Insufficient modification of atherosclerosis risk factors in PAD patients

Results. In the 77% of PAD patients diagnosed with dyslipidemia, 72% had hypertension and 31% had diabetes. Suboptimal treatment was being given to 85.5% of patients with dyslipidemia, to 26% of patients with hypertension and to 95% of diabetics. In this study, a diagnosis of dyslipidemia, hypertension and diabetes was made for the 1st time in 22%, 7% and 4% of patients, respectively. As many as 17.5% of PAD patients with claudication were not receiving any antiplatelet therapy.


Introduction
The guidelines on the Diagnosis and Treatment of Peripheral Artery Disease, established by the European Society of Cardiology (ESC) and applicable in Poland, determine and facilitate the treatment of atherosclerosis that occurs in different vascular beds. 1 The guidelines should help angiologists make proper decisions in their daily practice.However, due to a lack of cohort studies, the very general nature of the recommendations and the conservative character of the guidelines, the final decisions concerning individual patients must be made by the responsible physician.In peripheral artery disease (PAD) patients, a multidisciplinary approach is recommended in order to establish a management strategy (class of recommendation: I, level of evidence: C).The most effective strategy for PAD treatment, according to the ESC guidelines, is the aggressive reduction of atherosclerosis risk factors, which include atherogenic dyslipidemia, hypertension, diabetes, obesity, and smoking.
Apart from lifestyle modifications, such as regular exercise, a Mediterranean diet and cessation of smoking, patient care should include pharmacological treatment to control blood pressure (treatment with angiotensin-converting enzyme [ACE] inhibitors and beta-blockers have shown beneficial effects), an appropriate lipid-lowering statin therapy, and glycaemia treatment in diabetic patients. 1All PAD patients should receive antiplatelet therapy. 1 The aim of this study was to determine the adherence to the current recommendations regarding the reduction of atherosclerosis risk factors in patients with PAD in Poland.

Material and methods
From a group of 219 subjects with atherosclerosis of the lower extremities who were examined in the angiology outpatient unit over a 2-year period (2011-2013), 126 subjects fulfilled the criteria for participation in physical exercise training and were enrolled in the study.
Recruitment into the rehabilitation program was limited to patients with stable claudication without any limitations or contraindications for physical exercise.The inclusion and exclusion criteria for participation in physical training are listed in Table 1.

Risk factor profile
The profile of risk factors and treatment were determined during admission to the angiology outpatient unit based on a self-reported medical history.Measurement of blood pressure and laboratory tests were also performed during the visit.
In the study, references to current treatment guidelines for dyslipidemia, hypertension and diabetes reflected the ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Disease, 2011. 1 Dyslipidemia was defined in accordance with the Third Report of the Adult Treatment Panel (ATP III) of the National Cholesterol Education Program guidelines as a high concentration of total cholesterol, low-density lipoprotein (LDL) cholesterol ≥100 mg/dL, triglycerides ≥150 mg/dL, and/or a low high-density lipoprotein (HDL) cholesterol level of <40 mg/dL for men and <50 mg/dL for women. 3ptimal treatment of previously recognized dyslipidemia was defined as an LDL cholesterol level of ≤100 mg/dL (in asymptomatic PAD patients), or ideally, a level of ≤70 mg/dL (in symptomatic patients -that is, with intermittent claudication [IC]), and all cholesterol and triglyceride counts within normal ranges.
Arterial hypertension was outlined by the 8 th Joint National Committee guidelines and defined as an systolic blood pressure/diastolic blood pressure (SBP/DBP) of ≥140/90 mm Hg in patients aged <60 years and ≥150/90 mm Hg in patients aged ≥60 years, with or without antihypertensive treatment. 4ptimal treatment in patients with previously diagnosed arterial hypertension was defined as an SBP/ DBP of ≤140/90 mm Hg in patients aged ≤60 years and of ≤150/90 mm Hg in patients aged ≥60 years.
A glycated hemoglobin (HbA 1c ) level of ≥7% indicated suboptimal glycemic control in diabetics.Newly diagnosed diabetes was defined as a fasting glucose concentration of ≥126 mg/dL accompanied by symptoms of uncontrolled diabetes.Impaired fasting glucose (defined as prediabetes) was established as a fasting glucose level between 110 mg/dL and 125 mg/dL. 5outine laboratory tests were performed on peripheral blood collected in the morning after an 8-h fast.Laboratory tests included a complete blood count with a differential and biochemical profile, including blood urea, creatinine, C reactive protein (CRP), fibrinogen, a lipid panel with total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides, as well as sodium, potassium and glucose levels.This was performed using standard laboratory techniques carried out in the angiology unit (Table 2).
The patients' profile of atherosclerosis risk factors allowed for the division of the subjects into 3 groups: 1. Patients with previously diagnosed risk factors, treated optimally according to applicable standards; 2. Patients with previously diagnosed risk factors whose treatment was not optimal (the therapeutic objectives were not achieved); 3. Patients in whom atherosclerosis risk factors had not previously been diagnosed.

Statistical analysis
Normality was tested using the D'Agostino-Pearson test.Comparison between quantitative variables was performed using the Mann-Whitney U test (for 2 variables) and the Kruskall-Wallis test (for more than 2 variables).Analysis of the relationships between qualitative variables was performed using the c 2 test.Statistical analysis was performed using R for Windows (v.3.1.2).All results with p < 0.05 were considered significant.The demographic and clinical characteristics of the study group were reported as median and interquartile ranges or as counts and percentages, as appropriate.

Ethical approval
Ethical approval was obtained from the local bioethics committee (Bioethics Committee, Wroclaw Medical University, Poland, No. 130/2008 KB).All the patients were provided with written information on the purpose and design of the study.

Results
The main clinical and biochemical data of the examined group are summarized in Table 3.

Dyslipidemia
A history of dyslipidemia was reported in 97 subjects (77%), with a mean level of total cholesterol amounting to 167 ±36 mg/dL, mean LDL cholesterol of 92 ±30 mg/dL, mean HDL cholesterol of 46.5 ±11 mg/dL, and a mean level of triglycerides of 141 ±80 mg/dL.Optimal therapy was observed in 14 subjects (14.4% of the 97 patients) with a mean level of total cholesterol amounting to 122 ±17 mg/dL, mean LDL cholesterol of 53 ±9 mg/dL, mean HDL cholesterol level of 49 ±11 mg/dL, and triglycerides of 97 ±34 mg/dL.Suboptimal therapy was observed in 83 subjects (85.5% of the 97 patients) with a mean level of total cholesterol amounting to 174 ±33 mg/dL, mean LDL cholesterol of 98 ±27 mg/dL, mean HDL cholesterol of 46 ±11 mg/dL, and triglycerides of 148 ±83 mg/dL.Undiagnosed cases of dyslipidemia were found in 28 subjects (22% of the total sample of 126 patients).These were new cases of dyslipidemia with mean levels of total cholesterol amounting to 202 ±42 mg/dL, mean LDL cholesterol of 123 ±32 mg/dL, mean HDL cholesterol of 45 ±8 mg/dL, and triglycerides of 154 ±84 mg/dL.Patients that had not been diagnosed before participating in the study had significantly higher total cholesterol levels than the group undergoing treatment (p = 0.0003) and significantly higher LDL cholesterol levels (p = 0.0001).HDL cholesterol levels and triglycerides were higher in the untreated group, but not significantly.An absence of dyslipidemia was observed in only 1 case, with a total cholesterol amounting to 116 mg/dL, LDL cholesterol level of 70 mg/dL, HDL cholesterol of 33 mg/dL, and triglyceride level of 65 mg/dL.
In subjects with previously diagnosed dyslipidemia, the most commonly prescribed medications were statins (88 subjects -91%), while 5 subjects (5%) were taking 2 cholesterollowering agents (statin + fibrate) and 4 subjects (4%) were on fibrate therapy.Two main types of statins were being administered: 76% of patients (n = 67) received atorvastatin and 20% (n = 17) were given simvastatin.The patients considered to be receiving optimal treatment had significantly lower total cholesterol levels (p = 0.0001), LDL cholesterol levels (p = 0.0001) and triglycerides (p = 0.022).HDL cholesterol levels did not vary significantly, but were higher in the group treated optimally.

Hypertension
Arterial hypertension was diagnosed in 91 subjects prior to the study, representing 72% of the study sample; in this group of patients, the mean SBP was 134 ±16 mm Hg and DBP was 77 ±8 mm Hg.
Management of hypertension was suboptimal in 24 subjects (26% of subjects with hypertension).In this group, the mean SBP was 156 ±9 mm Hg and DBP was 80 ±7 mm Hg.
The optimal treatment was prescribed in 67 patients (74% of subjects with hypertension) with a mean SBP amounting to 127 ±10 mm Hg and DBP of 76 ±8 mm Hg.
Hypertension was unrecognized in 7% (n = 9) of the sample with a mean SBP of 150 ±8 mm Hg and DBP of 88 ±5 mm Hg.All 3 groups of patients (those treated optimally, treated suboptimally and undiagnosed) differed significantly in terms of both SBP (p = 0.0005) and DBP (p = 0.0001).An absence of hypertension was observed in 26 patients (20.63%).
In patients with previously diagnosed hypertension, 20% (n = 18) were receiving monotherapy, while 21% (n = 19) were receiving dual hypertensive therapy.Triple therapy had been prescribed in 30% of subjects (n = 27), representing the most common regimen.A combination of 4 medicines was prescribed to 21% of patients (n = 19).Five medicines had been prescribed less frequently (6%; n = 6), though 2 patients (2%) were taking 6 medicines.There were no significant differences in SBP or DBP relative to the number of antihypertensive medications used; nevertheless, the lowest pressure was observed in patients treated with 3 medications.
The most frequently administered drug combination, which was given to 14 patients (15%), consisted of perindopril and Indapen ® SR.

Diabetes
A history of diabetes was reported in 39 patients (31%).The mean fasting blood glucose level was 147 ±36 mg/dL, and the mean HbA 1c level was 10 ±0.5%.
Suboptimal glycemic control was found in 37 cases (95%), in which the mean fasting blood glucose level was 152 ±4 mg/dL.In 2 patients (5%) who exhibited optimal glucose control, the mean fasting blood glucose was 85.5 ±0.7 mg/dL.
During the study, prediabetes (impaired fasting glucose) was diagnosed for the 1 st time in 14 subjects (11%); the mean fasting glucose level in this group was 116 ±5 mg/dL.Newly diagnosed cases of diabetes affected 5 patients (4%).The mean fasting glucose level in this group was 181 ±40 mg/dL.
Normal glucose control was found in 68 patients (54%) with fasting blood glucose levels of 91 ±7 mg/dL.All 3 groups of patients (those with diagnosed diabetes, those with existing but previously undiagnosed diabetes, and healthy individuals without diabetes) differed significantly in terms of fasting glucose levels (p = 0.0001).
Out of the 39 subjects who had diabetes, 29 were taking oral hypoglycemic medications, 3 subjects were being treated with insulin therapy and 7 subjects received both insulin and oral hypoglycemic therapy.In the group of patients who were administered oral medicines, 16 received monotherapy (a mean fasting glucose level of 125 ±37 mg/dL), 11 patients received double therapy (a mean fasting glucose level of 152 ±21 mg/dL) and 2 patients were administered triple therapy (with a mean fasting glucose level of 152.5 ±37 mg/dL).The most frequently prescribed oral hypoglycemic medicine was metformin.Patients who were treated with insulin had a mean fasting glucose level of 144.6 ±5 mg/dL.
Diabetes, hypertension and dyslipidemia were observed in 28 subjects concomitantly (22.2% of the entire study population).Diabetes plus hypertension was observed in 6 subjects (5% of the entire study population).Diabetes plus dyslipidemia (without hypertension) was observed in 2 cases (1.6%).Only 3 subjects who were diagnosed with diabetes did not have either hypertension or dyslipidemia.

Anticoagulation/antiplatelet therapy
Antiplatelet therapy was being used by 104 subjects (82.5% of the 126 patients), the most common being monotherapy.Aspirin monotherapy was being taken by 74 subjects (59%), followed by clopidogrel (1.6%, n = 2) and ticlopidine (1.6%, n = 2).Dual therapy was administered to 19 patients (15%).The most common therapies were the concomitant treatment of aspirin with clopidogrel (17 patients, 13.5%) and aspirin with ticlopidine (2 patients, 1.6%).The prescription of dual therapy was not the result of previous invasive interventional cardiology, but was due to atherosclerosis of the lower limbs.One subject (0.8%) was administered triple therapy: aspirin, clopidogrel and acenokumarol.Anticoagulation therapy was being given to 3 patients only (4%).Twenty-two individuals (17.5%) were not currently receiving anticoagulant or antiplatelet therapy.

Other medicines taken for peripheral artery disease
Thirty-five subjects from the entire study population (28%) were taking pentoxifylline, the average dose being 1200 mg per day (600-1800 mg).Sulodexide was taken by 13 patients (10.3%) with an average dose of 500 mg per day.Bencyclane was taken by 15 patients (12%); the average dose was 400 mg per day.

Smokers
In the entire study group, 49 patients (39%) were current or ex-smokers, and 32 patients (25%) were current smokers.None of them had previously received any pharmacological tobacco cessation therapy, according to their self-declared medical history.The patients smoked 20 cigarettes a day on average.Ex-smokers accounted for 14% (n = 17) of the study population.

Physical activity
None of the patients in the study group were participating in any regular, long-lasting physical activity.

Discussion
The main finding of this study is that in the group of PAD claudicants admitted to an angiology outpatient unit, the atherosclerosis risk factors had been underestimated and when diagnosed, they were treated incorrectly.The current study revealed that 77% of PAD patients were diagnosed with dyslipidemia, 72% had hypertension and 31% had diabetes.Suboptimal treatment was received by 85.5% of patients with dyslipidemia, 26% of patients with hypertension and 95% of diabetics.In this study, dyslipidemia, hypertension and diabetes were diagnosed for the 1 st time in 22%, 7% and 4% of the subjects, respectively.A total of 17.5% of PAD patients with claudication were not receiving any antiplatelet therapy.

Lipid-lowering therapy
The ESC guidelines require an active search for atherogenic dyslipidemia in symptomatic PAD patients and, following diagnosis, aggressive lipid-lowering therapy.All patients with PAD should have their serum LDL cholesterol reduced to <100 mg/dL, or to <70 mg/dL, ideally; when the target level cannot be reached, the physician should consider lowering the LDL cholesterol by 50% or more of the level before treatment, according to the guidelines (class of recommendation: I, level of evidence: C).][8] The data revealed that 77% of PAD patients were dyslipidemic before the study began, and that a further 22% of subjects were not diagnosed with dyslipidemia beforehand.Nonetheless, when dyslipidemia was diagnosed, only 14.4% of the affected subjects achieved the goals of ESC treatment for LDL levels.These results could be the consequence of not following the guidelines or they may suggest a lack of awareness on the part of physicians and patients, who did not test for dyslipidemia.The 2 main types of statins administered were atorvastatin in 76% of patients (n = 67) and simvastatin in 20% of patients (n = 17).

Antihypertensive drugs
All patients with PAD, according to the ESC guidelines, should have their blood pressure reduced to ≤140/90 mm Hg (class of recommendation: I, level of evidence: A). 1,4 Treatment with angiotensin-converting enzyme inhibitors has shown a beneficial effect by lowering blood pressure in high-risk groups. 9,10Importantly, beta-blockers are not contraindicated in patients with PAD (class of recommendation: IIa, level of evidence: B).Beta-blockers should be considered in the treatment of concomitant coronary artery disease and/or heart failure (class of recommendation: IIa, level of evidence: B). 11 According to the results of this study, hypertension was detected in 72% of the study group, which was higher than the findings of the Framingham Offspring Study (69%) and lower than the findings in the PARTNERS study (88%). 12,13The detection of hypertension is imperative, but of even more importance to the current study is that 26% of patients with recognized hypertension were receiving suboptimal treatment.Seven percent of the entire study group had unrecognized hypertension. 1,6The detection of atherosclerosis risk factors and the achievement of treatment goals are better in the case of hypertension than in dyslipidemia in Poland.Nevertheless, almost 1/3 of antihypertensive PAD subjects were receiving suboptimal treatment.

Diabetes
6][17] Additionally, inadequate treatment of diabetes increases the risk of mortality in PAD patients. 12For these reasons detection and treatment of diabetes in PAD patients should be imperative.
In the current study, 31% of patients had previously diagnosed diabetes.Prediabetes was found in 11% of cases and unrecognized diabetes was found in 4%, using only the venous fasting glycaemia test.The majority of diabetics (95%) were being undertreated, with an HbA 1c level higher than the recommended range.The study revealed that although the recognition of diabetes seems to be sufficient in PAD patients in Poland, the level of inadequate treatment is considerable and requires improvement.

Antiplatelet and antithrombotic therapy
According to ESC guidelines, the incidence of vascular death, non-fatal myocardial infarction and non-fatal stroke was significantly reduced at follow-up by the use of antiplatelet drugs (class of recommendation: I, level of evidence: C). 1,18 A low dose of aspirin (75-100 mg daily) was at least as effective as higher daily doses. 1 The CAPRIE trial demonstrated that clopidogrel is as efficacious as aspirin in preventing major cardiovascular events in patients with PAD. 19The insignificant benefits of dual antiplatelet therapy do not overcome the increased risk of bleeding in patients with PAD, so its recommendation is not justified. 20,21Antiplatelet therapy is recommended in all patients with symptomatic PAD. 1 In the current study, 82.5% of the entire population were using antiplatelet therapy.Aspirin (an average daily dose of 150 mg), as a recommended therapy, was the most common antiplatelet therapy (59%), followed by clopidogrel and ticlopidine in the same proportions (1.6%).Anticoagulation therapy was being used in 4% of cases.Approximately 17.5% of the patients in the study sample (n = 22) were not currently receiving antiplatelet or anticoagulant therapy, but no contraindications to this therapy were identified in this group of patients.Moreover, 15% of the subjects were administered dual antiplatelet therapy, without any cardiological or angiosurgical indications for such treatment.

Other medicines taken for peripheral artery disease
Phosphodiesterase inhibitor was one of the 1 st drugs used in patients with arteriosclerosis obliterans.It improves the rheological properties of blood and is also believed to increase the claudication distance by about 100 m. 22 Our study revealed that 35 subjects from the entire population (only 28%) were taking pentoxifylline, with an average dose of 1200 mg per day (600-1800 mg ).Sulodexide was taken by 13 patients (10.3%), with an average dose of 500 mg per day.Bencyclane was taken by 15 patients (12%) at an average dose of 400 mg per day.

Lifestyle modifications
Smoking is an important risk factor for PAD.In the general population, smoking increases the risk of PAD between 2-fold and 6-fold.4][25] Smokers should be advised to quit smoking and be offered smoking cessation programs (class of recommendation: I, level of evidence: B). 1 A limitation of the study was the use of self-reported smoking history without validating it by means of biological markers.Out of the 126 patients who were admitted to the outpatient angiology unit with a low walking distance, 25% were active smokers.This number seems very low in comparison to the PARTNERS study and the Rotterdam Study, in which 70% of the PAD patients were active smokers. 25on-pharmacological methods of improving the length and quality of life in the form of a balanced diet, weight control and regular exercise were not being used by any of the patients.

Conclusions
There is a strong need to carefully diagnose dyslipidemia in PAD patients.The prescription of antiplatelet therapy to PAD patients should be more widespread.The rate of hypertension and diabetes in PAD patients appears to be high, but physicians should place greater emphasis on achieving optimal treatment goals.

Table 1 .
2nclusion and exclusion criteria for participation in the study2

Table 2 .
Entire population data (patients' characteristics and disease history).Descriptive data is presented as mean ± standard deviation or number (%)

Table 3 .
Risk factor profile of PAD patients (n = 126).Descriptive data is presented as mean ± standard deviation or number (%) p-value of <0.05 was considered statistically significant; BMI -body mass index; CRP -C reactive protein; LDL -low-density lipoprotein; HDL -high-density lipoprotein; SBP -systolic blood pressure; DBP -diastolic blood pressure; ABI -ankle brachial index.