; CV mortality p ¼ .006) (Supplementary Fig. S1 and S2). Supplementary Fig. S3 shows the comparison between the original and the modified (without CRP and medication) COPART Risk Score using trend statistics. Supplementary Table S1 and Supplementary Fig. S4eS6 show the re-calculated results on the basis of “medication at discharge”. The results have not changed significantly. As ABI is known to be an independent predictor of mortality in PAOD patients, further analysis was carried out and no significant difference between survivors and nonsurvivors was found (Supplementary Table S2 and Supplementary Fig. S7). DISCUSSION The present study shows that the COPART score is also suitable for the long-term prediction of death and CV events
in claudicants. The adequate recording of raised and lowered ABI as risk parameters, in particular, seems to play a significant role. Resnick et al.12 have shown that both decreased and increased ABI are important indicators for CV death. Thus, the COPART risk score does not exclusively determine the unfavorable prognosis of patients suffering from critical limb ischemia. A raised ABI indicates the presence of incompressible arteries due to medial sclerosis. This implies the poor prognosis of diabetics and renal impaired patients both of which are risk factors for medial sclerosis.13e15 A history of myocardial infarction proved to be a significantly different predictive factor among the three risk groups. This parameter is generally easy to determine and seems to be meaningful with regards to the COPART Risk Score even without further division of the previous myocardial event into ST segment elevated or non-ST elevated myocardial infarction, especially as it is known that the long-term mortality risk is largely independent of the first time manifestation of the acute coronary syndrome.16 In the present cohort, mortality was especially high in cases of myocardial infarction or stroke, as 30 out of 45 of these events were fatal. Furthermore, the parameter age differed significantly among the comparison groups and therefore like other risk scores, constitutes an essential and natural prognostic factor. Recently, numerous cellular and gene regulatory processes were identified in patients suffering from renal
Figure 1. KaplaneMeier curve for cardiovascular events between the three groups. Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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Figure 2. KaplaneMeier curve for survival between the three groups.
Figure 3. KaplaneMeier curve for survival of cardiovascular death between the three groups. Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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insufficiency which lead, via increased calcium and phosphate serum levels, to the progression and development of vascular calcification.17e21 Because of the calculation of eGFR within the COPART Risk Score, this effect is also detected in the present cohort. Chronic increases in CRP are well known in the context of atherogenesis. Atherogenesis is increasingly understood to be a slowly occurring chronic inflammatory process.22 The COPART Risk Score, however, takes a major CRP increase of > 70 mg/L into account. Thereby, the detection of inflammation in the context of PAOD in Rutherford Stages 5 and 6 needs to be considered. These stages, as is commonly known, usually have the poorest prognosis. The present cohort, however, only included patients in Rutherford Stages 2 and 3. Therefore, this parameter did not differ significantly between the three risk groups. This also applied to the combined continuous medication with antiplatelet agents, statins and RAS inhibitors, which again did not differ significantly among the three groups. This is mainly attributable to the small group sizes as a limiting factor, as numerous studies have already shown survival benefits from these medications.23,24 Full compliance with the drug combination of antiplatelet agents, statins, and RAS inhibitors could only be verified in 18.6% of patients making medication the weakest link of the COPART Risk Score. Furthermore, this parameter reflects on the enthusiasm of the primary care physician rather than the vascular specialist. Further survival analysis without taking the increase in CRP and medication into account did not change the results significantly. It could be shown that valid mortality results could still be predicted without knowledge of the medication. Because of this simplification, the score could be used more widely for mortality prediction in claudicants. Interestingly, the mortality differences between the LR and MR groups only became clear in the longer term, as at the start of the observation period the MR group had high excess mortality compared with the LR group. Similar overlaps between the curves also applied to the CV events, especially in the first half of the observation period. Overall for the present cohort, the combination of the COPART Risk Score variables is nonetheless a suitable tool for predicting CV events, all cause mortality, and CV mortality in claudicants before their first peripheral endovascular intervention despite the poor 5 year mortality prediction between the LR and MR groups. As a consequence of his study, the COPART risk score could potentially detect patients who would benefit from more intensive CV risk factor management during their follow up, for example, the aggressive reduction of lowdensity lipoprotein (LDL) to target values below 70 mg/dL. HR patients could also be potential candidates for the promising PCSK9 inhibitors in order to achieve LDL reduction.25 Supervised exercise could also achieve a further reduction of mortality, particularly in the HR group, as claudicants would be the ideal cohort for this type of therapy.26 Providing the calculated prognosis in the discharge letter after the first endovascular recanalization
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might help to minimise poor management of CV risk factors in PAOD patients by primary care physicians.27e30 Furthermore, closer control of coexistent CAD or cerebrovascular disease would help to achieve a reduction of mortality. The present study has some limitations. It is a single center study with small numbers. For testing scoring systems in particular, statistical limitations are likely. Further studies with larger numbers are needed for more general conclusions. Moreover, long-term results of the COPART Risk Score for surgically treated patients would allow comparisons between the two treatment techniques. This could potentially create an instrument that supports the decision making process with regards to revascularization strategies in relation to the prognosis, and help to assess which patients would profit from more or less invasive therapies. CONFLICT OF INTEREST None. FUNDING None. ACKNOWLEDGEMENTS We thank Anna Klambauer for proofreading and editorial assistance. APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2015.04.009 REFERENCES 1 Hirsch AT, Duval S. The global pandemic of peripheral artery disease. Lancet 2013;382(9901):1312e4. 2 Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382(9901):1329e40. 3 Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, et al. High prevalence of peripheral arterial disease and comorbidity in 6880 primary care patients: cross sectional study. Atherosclerosis 2004;172(1):95e105. 4 Feringa HH, Bax JJ, Hoeks S, van Waning VH, Elhendy A, Karagiannis S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med 2007;167(22):2482e9. 5 Schanzer A, Mega J, Meadows J, Samson RH, Bandyk DF, Conte MS. Risk stratification in critical limb ischemia: derivation and validation of a model to predict amputation free survival using multicenter surgical outcomes data. J Vasc Surg 2008;48(6):1464e71. 6 Pros N, Cambou JP, Aboyans V, Malloizel Delaunay J, Constans J, Lacroix P, et al. A hospital discharge risk score for 1year all-cause mortality or non-fatal cardiovascular events in patients with lower-extremity peripheral artery disease, with and without revascularisation. Eur J Vasc Endovasc Surg 2013;45(5):488e96.
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COPART Risk Score Predicts Long-term Mortality 7 Cambou JP, Aboyans V, Constans J, Lacroix P, Dentans C, Bura A. Characteristics and outcome of patients hospitalised for lower extremity peripheral artery disease in France: the COPART Registry. Eur J Vasc Endovasc Surg 2010;39(5):577e85. 8 Steg PG, Bhatt DL, Wilson PW, D’Agostino R, Ohman EM, Rother J, et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 2007;297(11):1197e 206. 9 Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg 2007;33:S1e 75. 10 Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83(3):416e20. 11 Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10year follow up of the prospective cardiovascular Münster (PROCAM) study. Circulation 2002;105(3):310e5. 12 Resnick HE, Lindsay RS, McDermott MM, Devereux RB, Jones KL, Fabsitz RR, et al. Relationship of high and low ankle brachial index to all-cause and cardiovascular disease mortality: the Strong Heart Study. Circulation 2004;109(6):733e9. 13 Janka HU, Standl E, Mehnert H. Peripheral vascular disease in diabetes mellitus and its relation to cardiovascular risk factors: screening with the Doppler ultrasonic technique. Diabetes Care 1980;3(2):207e13. 14 Tomson C. Vascular calcification in chronic renal failure. Nephron Clin Pract 2003;93(4):124e30. 15 Floege J, Ketteler M. Vascular calcification in patients with endstage renal disease. Nephrol Dial Transpl 2004;19(Suppl 5):59e 66. 16 Fox KA, Carruthers KF, Dunbar DR, Graham C, Manning JR, De Raedt H, et al. Underestimated and under recognized: the late consequences of acute coronary syndrome (GRACE UK-Belgian Study). Eur Heart J 2010;31(22):2755e64. 17 Cranenburg EC, Brandenburg VM, Vermeer C, Stenger M, Mühlenbruch G, Mahnken AH, et al. Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients. Thromb Haemost 2009;101(2):359e 66. 18 Floege J, Kim J, Ireland E, Chazot C, Drueke T, de Francisco A, et al. Serum iPTH, calcium and phosphate, and the risk of
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mortality in a European haemodialysis population. Nephrol Dial Transpl 2011;26(6):1948e55. Hamano T, Matsui I, Mikami S, Tomida K, Fujii N, Imai E, et al. Fetuin-mineral complex reflects extraosseous calcification stress in CKD. J Am Soc Nephrol 2010;21(11):1998e2007. Maréchal C, Coche E, Goffin E, Dragean A, Schlieper G, Nguyen P, et al. Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients. Am J Kidney Dis 2012;59(2):258e69. Noordzij M, Cranenburg EM, Engelsman LF, Hermans MM, Boeschoten EW, Brandenburg VM, et al. Progression of aortic calcification is associated with disorders of mineral metabolism and mortality in chronic dialysis patients. Nephrol Dial Transpl 2011;26(5):1662e9. Jang IK, Lassila R, Fuster V. Atherogenesis and inflammation. Eur Heart J 1993;14(Suppl K):2e6. Gargiulo G, Giugliano G, Brevetti L, Sannino A, Schiattarella GG, Serino F, et al. Use of statins in lower extremity artery disease: a review. BMC Surg 2012;12(Suppl 1):S15. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342(3):145e53. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014;11(10):563e75. Fokkenrood HJ, Bendermacher BL, Lauret GJ, Willigendael EM, Prins MH, Teijink JA. Supervised exercise therapy versus nonsupervised exercise therapy for intermittent claudication. Cochrane Database Syst Rev 2013;8:CD005263. D’Souza J, Patel NN, Rocker M, Townsend E, Morris-Stiff G, Magee TR, et al. Management of cardiovascular risk factors by primary care physicians in patients with peripheral arterial disease. Surgeon 2008;6(3):144e7. Ardati AK, Kaufman SR, Aronow HD, Nypaver TJ, Bove PG, Gurm HS, et al. The quality and impact of risk factor control in patients with stable claudication presenting for peripheral vascular interventions. Circ Cardiovasc Interv 2012;5(6):850e5. Rice TW, Lumsden AB. Optimal medical management of peripheral arterial disease. Vasc Endovascular Surg 2006;40(4): 312e27. Watson K, Watson BD, Pater KS. Peripheral arterial disease: a review of disease awareness and management. Am J Geriatr Pharmacother 2006;4(4):365e79.
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease G. Hackl a b
a,*
, K. Belaj a, T. Gary a, P. Rief a, H. Deutschmann b, G. Seinost a, M. Brodmann a, F. Hafner
a
Department of Internal Medicine, Division of Angiology, Medical University Graz, Graz, Austria Department of Radiology, Division of Interventional Radiology, Medical University Graz, Graz, Austria
WHAT THIS PAPER ADDS There are very few validated scores for assessing mortality risk in peripheral arterial occlusive disease (PAOD) patients. The present study uses the COhorte de Patients ARTériopathes (COPART) Risk Score in PAOD patients suffering from intermittent claudication with regard to their mortality rate in a long-term observation study. The COPART score is a suitable tool to highlight patients with a high all-cause and cardiovascular mortality risk.
Objectives: The COhorte de Patients ARTériopathes (COPART) Risk Score is a risk score assessing the 1 year outcome of patients who received inpatient treatment because of their peripheral arterial occlusive disease (PAOD). The COPART Risk Score consists of six variables each of which is allocated a different number of points (age, history of myocardial infarction, C-reactive protein, ankleebrachial index, estimated glomerular filtration rate, medication with antiplatelet agents, statins and renineangiotensin system inhibitors). Methods: 129 consecutive claudicants were included in a prospective trial with an average follow up of 8.8 ( 0.7) years. All patients were hospitalized for their first endovascular procedure to the pelvic and/or femoropopliteal arteries. The endpoints were all cause mortality and cardiovascular (CV) death. The COPART Risk Score was calculated for the three patient cohorts (low risk: 52 patients [40.3%]; medium risk: 41 patients [31.8%]; high risk: 36 patients [27.9%]). Results: During the follow up period 23.1% (n ¼ 12) of patients in the low risk group, 34.1% (n ¼ 14) of patients in the medium risk group, and 63.9% (n ¼ 23) of patients in the high risk group died. CV death occurred in 11.5% in the low, 22.0% in the medium, and 41.7% in the high risk groups. The three groups differed significantly with regard to all cause and CV mortality (p < .0001 and p ¼ .001). Conclusions: The COPART Risk Score is a suitable instrument to predict long-term all cause and CV mortality in claudicants preceding their first peripheral intervention. Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 2 September 2014, Accepted 9 April 2015, Available online XXX Keywords: COPART Risk Score, Peripheral arterial occlusive disease, Mortality, Endovascular
INTRODUCTION Chronic peripheral arterial occlusive disease (PAOD) as a manifestation of atherosclerosis in the pelvic and leg arteries has become common enough to be regarded as a pandemic.1,2 Patients predominantly die as a consequence of atherosclerotic events of the cerebral and coronary vessels.3 There are very few validated scores assessing the mortality risk of PAOD patients.4,5 The COhorte de Patients ARTériopathes (COPART) Risk Score is a well defined and * Corresponding author. Division of Angiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria. E-mail address: [email protected] (G. Hackl). 1078-5884/Ó 2015 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2015.04.009
simple to calculate score developed in France that assesses the mortality and CV event risk (low risk [LR], medium risk [MR], high risk [HR], very high risk [VHR]) of patients who had to receive inpatient treatment for their symptomatic PAOD during a 1 year follow up period.6 Unlike other scoring systems available for PAOD patients, during the creation of this score only patients who had to be hospitalized because of the severity of their disease were included. The COPART Risk Score consists of six variables (age, history of myocardial infarction, C-reactive protein [CRP], ankleebrachial index [ABI], estimated glomerular filtration rate [eGFR], medication with antiplatelet agents, statins, and renineangiotensin system [RAS] inhibitors), which are assigned a variable number of points.7 As claudicants have a 1 year mortality of 3%, observations over a longer period of time are of particular interest.8 Therefore the COPART Risk Score for prediction of CV events and long-term mortality in claudicants prior to their first endovascular procedure were evaluated. The decision
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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to use the score for claudicants exclusively was made because intermittent claudication is the most prominent lead symptom of the disease. Additionally, the presence of this symptom is frequently the point in time when the first contact with a vascular specialist takes place. Furthermore, it was believed it to be of interest to investigate how applicable this scoring system is in a highly selected patient cohort (Rutherford Stages 2 and 3). MATERIALS AND METHODS
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the same survey. If the patient had died or could not be reached by phone, the primary care physician was contacted. The required mortality and CV event data and current medication (antiplatelet agents, coumarins, statins, and antihypertensive drugs in particular) were collected. In a final step, data collection was completed by a review of all medical files in all public Styrian hospitals including their emergency rooms as well as divisions of pathology. The study was approved by the Institutional Review Board of the Medical University Graz, Austria (EK 23-038 ex 10/11).
Study design and patient cohort Between March 2002 and November 2004, 129 consecutive patients were included in a prospective observational study of death or a CV event (myocardial infarction, stroke, amputation). Patients presented at the outpatient clinic of the Division of Angiology, Graz with intermittent claudication (Rutherford Stages 2e3), and those who had to undergo their first endovascular procedure of the pelvic and/ or femoropopliteal arteries (including the P3 segment of the popliteal artery) were included in this study. All interventions were carried out via the common femoral artery by either antegrade or retrograde access. As intermittent claudication is not an indication for endovascular recanalization of below knee (BTK) arteries, these patients were not included in this series.9 If there was no therapy with antiplatelet agents preceding the endovascular intervention, therapy with acetylsalicylic acid (ASA) 100 mg per day was started. Patients who already received other antiplatelet agents prior to the endovascular intervention because of their known coronary artery disease (CAD) were not changed to ASA. Patients who were suffering from unstable angina pectoris or the consequences of a stroke at the time of enrollment were excluded. Furthermore, patients with malignant arterial hypertension, decompensated heart failure, life expectancy of less than a year, wound infections, and contraindications to anticoagulants and/or antiplatelet agents were also excluded. All patients gave their written informed consent after being accurately informed about the clinical trial. Data collection The baseline characteristics of the patients were assessed on the day of the endovascular intervention. All blood samples were taken on the day before the intervention. This also applied to ABI measurements. In total, four follow up visits were conducted after 1, 3, 6, and 12 months. The patients’ concomitant medication and the occurrence of CV events were noted at each study visit. Between October 2010 and May 2011 the final examination was undertaken. In the course of the final examination, the occurrence of CV events was established. For this purpose, patients were invited to an outpatient examination/survey, in which they answered questions about their PAOD symptoms, medical history, and current medication. Patients who could not attend the examination were interviewed by phone using
COPART Risk Score The COPART Risk Score was calculated using the following parameters: age 75e84 years, þ 2 points; age 85, þ 3 points; history of myocardial infarction, þ 1 point; CRP 70 mg/L, þ 2 points; ABI < 0.3, þ 2 points; ABI 0.3e0.49, þ 1.5 points; ABI 1.3, þ 2 points; eGFR, > 30e60 mL/min/ 1.73 m2, þ 1 point; eGFR 30 mL/min/1.73 m2, þ 1.5 points; medication with antiplatelet agents and statins and RAS inhibitors, e 1.5 points. Medication assessment was made at the end of the follow up period. Unlike the original COPART Risk Score with a division into four groups (LR: 0 points, MR: 0.5e2 points, HR: 2.5e4 points, VHR: 4.5 points), the present study only distinguished three groups: LR ( 0 points), MR (0.5e2 points), HR ( 2.5 points). These groupings were chosen because no therapeutic consequences of the long-term influence of the prognosis between HR and VHR patients were to be expected in clinical practice. Moreover, risk stratification in LR, MR, HR has been a reliable method for other medical conditions.10,11 The division into only three risk groups was also chosen because a VHR group would have consisted of only eight patients, and consequently a statistically relevant comparison could not have been drawn. Statistics For continuous variables, patient characteristics were described as mean ( standard deviation). Skewed data were expressed as median and interquartile range. Categorical variables were expressed as frequency and percentages. The normal distribution was examined via KolmogoroveSmirnov and ShapiroeWilk test. For parametric distribution the three groups were compared by analysis of variance (ANOVA). For non-parametric data, a KruskaleWallis test was used. A Jonckheere Terpstra test was used for the comparison of the COPART Risk Score variables among the three groups and for trend statistics. Survival analysis was assessed by KaplaneMeier curves and Log-rank statistics. Statistical significance was set at p < .05. Statistical analyses were performed using SPSS version 20.0. RESULTS 129 patients were included in the study. The majority of patients were male (n ¼ 92; 71.3%). At the time of enrollment the median age was 66 years (min. 39; max. 86), and the average body mass index (BMI) was 26.2 ( 3.2)
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
COPART Risk Score Predicts Long-term Mortality
kg/m2. The average follow up was 8.8 years ( 0.7). Patient characteristics are shown in Table 1. Procedural details are shown in Table 2. The median COPART Risk Score was 1 point. Fifty two patients (40.3%) were assigned to the LR group, 41 patients (31.8%) to the MR, and 36 patients (27.9%) to the HR group. The distribution in relation to the variables and a comparison of the variables among the three groups is shown in Table 3. CRP and medication with antiplatelet agents, statins and RAS inhibitors were not significantly different among the three groups.
Table 1. Patient characteristics. n 129 Men, n (%) 92 (71.3) Age (yrs), median 66 (60e76) (25the75th percentile) BMI kg/m2, mean 26.2 ( 3.2) ( standard derivation) Observation time years, 8.8 ( 0.7) mean ( standard derivation) Previous history, n (%) Myocardial infarction 12 (9.3) Cerebrovascular disease 9 (7) (stroke, TIA) Diabetes mellitus 40 (31) Arterial hypertension 101 (78.3) Smoking 96 (74.4) Current 52 (40.3) Ex 44 (34.1) Hypercholesterolaemia 67 (51.9) Kidney function eGFR mL/min/1.73 m2, median 64 (51e85.5) (25the75th percentile) Creatinine mg/dL, median 1.1 (1.0e1.3) (25the75th percentile) ABI, median (25the75th percentile) 0.68 (0.55e0.89) Drug therapies at discharge, n (%) Antiplatelet agents 113 (87.6) Beta blockers 36 (27.9) ACE inhibitors or ARBs 71 (55) Statins 58 (45) Hemoglobin g/dL, median 14.05 (13e15.1) (25the75th percentile) Platelets g/L, median 237 (198e272) (25the75th percentile) CRP mg/L, median 4 (3e9.5) (25the75th percentile) Lipids mg/dL, median (25the75th percentile) LDL 118 (94.5e148) HDL 47 (40e59.5) Triglycerides 141 (102e195) Lipoprotein (a) 12 (9.5e47.1) HbA1c %, median (25the75th percentile) 5.8 (5.4e6.4) BMI ¼ body mass index; TIA ¼ transient ischemic attack; eGFR ¼ estimated glomerular filtration rate; ABI ¼ ankle brachial index; ACE ¼ angiotensin converting enzyme inhibitors; ARB ¼ angiotensin receptor blockers; CRP ¼ C-reactive protein; LDL ¼ low density lipoproteins; HDL ¼ high density lipoprotein; HbA1c ¼ hemoglobin A1c.
3 Table 2. Procedural details. Revascularization, n (%) PTA PTA þ stent Lesions treated, n (%) One Two Three Treated vessels, n (%) Iliac artery Common femoral artery Superficial femoral artery Popliteal artery Infrapopliteal arteries Median stenosis treated % (25the75th percentile) PTA ¼ percutaneous transluminal angioplasty.
100 (77.5) 29 (22.5) 99 (76.7) 25 (19.4) 5 (3.9) 30 0 81 18 0 85
(23.2) (0) (62.8) (14.0) (0) (80e95)
During the follow up period, 23 patients (17.8%) suffered myocardial infarction, 22 patients (17.1%) had a stroke, and 14 patients (10.9%) underwent amputation of the initially treated lower extremity. The average time to myocardial infarction was 42.3 22.3 months. The average time to stroke was 48.7 28.6 months. The three risk groups differed significantly with regards to CV events (p ¼ .035). Fig. 1 shows the comparison of CV events among the three groups. Forty nine patients (38%) died during the observation period, and 30 (23.3%) suffered CV death. There were no deaths within 30 days of the procedure. The average survival was 47.8 25.5 months. In the LR group, 23.1% (n ¼ 12) had died by the end of follow up, 11.5% due to CV disease (mean survival 96.7 4.1 months). In the MR group 34.1% (n ¼ 14) died during follow up (mean survival Table 3. Scoring model for each variable. Variable
Frequency, n (%)
p between the groups*
Age 75e84 years (þ 2 points) 37 (28.7) 0.0001 85 (þ 3 points) 2 (1.6) 0.074 History of myocardial 12 (9.3) 0.048 infarction (þ 1 point) CRP 70 mg/L (þ 2 points) 2 (1.6) 0.5 ABI < 0.3 (þ 2 points) 6 (4.7) 0.007 0.3e0.49 (þ 1.5 points) 15 (11.6) 0.003 1.3 þ (2 points) 13 (10.1) 0.008 eGFR 30e60 mL/min/1.73 m2 49 (38.0) 0.0001 (þ 1 point) 30 mL/min/1.73 m2 6 (4.7) 0.007 (þ 1.5 points) Medication with antiplatelet 24 (18.6) 0.2 agents, statins and RAS inhibitors during follow up (e 1.5 points) CRP ¼ C-reactive protein; ABI ¼ ankleebrachial index; eGFR ¼ estimated glomerular filtration rate; RAS ¼ renin angiotensin system. *p values were calculated using the JonchkheereeTerpstra test.
Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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93.9 4.3 months) whereas 63.9% (n ¼ 23) of the HR group patients died (mean survival 66.9 3.1 months). 22% of MR group and 41.7% of HR group patients suffered a CV death. The three groups differed significantly with regards to both, overall mortality and CV mortality (p < .0001 and p ¼ .001). Figs. 2 and 3 show the chronological sequence for the endpoints, overall survival and CV death, between the three groups with KaplaneMeier curves. Further analyses were done omitting the non-statistically significant variables CRP and medication between the three groups. It was shown that the mortality results were not substantially influenced by omitting these parameters (overall mortality p ¼ .002; CV mortality p ¼ .006) (Supplementary Fig. S1 and S2). Supplementary Fig. S3 shows the comparison between the original and the modified (without CRP and medication) COPART Risk Score using trend statistics. Supplementary Table S1 and Supplementary Fig. S4eS6 show the re-calculated results on the basis of “medication at discharge”. The results have not changed significantly. As ABI is known to be an independent predictor of mortality in PAOD patients, further analysis was carried out and no significant difference between survivors and nonsurvivors was found (Supplementary Table S2 and Supplementary Fig. S7). DISCUSSION The present study shows that the COPART score is also suitable for the long-term prediction of death and CV events
in claudicants. The adequate recording of raised and lowered ABI as risk parameters, in particular, seems to play a significant role. Resnick et al.12 have shown that both decreased and increased ABI are important indicators for CV death. Thus, the COPART risk score does not exclusively determine the unfavorable prognosis of patients suffering from critical limb ischemia. A raised ABI indicates the presence of incompressible arteries due to medial sclerosis. This implies the poor prognosis of diabetics and renal impaired patients both of which are risk factors for medial sclerosis.13e15 A history of myocardial infarction proved to be a significantly different predictive factor among the three risk groups. This parameter is generally easy to determine and seems to be meaningful with regards to the COPART Risk Score even without further division of the previous myocardial event into ST segment elevated or non-ST elevated myocardial infarction, especially as it is known that the long-term mortality risk is largely independent of the first time manifestation of the acute coronary syndrome.16 In the present cohort, mortality was especially high in cases of myocardial infarction or stroke, as 30 out of 45 of these events were fatal. Furthermore, the parameter age differed significantly among the comparison groups and therefore like other risk scores, constitutes an essential and natural prognostic factor. Recently, numerous cellular and gene regulatory processes were identified in patients suffering from renal
Figure 1. KaplaneMeier curve for cardiovascular events between the three groups. Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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Figure 2. KaplaneMeier curve for survival between the three groups.
Figure 3. KaplaneMeier curve for survival of cardiovascular death between the three groups. Please cite this article in press as: Hackl G, et al., COPART Risk Score Predicts Long-term Mortality in Peripheral Arterial Occlusive Disease, European Journal of Vascular and Endovascular Surgery (2015), http://dx.doi.org/10.1016/j.ejvs.2015.04.009
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insufficiency which lead, via increased calcium and phosphate serum levels, to the progression and development of vascular calcification.17e21 Because of the calculation of eGFR within the COPART Risk Score, this effect is also detected in the present cohort. Chronic increases in CRP are well known in the context of atherogenesis. Atherogenesis is increasingly understood to be a slowly occurring chronic inflammatory process.22 The COPART Risk Score, however, takes a major CRP increase of > 70 mg/L into account. Thereby, the detection of inflammation in the context of PAOD in Rutherford Stages 5 and 6 needs to be considered. These stages, as is commonly known, usually have the poorest prognosis. The present cohort, however, only included patients in Rutherford Stages 2 and 3. Therefore, this parameter did not differ significantly between the three risk groups. This also applied to the combined continuous medication with antiplatelet agents, statins and RAS inhibitors, which again did not differ significantly among the three groups. This is mainly attributable to the small group sizes as a limiting factor, as numerous studies have already shown survival benefits from these medications.23,24 Full compliance with the drug combination of antiplatelet agents, statins, and RAS inhibitors could only be verified in 18.6% of patients making medication the weakest link of the COPART Risk Score. Furthermore, this parameter reflects on the enthusiasm of the primary care physician rather than the vascular specialist. Further survival analysis without taking the increase in CRP and medication into account did not change the results significantly. It could be shown that valid mortality results could still be predicted without knowledge of the medication. Because of this simplification, the score could be used more widely for mortality prediction in claudicants. Interestingly, the mortality differences between the LR and MR groups only became clear in the longer term, as at the start of the observation period the MR group had high excess mortality compared with the LR group. Similar overlaps between the curves also applied to the CV events, especially in the first half of the observation period. Overall for the present cohort, the combination of the COPART Risk Score variables is nonetheless a suitable tool for predicting CV events, all cause mortality, and CV mortality in claudicants before their first peripheral endovascular intervention despite the poor 5 year mortality prediction between the LR and MR groups. As a consequence of his study, the COPART risk score could potentially detect patients who would benefit from more intensive CV risk factor management during their follow up, for example, the aggressive reduction of lowdensity lipoprotein (LDL) to target values below 70 mg/dL. HR patients could also be potential candidates for the promising PCSK9 inhibitors in order to achieve LDL reduction.25 Supervised exercise could also achieve a further reduction of mortality, particularly in the HR group, as claudicants would be the ideal cohort for this type of therapy.26 Providing the calculated prognosis in the discharge letter after the first endovascular recanalization
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might help to minimise poor management of CV risk factors in PAOD patients by primary care physicians.27e30 Furthermore, closer control of coexistent CAD or cerebrovascular disease would help to achieve a reduction of mortality. The present study has some limitations. It is a single center study with small numbers. For testing scoring systems in particular, statistical limitations are likely. Further studies with larger numbers are needed for more general conclusions. Moreover, long-term results of the COPART Risk Score for surgically treated patients would allow comparisons between the two treatment techniques. This could potentially create an instrument that supports the decision making process with regards to revascularization strategies in relation to the prognosis, and help to assess which patients would profit from more or less invasive therapies. CONFLICT OF INTEREST None. FUNDING None. ACKNOWLEDGEMENTS We thank Anna Klambauer for proofreading and editorial assistance. APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2015.04.009 REFERENCES 1 Hirsch AT, Duval S. The global pandemic of peripheral artery disease. Lancet 2013;382(9901):1312e4. 2 Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013;382(9901):1329e40. 3 Diehm C, Schuster A, Allenberg JR, Darius H, Haberl R, Lange S, et al. High prevalence of peripheral arterial disease and comorbidity in 6880 primary care patients: cross sectional study. Atherosclerosis 2004;172(1):95e105. 4 Feringa HH, Bax JJ, Hoeks S, van Waning VH, Elhendy A, Karagiannis S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med 2007;167(22):2482e9. 5 Schanzer A, Mega J, Meadows J, Samson RH, Bandyk DF, Conte MS. Risk stratification in critical limb ischemia: derivation and validation of a model to predict amputation free survival using multicenter surgical outcomes data. J Vasc Surg 2008;48(6):1464e71. 6 Pros N, Cambou JP, Aboyans V, Malloizel Delaunay J, Constans J, Lacroix P, et al. A hospital discharge risk score for 1year all-cause mortality or non-fatal cardiovascular events in patients with lower-extremity peripheral artery disease, with and without revascularisation. Eur J Vasc Endovasc Surg 2013;45(5):488e96.
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