Interventional Therapy in Diabetic Foot: Risk Factors, Clinical Events and Prognosis
at One Year Follow-up (A Study of 103 Cases)
Marco Matteo Ciccone,
Diabetic foot is a common complication in diabetes mellitus course, able to increase the overall morbidity/mortality risk of such a disease. The aim was to investigate the outcomes, the incidence of clinical events, the number of recurrent ulcers in patients with diabetic foot during 1 year follow-up after angioplasty (PTA) revascularization. From January 2007 to August 2009, 103 diabetic patients with diabetic foot undergoing revascularization of a lower limb by PTA were recruited. At 1 year follow-up we assessed: major (death, stroke, Myocardial Infaction (MI) and minor (Deep Vein Thrombosis (DVT), renal failure, restenosis) events incidence; recurrent ulcers incidence; the predictive elements of all these events. At 1 year follow-up, major/minor events incidence was 15% (deaths:5, stroke:1, MI: 9%) and 34% (renal failure: 11, DVT: 9, restenosis: 14%), respectively. Obesity, high low density level-cholesterol levels and distal arterial lesions (at posterior tibial artery in particular) were statistically significantly associated with major events (p<0.05); only obesity resulted statistically associated with minors (p = 0.043). High levels of C-reactive protein had a statistically significant relationship with the recurrence of ulcers (p = 0.006) while distal arterial obstructions showed a trend toward significance. To improve diabetic foot mortality and morbidity rate, our study underlines the importance of a prompt diagnosis and appropriate revascularization treatment. Other studies are needed to ascertain these.
to cite this article:
Marco Matteo Ciccone, Alfredo Marchese, Aikaterini Generali, Cataldo Loiodice, Francesca Cortese, Rosa Carbonara, Pietro Scicchitano, Luigi Laviola and Francesco Giorgino, 2012. Interventional Therapy in Diabetic Foot: Risk Factors, Clinical Events and Prognosis
at One Year Follow-up (A Study of 103 Cases). Pakistan Journal of Biological Sciences, 15: 789-794.
Received: October 04, 2012;
Accepted: December 08, 2012;
Published: February 11, 2013
According to the World Health Organization (WHO), the total number of diabetic
subjects was 171 million in 2000 and is expected to rise to 366 million in 2030
due to population ageing, obesity, a sedentary lifestyle, as well as changes
of diet (Setacci et al., 2009). There is a high
prevalence of peripheral occlusive vascular disease in diabetic individuals
(Andrade et al., 2004). In fact, the metabolic
abnormalities caused by diabetes induce a vascular dysfunction that predisposes
to atherosclerosis (Beckman et al., 2002). However,
the true prevalence of peripheral occlusive vascular disease in diabetic subjects
is difficult to determine, as most patients are asymptomatic, many do not report
their symptoms, screening modalities have not been uniformly agreed upon and
pain perception may be attenuated by the presence of peripheral neuropathy.
All such characteristics define diabetic foot, i.e. the foot of
a diabetic patient that has the potential risk of pathologic consequences including
infection, ulceration and/or destruction of deep tissue associated with neurologic
abnormalities, various degrees of peripheral vascular disease and/or metabolic
complications of diabetes in the lower limbs (Schaper et
al., 2003; Apelqvist et al., 2008).
Among patients diagnosed with diabetes mellitus, the prevalence of foot ulcers
is 4-10%, while the annual population-based incidence is 1.0-4.1% and the lifetime
incidence may be as high as 25% (Setacci et al.,
2009). Lower extremity complications in diabetics are becoming an increasingly
significant public health concern. These ulcers frequently become infected,
cause great morbidity and are the usual first step to lower extremity amputation,
even in the absence of critical limb ischemia (Singh et
al., 2005; Wu et al., 2007). Amputation,
the ultimate endpoint of diabetic foot disease, is associated with significant
morbidity and mortality rates, besides having immense social, psychological
and financial consequences (Khanolkar et al., 2008).
Foot ulcer associated to peripheral occlusive vascular disease requires revascularization,
although the outcome in these subjects is less successful than in non-diabetic
patients (Setacci et al., 2009). The number
of Percutaneous Angioplasty (PTA) procedures performed for revascularization
of an ischemic limb has increased over the last few years, with the offer of
minimally invasive therapeutic alternatives to surgical procedures, which result
in significant morbidity and mortality (Al-Omran et
al., 2003). In present study we evaluated the clinical course, the outcome,
the incidence of some major and minor vascular events, the recurrence
of lower limb arterial ulcers and the risk factors associated to these complications
in patients with diabetic foot in the first year after PTA revascularization.
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.
|| 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 Students t test for independent samples or non-parametric
Mann-Whitney U test. Frequencies were compared using the chi-squared or Fishers
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).
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).
||Incidence of major (death, stroke and myocardial infarction)
and minor (vascular restenosis, renal failure and deep vein thrombosis)
events at 1 year follow-up
||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
||Correlation among smoke, obesity, triglyceridemia and minor
||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).
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).
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.
The authors thank prof. M. Pragnell for her great contribution in developing English version of our manuscript.
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