Interventional Therapy in Diabetic Foot: Risk Factors, Clinical Events and Prognosis at One Year Follow-up (A Study of 103 Cases)

MATERIALS AND METHODS

The study was conducted by recruiting, over the period from January 2007 to August 2009, 103 consecutive patients, all suffering from diabetes (type 2) for at least 10 years, with diabetic foot, namely ulcers, gangrene or amputations of the distal ends of the legs, who underwent revascularization by angioplasty (with balloon or stent). At enrolment patients had an Ankle/brachial Index (ABI) <0.6 and Echo Colour Doppler diagnosis of at least one hemodynamically significant stenosis or occlusion of the vascular bed of a lower limb. All patients were informed of the purpose and the nature of the study and gave informed consent to take part. The study was performed in accordance with the guidelines proposed in the Declaration of Helsinki and approved by the Ethic Committee.

Study population: All 103 patients enrolled (68% men, mean age 68+10 years) had suffered from diabetes (type 2) for at least 10 years, treated with oral antidiabetic drugs (74%) and/or with insulin (36%). All patients had lower limb ischemia-diabetic foot-with ulceration (92%), gangrene (1%) and amputations (8%) of the lower limbs. A smoking habit was present in 30% of patients, with a daily consumption of 23±9 cigarettes, 71% were hypertensive, 69% dyslipidemic and 70% overweight, with a Body Mass Index (BMI) of 27±5 kg m^-2. Erythrocyte Sedimentation Rate (ESR) and C-reactive Protein (CRP), performed during hospitalization for angioplasty, were 39±30 mm h^-1 and 16±29 mg L^-1, respectively. The Glomerular Filtration Rate (GFR) was 65±25 mL min^-1 with a blood creatinine value of 1.29±1.3 mg dL^-1. Patients demographic, pharmacological and relevant clinical findings are summarized in Table 1.

Table 1:	Patients demographic, clinical and treatments data
Values are Mean±SD, PTA: Percutaneous transluminal angioplasty, POBA: Plain old balloon angioplasty, Tibial ant.: Tibial anterior; Tibial post.: Tibialis posterior, GFR: Glomerular filtration rate, HDL: High density lipoprotein, LDL: Low density lipoprotein, CRP: Creactive protein, ESR: Erythrocyte sedimentation rate, ACE: Angiotensin-converting enzyme

PTA technique: All patients underwent quantitative angiography and subsequent angioplasty with the same protocol: after local anesthesia with Xylocaine 2%, vascular angiography was performed with a percutaneous femoral artery approach using the Judkins technique with a 6 french pig-tail catheter. PTA was performed using the monorail or over-the-wire system with an antegrade or retrograde approach, as needed, after intravenous administration of Unfractionated Heparin (UFH) 5000 UI. The diameter of the balloon used for angioplasty was calculated by Philips angiographic software using the calibre of the vessel to be treated as reference. All patients underwent single or multiple balloon inflation, depending on the operator's needs, while stents were applied only in presence of large spiral dissection of vessels. The inflation pressure, number and size of stents placed were determined by individual needs during the procedure. In particular, angioplasty was performed with the use of stents in 65% of cases and only balloon dilation in the remaining 35%. Each patient received, on average, 4 insufflations at a pressure of 12 ATM and with an inflation time of 231 sec.

Site and occlusion grade of vascular lesions treated with PTA: Treated lesions were distributed along the entire vascular tree of the lower leg from the femoral artery, through the popliteal artery to the tibio-peroneal trifurcations including the anterior tibial artery, posterior tibial artery and interosseous artery. Specifically, vascular lesions are located in Table 1.

Stenosis ranged from a minimum of 75-100% with complete occlusion of the vessel. The success rate of the procedure was 100%, with a residual stenosis of less than 20%. After PTA, 24 patients were discharged with a single antiplatelet drug: acetyl salicylic acid, clopidogrel or ticlopidine; 79 with two drugs, while low molecular weight heparin was prescribed to 21 patients over a period of one month.

Follow-up: All patients were subsequently monitored by phone follow-up after about 12 months from the revascularization treatment, to assess the major end-points: death, strokes and MI and “minor” end-points: deep vein thrombosis, renal failure, clinic vascular restenosis and recurrence of ulcers. We also searched for risk factors of these events.

Statistical analysis: Continuous variables were expressed as Mean±SD deviation and frequencies as percentage of patients. Between-group comparisons were made by using Student’s t test for independent samples or non-parametric Mann-Whitney U test. Frequencies were compared using the chi-squared or Fisher’s exact test when appropriate. P-values of p<0.05 were considered statistically significant. The data were analysed using the statistical software packages Statistica version 6.1 (StatSoft Inc., Tulsa, Oklahoma).

RESULTS

At 1 year follow-up the incidence of major events: death, stroke and MI was 15% and of “minor” events: vascular restenosis, renal failure and deep vein thrombosis was 34%. With regard to major events (15%), deaths accounted for 5% (including 2 patients who died of cancer), strokes for 1% and MI for 9% (Table 2). As regards “minor” events, 11% of patients developed renal failure, 9% a deep vein thrombosis and 14% a restenosis (including 5 subjects who underwent PTA with a balloon only) (Table 2). Smokers had a higher risk of major events, although this was not statistically significant (p = 0.14). Another interesting datum emerged, namely that subjects taking insulin therapy and subjects using oral antidiabetic drugs did not differ statistically about the incidence of major events (p = 0.77). The presence or absence of obesity was significant (p = 0.035), so obese subjects with ulcers have an increased risk of major events. Dyslipidemia (total cholesterol >200 mg mL^-1) (p = 0.77) was not related to major events; nevertheless, increased Low Density Level (LDL) (>130 mg d^-1) (p = 0.017) resulted positively correlated with major events. Analysing our population blood tests, there was not a significant correlation with increased values of ESR and CRP (p = 0.31 and 0.23, respectively), indicating that these markers were not potential predictors of major events for the population sample considered. Regarding the vascular lesion site, we observed that patients with more distal lesions, especially of the posterior tibial artery, exhibited a statistically significant (p = 0.017) higher incidence of major events (Table 3).

Table 2:	Incidence of major (death, stroke and myocardial infarction) and minor (vascular restenosis, renal failure and deep vein thrombosis) events at 1 year follow-up

Table 3:	Correlation among smoke, insulin therapy, obesity, dyslipidemia, CRP, ESR values, vascular lesion site and major events
p<0.05, Col TOT: Total cholesterol, Col HDL: High density lipoprotein cholesterol, LDL Col: Low density lipoprotein cholesterol, CRP: Creactive protein, ESR: Erythrocyte sedimentation rate, Fem: Femoral artery, Popl: Popliteal artery, Ant Tib: Anterior tibial artery, Post Tib: Posterior tibial artery, Inter: Interosseous artery

Table 4:	Correlation among smoke, obesity, triglyceridemia and minor events
p<0.05

Table 5:	Correlation among insulin therapy, obesity, CRP, ESR values, vascular lesion site and ulcer relapse
p<0.05, CRP: Creactive protein, ESR: Erythrocyte sedimentation rate, Fem: Femoral artery, Popl: Popliteal artery, Ant Tib: Anterior tibial artery, Post Tib: Posterior tibial artery, Inter: Interosseous artery

As regards “minor” events (Table 4), smokers again showed a higher incidence of events, though this did not reach statistical significance (p = 0.43).

Hypertriglyceridemia (triglycerides >150 mg dL^-1) was also positively correlated with the incidence of “minor” events even if this did not reach statistical significance (p = 0.25), as well as obesity (p = 0.043), which represent thus a risk factor of minor events.

No important data emerged about blood tests, the type of therapy and the stenosis site. Finally, evaluating the incidence of recurrent ulcers (Table 5), that occurred in 21% of patients, we observed that subjects under insulin therapy were not at higher risk than those who did not use insulin (p = 0.21). Furthermore, obese subjects seemed not to have a tendency to ulcer relapse (p = 0.45). Instead, we found a strong association with blood chemistry marker levels, in particular with CRP levels, which were elevated (p = 0.006) in patients with recurrent ulcer. The last interesting finding was about the site of the vascular disease. We observed, in fact, that patients with a proximal stenosis (femoral artery, p = 0.11) had a lower tendency to develop a new ulcer than patients with distal lesions (anterior tibial in particular, p = 0.09).

DISCUSSION

In diabetic patients with lower limb ischemia the risk of cardiovascular disease increases significantly, as amply reported in literature (Faglia et al., 2009). In particular, the 5-year mortality rate in patients with ulcer is between 43% and 55%, increasing to 74% in patients subjected to amputation of the distal extremities. These figures far exceed those related to mortality for many types of cancers including prostate, colon and Hodgkin's lymphoma (Robbins et al., 2008). Assessing a series of studies (Faglia et al., 2009; Robbins et al., 2008) comparing the 1-year mortality rate of patients with diabetic foot, we observed that this varied from 15-40%, increasing to 50% at 3 years and up to 60% at 5 years. In particular, the overall annual rate of major cardiovascular events, MI, ischemic stroke and cardiovascular death, was 20-30%. At 5, 10 and 15 years the morbidity and mortality rates for all causes are 30%, 50% and 70%, respectively (Faglia et al., 2009). Ischemic heart disease is the most frequent cause of death in patients with diabetic foot (40-60%), while cerebrovascular disease accounts for 20-30% of cases. Other vascular events, especially rupture of an aortic aneurysm, cause about 10% of deaths. Thus, 20-30% of patients do not die of cardiovascular causes. Analyzing clinical trials that evaluated patients who could not undergo artery reconstruction and those in which the attempt had failed, 40% of patients lost the limb at 6 months and 20% died. However, these data were referred to patients with diabetic foot who had not undergone any revascularization treatment (Norgren et al., 2007). Literature data on the mortality incidence are rather limited. In a relatively recent study, Faglia et al. (2006) documented the clinical course and outcome of patients with diabetic foot at 5 years after revascularization: 173 of 566 patients died (30.7%). However, the non-revascularized control group consisted of only 27 subjects versus 566 revascularized subjects. Jamsen et al. (2002) reported a survival incidence of 41% at 2 years, 26% at 5 and 14% at 10 years, in 100 diabetic patients with lower limb ischemia. Bailey et al. (2003) reported data from 134 patients with diabetic foot followed up for 9 months. They found a mortality incidence of 12%, which was higher in patients with ulcers or gangrene. Finally, Bertele et al. (1999) found a mortality of 19% at one year's follow-up in a cohort of 1560 patients with ischemic diabetic foot. Against this literature background, results of our observational study show that patients suffering from diabetes for at least 10 years, with lower limbs ulcers, revascularized using a PTA technique, had a total mortality of only 5% with a negligible incidence of stroke (1%) and MI (9%). This result may be related to lower limb revascularization with angioplasty, which can clearly improve the prognosis of these subjects. Therefore, our study highlights firstly the relative importance of an early diagnosis of diabetic foot because of the high mortality that literature data (Norgren et al., 2007) showed for non-treated cases. Secondly, a prompt reperfusion treatment, either endovascular or surgical, could ameliorate the quality of life of diabetic foot patients. The lacking of a control group could be considered as a limitation of the present study, although we preferred not to consider a control group formed by diabetic foot patients not undergoing to revascularization therapy in relation to the life-threating risk that literature data pointed out in such comparisons.

Regarding predictive factors of events and new ulcers, analytical and experimental studies have identified several independent risk factors such as smoking, dyslipidemia and obesity (Norgren et al., 2007). None of these, however, proved to be a sure marker of events. In our study, confirming this, we identified obesity and LDL cholesterol as likely indicators of an unfavourable evolution in these patients. Finally distal vascular lesions, typical of diabetes involving mainly small-sized arteries (Dinh et al., 2009), were associated with an increased risk of developing new ulcers. This finding is no surprise, since vascular restenosis, which does not always reflect a clinical relapse, is more frequent in small vessels compared with vessels of a larger calibre (West et al., 2004).

CONCLUSIONS

Our analysis, far from being a comprehensive research about the matter and although with its limitations, highlights the fact that diabetic foot disease is an important social problem because of the high incidence in the population and the risk of major and minor complications. A rapid diagnosis and prompt revascularization treatment, if needed, are essential to improve the quality of life and prolong survival.

Unfortunately, no certain markers of risk for diabetic foot disease have yet been identified. Insulin therapy, smoking, obesity, dyslipidemia may be taken into consideration but further studies are needed to confirm this.

ACKNOWLEDGMENT

The authors thank prof. M. Pragnell for her great contribution in developing English version of our manuscript.