Servier – Phlebolymphology

Atherothrombotic risk associated with peripheral arterial disease

Moderators: J Belch (Scotland), D Clement (Belgium)
Participants: J Belch (Scotland), P Cacoub (France), D Clement (Belgium), E Wahlberg (Sweden)

Peripheral arterial disease today: what do the registries tell us?
P Cacoub (France)

The author emphasized the importance of data from registries and epidemiological studies to understand the prevalence of, and risk associated with, peripheral arterial disease (PAD) in different populations. The target population is large: in the IPSILON study, which included 5679 patients (aged >55 years) treated in the French primary care system, PAD (defined as an ankle brachial index [ABI] <0.9) was present in 38% of patients with documented atherothrombotic disease and only 10.4% of those with cardiovascular (CV) risk factors. In the getABI study in 6880 patients treated in primary care in Germany, the prevalence of PAD was 19.8% in men and 16.8% in women. The IPSILON study suggests risk factors that may identify patients who may benefit from screening for PAD. These include age, smoking, diabetes, hypertension, intermittent claudication, and atherothrombotic events.

PAD is associated with a high risk of CV events and death. This is clear in data from the REACH registry, which includes 68 000 patients with established atherothrombotic disease or >3 CV risk factors. Over the subsequent 2 years among 8581 patients with PAD, 10.09% had a myocardial infarction (MI), stroke or CV death. These event rates remained high even in asymptomatic PAD patients (9.30%). In the getABI study, the risk of all-cause mortality after 5 years was almost equal in patients with or without manifest PAD symptoms. In the registry data PAD frequently occurs with other manifestations of atherothrombotic disease. In the REACH registry at 2 years, 44% of PAD patients had diabetes, 24% were smokers and 66% had hypercholesterolemia. The use of risk-modifying therapies was high, in contrast with the ATTEST study in which only 13% of PAD patients were receiving a combination of ACE inhibitors, statins, and antiplatelet agents, suggesting that clinicians were underestimating CV risk.

These data encourage early detection of PAD and indicate the need to establish optimal risk reduction strategies to reduce the morbidity and mortality due to this prevalent and underestimated condition.

Adherence to guidelines: myth or reality?
D Clement (Belgium)

The Transatlantic Inter-Society Consensus Document for the Management of Peripheral Arterial Disease (TASC II) has provided new information on optimal treatment. In the TASC guidelines, treatment and therapy options are similar in symptomatic and asymptomatic patients. In the TASC guidelines, the low-density lipoprotein (LDL) target for PAD patients is <2.59 mmol/L. For patients with PAD and history of acute coronary syndrome the target is <1.8 mmol/L. The blood pressure target with hypertension should be <140/90 mm Hg or <130/80mm Hg in patients also with diabetes or renal insufficiency. In diabetic patients, the HbA1c target is <7.0%. TASC II recommends for all PAD patients the use of an antiplatelet agent (aspirin or clopidogrel monotherapy).

In reality, in registry data risk factors remain prevalent among PAD patients. In the EUROASPIRE registry, the control of hypertension among patients with PAD is poor and has not changed over 12 years. Primary care practitioners are often unaware of PAD. In the REACH registry, the number of risk factors is associated with improved clinical outcome in PAD. On the basis of these data, the first step should be to inform both patients and their families of the risk associated with PAD and the possible options available for controlling and preventing complications linked with the disease.

Antiplatelet therapy in peripheral arterial disease. How to improve the management of atherothrombotic risk.
E Wahlberg (Sweden)

Peripheral arterial disease (PAD) is associated with a similar risk of cardiovascular (CV) events to coronary artery disease and reduction of CV risk is a priority in the treatment of PAD patients.

Risk modification has three major aspects: lipid-lowering, antiplatelet therapy, and ACE inhibitor therapy. Patients with diabetes should also receive therapy for glucose control.

Some data have demonstrated the efficacy of aspirin in PAD. The Antithrombotic Trialists’ Collaboration showed that antiplatelet therapy is associated with a 23% relative risk reduction for vascular events vs placebo. CLIPS, a randomized placebocontrolled trial of aspirin in 366 PAD patients with critical limb ischemia, showed a 64% reduction in vascular events, but the confidence interval was wide. When CLIPS data were included in another meta-analysis, antiplatelet therapy was associated with 26% relative risk reduction in vascular events vs placebo.

In the CAPRIE registry, clopidogrel, compared with aspirin, was associated with an 8.7% relative risk reduction for the primary end point of myocardial infarction, ischemic stroke, and vascular death. In subgroup analyses, compared with aspirin, clopidogrel was associated with a 23.8% relative risk reduction in the primary end point. As the CAPRIE trial was not powered to evaluate efficacy of individual subgroups, it is unclear whether the differences in relative risk reduction across qualifying condition are real or a result of chance.

Current data support the use of antiplatelet therapy for the reduction of CV risk in PAD and either aspirin or clopidogrel monotherapy is recommended by TASC II in all patients with PAD. However, there is a need to establish the treatment in different patient populations (such as obese patients or those with diabetes) and whether particular treatment combinations are beneficial in PAD.

Renal interventions and peripheral arterial disease

Moderators: M. Jacobs (The Netherlands), J. Moros (Greece)
Participants: G Geroulakos (UK), M Henry (France), C Klonaris (Greece), A Von Ristow (Brazil)

Renal revascularization: when is it indicated?
G. Geroulakos (UK)

The results of a systemic review of all prospective studies of renal artery revascularization or medical treatment of patients with atherosclerotic renal artery stenosis (RAS), reported mortality rates, kidney function, blood pressure, cardiovascular events, or adverse events at 6 months or later. Overall there was weak evidence suggesting no large difference in mortality rates or cardiovascular events between medical and revascularization treatments; similar kidney-related outcomes, but better blood pressure outcomes with angioplasty, particularly in patients with bilateral disease; and finally that the available evidence does not clearly support one treatment approach over another for atherosclerotic renal artery stenosis.

In order to determine which patients, if any, with atherosclerotic RAS would benefit from angioplasty and stenting (percutaneous transluminal renal angioplasty [PTRA]) as opposed to aggressive medical treatment, two large, randomized, multicenter studies are currently being conducted: the CORAL study in the USA and the ASTRAL trial in the UK.

According to the recommendations of the ACC/AHA/SVS/Society for Vascular Medicine and Biology on the indications for renal revascularization published in Circulation in 2006, PTRA is reasonable for patients with RAS and accelerated hypertension, resistant hypertension, malignant hypertension, hypertension with an unexplained small kidney, and hypertension with intolerance to medication. In addition, PTRA seems reasonable for patients with RAS and progressive chronic kidney disease with bilateral RAS or RAS to a solitary functioning kidney.

Protection during renal intervention: is it worthwhile?
M Henry (France )

Despite good immediate and long-term results, postprocedural deterioration of renal function may occur after percutaneous transluminal renal angioplasty (PTRA) in 20-40% of patients, which limits the immediate benefits of the technique, and atherothrombosis seems to play an important role.

Dr Henry presented his own results of 141 PTRAs performed using a distal protection device to reduce the risk of intraprocedural atheroembolism. He reported an immediate technical success rate of 100% with 112/141 lesions stented directly, debris removed in 80% of cases, one acute renal function deterioration, and a mean follow-up of 29.6 ± 14 months. At 2 years (84 patients included), he observed that 60 were stabilized, 20 improved, and only 4 (5%) had renal function deterioration. He concluded that these results demonstrate the feasibility and safety of distal protection during renal interventions which seem to avoid renal function deterioration after the procedure and in the long term. The beneficial effects of this technique should be evaluated by large, multicenter, randomized studies.

Primary stenting in the solitary functioning kidney, under distal embolic protection
C Klonaris (Greece)

Significant renal artery stenosis (RAS) in a solitary functioning kidney represents one of the most acceptable indications for renal revascularization. According to some reports from the literature, percutaneous transluminal renal angioplasty (PTRA) is increasingly used as first-line treatment for renal revascularization, and is associated with renal improvement or stabilization in the majority of patients with solitary kidneys, but also with deterioration in up to 38% of cases. Based on the hypothesis that this phenomenon may be partly or totally due to distal atheroembolization during the procedure, the use of distal embolic protection was investigated in patients undergoing primary stenting of the renal artery for solitary kidney salvage. The authors treated 14 patients with uncontrollable hypertension, stenosis (range 70%-100%) located at the ostium, all of them with primary stenting and an immediate technical success rate of 100%. They observed macroscopic visible debris collected in the filter in 9 cases and microscopic particles detected in 11 of 14 filters. No deterioration was noted in any patient at 6 months of follow-up, and additionally there was a statistically significant reduction in the mean serum creatinine level, in both systolic and diastolic BP and in the number of antihypertensive drugs. Despite the inherent limitations of this small nonrandomized study, the authors concluded that filter protection devices should probably be used routinely in this patient population with significant RAS and a solitary functioning kidney.

Arteriopathy and diabetes

Diabetic arteriopathy
Moderators: C Allegra (Italy), E Diamantopoulos (Greece)
Participants: C Allegra (Italy), PL Antignani (Italy), E Diamantopoulos (Greece), A Stella (Italy), GM Andreozzi (Italy)

This session consisted of a number of presentations which addressed the diagnosis and treatment of diabetic arteriopathy.

PL Antignani suggested the optimal vascular diagnostic protocol in patients with diabetes.

Once a year objective vascular examination (pulses, bruits, claudication) and ankle brachial index (ABI) measurement in patients with insulin-dependent diabetes mellitus and >35 years, noninsulin-dependent diabetes mellitus and >40 years, diabetes >20 years. ABI measurement has to be repeated every 2 years with a negative screening, every year with arteriopathy, every six months with moderate arteriopathy (ABI <0.6 on ultrasound). An ABI of more than 1.2 should be considered indicative of medial calcification. The most definitive evidence is provided by X-ray of the forefoot in which the medial calcification is visualized as a “tramline finding”. In these cases, a toe systolic blood pressure (TSBP) measurement should be performed. A TSBP index 0.6-1 is normal, an absolute TSBP <50 mm Hg is a cut-off for the diagnosis of critical ischemia, and absolute TSBP >30 mm Hg is a cut-off for a possible healing of trophic lesions. If ultrasound does not produce a clear-cut result on the morphological features of occlusions, angio computed tomography (aCT) and nuclear magnetic resonance (MR) should be used when considering revascularization options.

Diabetic foot: the primary task in assessing diabetic foot lesions is the differentiation of neuropathic and (neuro-) ischemic findings. The underlying differences between the two forms is the existence (or absence) of foot pulses. The most important basic diagnostic measure is therefore the palpation of foot pulses. Doppler examination of the peripheral arteries using ABI and, where necessary, a toe pressure measurement are noninvasive examinations. The diagnostic structure in diabetic foot: underlying disease, localization, extent of injury, wound healing stage, infection.

Microcirculatory disorders: the significance of microcirculatory disorders at the capillary level is still a matter of debate. The presence of lumen-occluding processes in the microcirculation of diabetics was used before as justification for early and extensive limb amputation. Today, the presence of occlusive disease can be measured and hence excluded. However, functional abnormalities of the microcirculation with deterioration of hemodynamic, endothelial, and cell function as a consequence of poor blood glucose control must be considered definite. These conditions impair healing. Therefore, the presence of gangrene with palpable foot pulses in patients with diabetic foot syndrome should no longer be considered a consequence of occlusive microangiography but much more as evidence of a neuropathic infected foot. At present, capillary microscopy, laser flow measurement, and transcutaneous oxygen tension measurement are standard procedures used in the investigation of microcirculatory problems.

E Diamantopoulos discussed medical treatment of diabetic foot. The most common precursor of amputation is diabetic foot ulceration. The therapeutic objectives include debridement, pressure relief, appropriate wound management, infection control, revascularization, and medical management of comorbidities. In neuro-ischemic foot the preferred method is frequent sharp debridement. The ischemic foot should be revascularized and the digital necrosis removed surgically but, if revascularization is not possible, necrotic amputation may be allowed . Indications for surgical debridement: presence of necrotic tissue, localized fluctuance and drainage of pus or crepitus with gas in the soft tissue. Occlusive dressings may lower the risk of infection.

Diabetic foot infections may be classified as non-limb-threatening or limbthreatening. Initial antibiotic treatment is based on the most commonly involved bacteria. Diabetic foot infections that are non-limb-threatening can usually be treated with minor surgical debridement, whereas those that are limb-threatening are often polymicrobial, and require hospitalization and prolonged intravenous treatment with broad-spectrum antibiotics.

The pharmacological treatment to improve perfusion has not been well established. The only drug that has showed a positive influence on the outcome of ischemic diabetic foot ulceration is prostacyclin. The majority of studies have found that the parenteral administration of iloprost reduces ischemic pain, ulcer size, and amputation rate. Wound healing and neutrophil function is impaired by hyperglycemia. Glycemic control is essential. An antiplatelet drug with aspirin or clopidogrel is indicated in all diabetic patients. Hyperlipidemia and hypertension should be treated.

A Stella reported his personal experience of peripheral angioplasty (percutaneous transluminal angioplasty [PTA]) in 993 diabetic patients with critical limb ischemia followed between 1999-2003. PTA criteria for inclusion: single or multiple stenosis >50%, calcified or noncalcified occlusion. Results: restenosis with symptoms 2.2 per year, 5-year limb salvage 88%, death rate/year 6.7%. Angioplasty was the treatment of choice in diabetic patients with critical limb ischemia. In another study from Jan 2005 to Aug 2007, 87 limbs were treated with tibial angioplasty. Inclusion criteria: single or multiple stenosis and/or occlusion <4 cm long. Primary patency at 12 months 37.9%. Negative prognostic factors for primary patency: infected gangrene, smoking, PTA of posterior tibial artery. The rate of assisted patency at 12 months was 71.2%.

From Jan 2005 to Dec 2007, 38 diabetic patients with critical limb ischemia (inclusion criteria: complete occlusion of tibial arteries, patency of peroneal without perforating branches, poor run-off, TUC III D gangrene) were treated for ankle and pedal by-pass. Follow-up at 6 months: primary patency 62%, limb salvage 75%, wound healing 65% (100% at 12 months), survival at 12 months 88.2%.

GM Andreozzi emphasized the role of the physical training to improve walking ability in claudicants and reported his personal experience. Initial and absolute claudication distances, recovery time (RT) and ankle brachial index were measured by maximal treadmill exercise in 74 patients at day 0 and repeated after 18 days of supervised physical training (daily walk with a distance goal 1-2 km or a time goal of at least 30 min). The patients were divided into three groups: 33 nondiabetics, 20 with HbA1c <7% (balanced diabetics), 21 with HbA1c >7% (unbalanced diabetics). After the training period, absolute claudication distance increased from 106.12 m to 195.97 in nondiabetics, from 92.50 m to 173.85 in balanced diabetics, and from 114.62 to 214.0 in unbalanced diabetics.

Ankle brachial index increased from 0.66 to 0.71 in nondiabetics, from 0.65 to 0.69 in balanced diabetics, and from 0.65 to 0.69 in unbalanced diabetics.

In conclusion, physical training was effective for treatment of claudicant patients. In the improvement of walking ability there was no difference between patients without diabetes, balanced diabetics, and unbalanced diabetics. The persistence of unbalanced metabolic status is predictive of mediocre results. Ankle brachial index changes, which were statistically significant but clinically irrelevant, were likely due to improvement in endothelial function after physical training, with a higher arteriolar vasodilation and reduction in peripheral resistance.

Myopathy and peripheral arterial disease

Moderators: G Torsello (Germany), J Iliopoulos (Greece)
Participants: H Pipinos (USA), S Merreilles (Brazil), F Moll ( The Netherlands), I Vanhandenhove (Belgium)

Myopathy of Peripheral Arterial Disease
H. Pipinos (USA)

In the first part of the presentation, the author described the anatomical changes observed in the muscles of patients with peripheral arterial disease (PAD). In these patients one can observe myopathy with advanced atrophy of muscle fibers, muscle fiber vacularization, target lesions, perimysial thickening and fibrosis, and fibrofatty infiltration of the muscle. The author remarked that PAD pathophysiology is much more than a simple imbalance between blood supply and demand. The mitochondria of the muscles are directly affected by PAD, and have an abnormal ultrastructure, altered enzymatic activities, and altered carnitine metabolism.

In the second part of the presentation, the author considered different questions and their answers.

Question – Are these mitochondrial abnormalities in structure and biochemical composition associated with defective energy production? To answer this question the author designed an in vivo study to compare the gastrocnemius muscle of PAD patients with that of a control group, by determining the spectra of phosphorus (31P), which represents the ATP, ADP, PCr and Pi levels as mitochondrial function markers. The study demonstrated that PCr recovery and ADP recovery are lower in the PAD patients.

Question.- Is mitochondriopathy initiated by PAD or the associated comorbid conditions (chronic heart failure, diabetes mellitus, kidney failure, dyslipidemia, etc)? The author recruited patients with unilateral PAD and compared the muscle bioenergetics in ischemic versus normal legs. PCr recovery and ADP recovery were lower in the symptomatic leg than in the asymptomatic leg.

The conclusion arising from these questions is that PAD, rather than comorbid conditions, is the primary association with this mitochondriopathy.

Question.- Where in the mitochondria is the problem underlying the observed defective bioenergetics? The hypothesis was that a deficiency in the respiratory chain causes PAD mitochondriopathy. The study designed to answer the question was to measure mitochondrial respiration in PAD patients and in normal controls. Respiration was measured in vitro after stimulation with substrates and ADP. After stimulation, the mitochondrial respiration increases in the normal population but not in the PAD patients. The conclusion is that a deficiency in the respiratory chain seems to be the underlying cause of PAD mitochondriopathy.

In the third part of his presentation, the author discussed the inflammatory changes produced in the muscles during exercise in the PAD patients. During exercise, patients with ischemic claudication develop leg muscle pain, which forces them to rest. When rested, perfusion returns to normal levels. These cycles of ischemia and reperfusion launch a cascade of inflammatory changes and induce the production of reactive oxygen species (ROS). The next question was whether there is any evidence of oxidative stress/damage in PAD skeletal muscle. The authors designed one study to evaluate PAD patients and normal controls for evidence of oxidative stress and damage and for alteration in the activities of the antioxidant defense enzymes. The multiple daily ischemia-reperfusion events produce morphological and ultrastructural changes in the contractile elements of the muscle and its mitochondria. Dysfunctional mitochondria then further lower the already decreased (by compromised blood supply) energy levels in the pathologic muscle, and become sources of ever increasing levels of ROS, and possibly induce apoptosis. This vicious cycle impairs mitochondrial function and escalates ROS production, which results in damage to every structure in the myocytes. Apoptosis leads to severe myopathy that significantly affects the function and performance of PAD limbs.

There is increasing evidence that the injury route expands to damage nerves, skin, and subcutaneous tissues, ultimately leading to the characteristically atrophic legs of patients with advanced PAD.

New stents and stentgrafts in the treatment of superficial femoral occlusions: will they provide long term patency?
I Vanhandenhove and J Bleyn (Belgium)

Neo-intimal hyperplasia has limited the success of several techniques in the treatment of the long (more than 7 cm) superficial femoral artery occlusions. The authors reported follow-up from 1997 to 2008 of 65 patients with superficial femoral occlusions treated with subintimal recanalization and implantation of a polytetrafluoroethylene-covered nitinol stentgraft (Hemobahn® WL Gore). Polytetrafluoroethylene acts as a barrier to growth of tissue through the stent struts and eliminates the deleterious effects of neo-intimal hyperplasia.

At 10 years the primary patency rate was 55.5% and every occlusion was treated by thrombolysis with urokinase. Secondary patency was 83.8% at 10 years.

This was a retrospective study with good results. Prospective randomized studies are needed to demonstrate to superiority of covered stent grafts over other techniques in the treatment of superficial femoral occlusions.

Moderators: A. Mansilha (Portugal), J. Aggelakas (Greece), N. Tentolouris (Greece)
Participants: M. Mooschou (Greece), A. Bairaktari (Greece), FA Allaert (France)

Is graft type related to perigraft fluid collection after aortobifemoral bypass?
M. Mooschou (Greece)

Perigraft reaction and groin fluid accumulation following aortobifemoral bypass were seen in all three reported cases, along with negative ultrasound examinations for false aneurysms, and negative cultures, all managed conservatively with groin aspiration, daily wound changes, blood examinations, and prophylactic antibiotics. She reminded the audience that noninfectious inflammation is a rare complication following vascular synthetic graft abdominal implantation, which can mimic microbial infection, and such a complication must be taken into consideration before making the decision to remove the hypothetically infected graft.

Efficacy of pregabalin for painful diabetic neuropathy
A. Bairaktari (Greece)

Results of a small, open, non-controlled study to evaluate the efficacy of pregabalin in painful diabetic neuropathy were reported. Thirteen patients (64-75 years) with VAS>6 were given pregabalin at total doses of 450-600 mg per day. Improvements in pain (VAS<5) and sleep in 9 patients after two weeks of treatment were maintained 12 weeks later, with common side effects including dizziness, somnolence, headache, and dry mouth. Effect of body mass index on antihypertensive treatment: meta-analysis of 41 625 observations
F. Allaert (France)

A meta-analysis of 41 625 patients (age 63±11 years; 55% male) studied the effect of body mass index (normal <25, overweight 25 to 30, obese >30) on the rate of blood pressure control (d140 mm Hg and d90 mm Hg) by antihypertensives. The normalization rate did not vary as a function of gender but decreased significantly with body mass index: 63.7% in patients with normal weight, 61.1% in overweight patients, and 56.7% in obese patients. These results remained statistically significant after adjusting for weight and gender using logistic regression analysis. In conclusion, body mass index, which is a recognized risk factor for hypertension, also appears statistically to limit the effect of antihypertensive treatment.