Servier – Phlebolymphology

1.1. Aneurysms

W. Wisselink (The Netherlands)

A total of 116 patients with ruptured aneurysms, out of a population of 1.2 million inhabitants in the Amsterdam area, were treated during the period from 2004 to 2011.

After randomization, the authors treated 59 patients with open repair and 57 with endovascular aneurysm repair (EVAR). The hospitalization death rate was 21% in the EVAR group and 25% for the open repair group. They concluded that open repair was performed much better than expected and that open repair for ruptured aneurysms should not be abandoned.

A. Jawien (Poland)

This latest meta-analysis, with at least 10 years of follow-up, suggests that screening reduces abdominal aortic aneurysm (AAA)–related mortality by 45%, with a strong reduction in all-cause mortality. Various national screening programs have been carried out. In the USA, AAAs were diagnosed in 5.1% of men of 65 to 75 years of age. In Northern Ireland, AAAs were detected in 5.4 % of men of 65 years of age. In Genoa, AAAs were found in 6.2% of males and females of 65 years of age or more. In Poland AAAs were detected in 5.7% of males of 60 years of age or more.

In the UK, AAA rate in patients of 65 years of age was 1.7%. The prevalence of AAA was lower than expected due to the younger age of this cohort.

In Sweden, AAAs were detected in 1.7% of 65-year-olds. In 3.3% of the examined men the aortic diameter was of 25 mm, while it was of 30 mm in 1.3%. The cutoff for further follow-up was 30 mm. An aorta with a diameter between 25 and 29 mm was classified as an «aneurysm in formation.»

Consensus exists across guidelines on the one-time screening of elderly men to detect and treat AAAs. Further studies are needed for other target groups, management of small AAAs, prediction models, and cost-effectiveness.

D. Karetova (Czech Republic)

Abdominal aortic aneurysm (AAA) is a multifactorial complex disease involving genetic defects, inflammatory reactions, hemodynamical stress, and risk factors.

Comprehensive treatment includes smoking cessation, blood pressure control, dyslipidemia treatment, specific therapy (antiproteolytic/anti-inflammatory), statins, angiotensin II inhibitors. However, the only verified method for the prevention of AAA rupture is mechanic exclusion.

The aim of conservative therapy is the limitation of growth. In a meta-analysis including 14 studies, 13 different drugs belonging to 4 main drug classes were evaluated: β-blockers, antihypertensives, antibiotics, and statins.

Although propranolol showed no effect in aneurysm growth and impaired quality of life, it demonstrated a positive effect in perioperative cardiovascular risk reduction. There was no relationship between angiotensin receptor blockers or statins and AAA expansion rate. These drugs were recommended to patients with an AAA because of coexisting cardiovascular disease. Antibiotics like macrolides and tetracycline were studied in animal models for potential inhibitory effects on metalloproteinase activity. The significant changes in AAA expansion rates were controversial.

In conclusion, there is no specific proven medication to prevent AAA growth. Suboptimal «antiatherosclerotic» medication in patients with AAA, like statins and acetylsalicylic acid should be prescribed. Controlling hypertension is essential.

P. Gloviczki (USA)

The management of abdominal aortic aneurysms (AAAs) has dramatically changed in the past decade. Nowadays, more than 60% of patients with AAA are treated with endovascular aneurysm repair (EVAR).

At Mayo Clinic, from 1996 to 2011 (3473 AAA patients), the use of EVAR increased compared with the use of open repair (OR). From 2007, EVAR was performed in 63% of patients. In 969 elective EVARs, the mortality rate at 30 days was 0.93%.

In the United States, from 1999 to 2008, the number of AAA repairs increased (+ 26.3%) while the risk-adjusted mortality rate decreased from 4.4% to 2.8 % (– 36%).

In a recent survey, survival at 8 years after open AAA repair and after EVAR showed an aneurysm-related survival of 93% and lower rates of complications and reinterventions for EVAR.

In a randomized trial, the early mortality rate with EVAR was 0.5%, while mortality at 2 years with EVAR was 7%. Procedure time, hospital stay, and blood loss were all reduced in patients undergoing EVAR. No major difference in morbidity, reinterventions, and erectile dysfunction were observed.

The data from high-risk patients in five FDA trials (565 EVAR patients, 61 OR controls) showed a mortality rate at 30 days of 2.9% with EVAR and 5.1% with OR. Aneurysm-related deaths at 4 years were 4.2% (EVAR) and 5.1% (OR).

Repair of AAA in high-risk patients provides excellent protection from AAArelated death at 4 years.

EVAR can be performed with a low rate of mortality and an acceptable rate of complications. EVAR is a less invasive procedure, thereby allowing treatment of high-risk patients with large aneurysms. However, long-term survival benefits, high costs, reintervention rates, and late rupture remain concerns.

1.2. Carotid stenosis

R. C. Shields (USA)

R. C. Shields talked about the debate over the treatment of patients with asymptomatic carotid artery stenosis: should they be treated with an aggressive or a conservative approach?

Carotid disease is an important source of strokes (accounting to as many as 15% to 30% of them). The ACST trial (Lancet 2004 and 2010) shows a risk of stroke at 5 years of 6.9% for patients undergoing an immediate intervention and 10.9% in patients with deferred medical treatment, which rises to 13.4% and 17.9%, respectively, at 10 years. In those patients, the benefit of surgery was limited to males and those less than 75 years of age and the perioperative stroke and death rate was of 3.1%. The results of the CREST study (New Engl J Med) seem to be slightly superior in the carotid endarterectomy (CEA) group versus the carotid artery stenting (CAS) group.

The treatment of hypertension in carotid artery disease was the objective of the SECURE trial (Circulation 2001), which showed that ramipril significantly reduces carotid intimal medial thickness in 37% of cases; however, the clinical significance of this result is unclear. The HOPE trial (New Engl J Med 2000), another trial with ramipril versus placebo, showed a 32% reduction in the number of strokes in the treatment group.

If we focus on statins and the risk of stroke, the JUPITER trial (primary prevention) shows a hazard ratio of 0.52 with treatment, and in a meta-analysis of secondary prevention studies (J Am Coll Cardiol 2008) the reduction in stroke was 25. The ASTEROID trial, conducted with intravascular ultrasonography, showed that statins decrease plaque volume at 24 months in all age groups and in both sexes.

Antiplatelet therapy achieves primary risk reduction but its risks and benefits must be individually balanced.

Thus, with the best medical therapy, the annual risk of ipsilateral stroke is 0.4% to1.0 % in asymptomatic patients, and it is difficult for either CEA or CAS to improve on it.

What are the future directions? Surely, the new frontier is risk stratification, to identify those patients with increased risk of stroke for operative management, with the use of inflammatory markers (hs-CRP, lipoprotein-associated phospholipase A2), carotid intimal medial thickness, and vulnerable plaque analysis.

In conclusion, medical management has become an indispensable part of the care of patients in every phase of carotid disease for primary prevention, secondary prevention, and perioperative management.

Can carotid intervention be dispensed of for asymptomatic disease? Possibly not, but we must determine who should receive surgery with the best medical possible treatment and who should receive conservative management alone.

P. Gloviczki (USA)

Stroke occurs in 2.9% of high-risk patients and in 0.9% of low-risk patients, while death occurs in 0.6% of high-risk patients and in 0% of low-risk patients. Data from Maryland (USA) in the period 1994-2003 (23 237 carotid endarterectomies [CEA] by 438 surgeons) show an in-hospital stroke rate of between0.58% and 0.73%.

To compare carotid endarterectomy and stenting, Murad (J Vasc Surg, 2011) looked at different outcomes from the literature: risks of stroke, death, myocardial infarction, cranial nerve injuries, bleeding, wound complications, quality of life, and cost in 7484 patients data from different studies (Naylor, 1998; Alberts, 2001; Brooks, 2001, CAVATAS 2001; Yadev 2004; EVA-3S 2004; SPACE 2006; Ling 2006; BACASS 2006; Steinbauer 2008; CREST 2010; ICSS 2010).

Risks of stroke, death, and myocardial infarction: Results showed that carotid artery stenting (CAS) is associated with an increased risk of any type of stroke (relative risk, [RR], 1.45), a decreased risk of myocardial stroke (RR, 0.43), and a nonsignificant increase in deaths (RR, 1.45). There is a trend suggesting that CAS was more effective in patients <70 years of age. On the other hand, CAS is associated with 19 times more strokes than CEA, with 3 times more deaths, but with 10 times fewer myocardial infarctions than CEA. The conclusion of this study is that CAS significantly increases the risk of any type of stroke and decreases the risk of myocardial infarction.

Cost: Markov’s analysis in symptomatic patients suitable for both CEA and CAS shows that CAS resulted in fewer quality-adjusted life years (8.97 vs 9.84) while the cost per patient was increased.

Therefore, given the current evidence, the United States Center for Medicare and Medicaid Services (CMS) has decided not to extend reimbursement for carotid artery angioplasty/stenting in patients with low or standard risk for carotid endarterectomy. However, this situation may change in the future.

In conclusion, in most patients with carotid stenosis who are candidates for intervention, CEA is preferred to CAS for the reduction of all-cause stroke and periprocedural death (grade 1, level of evidence B)

• CEA is preferred to CAS in patients aged >70 years of age (grade 1, level of evidence A).

• Carotid artery stenting (CAS) should be reserved for symptomatic patients with 50% to 99% stenosis who are at high risk for CEA for anatomical or medical reasons.

• There are insufficient data to recommend CAS as primary therapy for neurologically asymptomatic patients with 70% to 99% diameter stenosis.

P. Poredos (Slovenia)

Carotid atherosclerosis causes 15% to 30% of acute ischemic strokes. In patients with asymptomatic carotid stenosis (ASCS), the average annual risk of stroke is up to 2% per year and the risk of coronary events is around 7%, while it rises to 20% in 3 months in symptomatic patients.

From the 10-year follow-up of theACST study, we know more about the natural history of carotid atherosclerosis. Of the 3210 followed-up patients, 50% had died at the end of the study, even in the younger groups (<75 years), stroke was the underlying cause in only 10%, and cardiovascular causes were responsible for almost 50% of total mortality.

The factors predicting the risk of ischemic cardiovascular events in asymptomatic carotid atherosclerosis are: severity of stenosis, progression of stenosis, structure of plaques, risk of atherosclerosis (systolic blood pressure, cholesterol, diabetes, smoking habits, and age), contralateral symptomatic carotid stenosis or occlusion, and silent ipsilateral cerebral infarctions. The risk of cardiovascular events increases with the grade of stenosis (up to 94%).

Atherosclerotic plaques, which are found in a majority of adults, represent a potential risk of vascular complications. The structure of plaque can be determined by ultrasound scan.

Geroulakos describes 5 types of plaques: type 1, uniformly echolucent; type 2, predominantly echolucent; type 3, predominantly echogenic; type 4, uniformly echogenic; and type 5, unclassified calcified plaque.

The histology of plaques is also related to embolic events and cerebrovascular complications. Echogenic and echolucent plaques have different compositions in terms of lymphocytes and macrophages, which determines their stability. Vulnerable carotid plaques are echolucent on ultrasound, have low gray-scale medians (GSM) and high concentration of inflammatory cells.

Take-home messages:

• Up to 30% of ischemic strokes are related to extracranial carotid atherosclerosis.

• As only a small portion of subjects with carotid atherosclerotic lesions develop cerebrovascular complications, it is important to identify those subjects at highest risk.

• The most significant predictors of cerebrovascular incidents are the degree of carotid stenosis, the structure of atherosclerotic lesions, and the degree of inflammation.

• Using new, noninvasive technologies (ultrasonography, positron emission tomography-computed tomography [PET/CT] scan), it is possible to identify the structure and stability of atherosclerotic plaques in vivo.

• It is expected that new diagnostic procedures will help identify those patients in whom intensive—including invasive—treatments would be most effective and indispensable.

G. Szendro (Israel)

Emergency carotid endarterectomy (CEA) can be performed in several symptomatic situations: in crescendo transient ischemic attack (TIA), stroke in evolution, or within 48 hours of the index event; however, the risk of postoperative stroke (immediate or late) is higher.

The merits of emergency carotid revascularization for acute stroke and fluctuating neurological deficits is no longer controversial and is becoming increasingly common. The indications for this procedure are acute or fluctuating hemispheric symptoms, significant carotid stenosis, no cerebral hemorrhage, and stable cardiopulmonary state.

The combined risk of neurological and cardiac complications after carotid endarterectomy (CEA) for crescendo TIA is high but still acceptable considering the natural history of patients with unstable neurologic symptoms (combined stroke/death rate of 7% compared with 2.4% in elective cases). In Szendro’s group, the combined stroke/death rate in the last 36 months in symptomatic patients was of only 1.5%.

Randomized trials confirmed the benefit of CEA in symptomatic patients with tight carotid stenosis. The timing of surgery in these patients is debated, the dilemma being the risk of recurrent stroke during the waiting period versus the risk of early intervention. There is a benefit from early intervention (<2 weeks). Two recent meta-analyses confirmed this with a stroke risk of 6.7% at 48 hours and 10 % at 7 days. The North Dublin population Stroke study reported a 5.6% rate of recurrent stroke at 72 hours with carotid stenosis being the only predictor.

However, so far no randomized controlled trial data support early CEA after an acute neurological event. In a systematic review, Rerkasem (Stroke, 2009) found no substantially elevated risk with early surgery in stable patients but found an elevated risk in patients with stroke in evolution or in crescendo TIAs. However, many other reports suggest a risk similar to that of stable patients. In their metaanalysis, Naylor and coworkers also reported a high rate of combined neurological and cardiac complications following urgent CEA for unstable neurological symptoms, and for crescendo TIA they found a 6.5% rate of perioperative stroke, a 9.0%rate of perioperative stroke and death, and a 10.9% rate of perioperative stroke, death, and major cardiac event. In patients with crescendo TIA and evolving stroke these risks rose to 16.9%, 20%, and 20.8%, respectively. Despite these numbers, most reports describe instantaneously improved neurological deficits and even full recovery in most cases of rescue CEA in selected patients. Intraoperative shunting is recommended although this recommendation is not evidence-based.

Carotid artery stenting (CAS) in emergency carotid stenosis is more controversial, because the safety and efficacy of urgent stenting have not been established and are usually not recommended in the acute setting. Sporadic reports show the feasibility and efficacy of urgent CAS, which can sometimes be helpful if combined with thrombolysis in acute symptomatic internal carotid artery occlusion.

Emergency intervention for internal carotid artery dissection could be performed with conservative treatment, open surgery, or CAS. Dissection can be spontaneous or post-trauma. There are very little controlled data, and most papers report casecontrolled and observational studies.

Conservative options include anticoagulation, antiplatelet drugs, and thrombolysis (intravenous or intra-arterial). A meta-analysis (Georgiadis, Neurology 2009) showed no benefit for anticoagulation compared with aspirin in stroke prevention. This was confirmed in a meta-analysis including 762 patients (Menon, J Neurosurg Psychiatry, 2008), which concluded that there are no data to support the superiority of anticoagulants over antiplatelet therapy, that thrombolysis appears safe but that more data is required, and finally that stenting is technically possible although there is no data to demonstrate its efficacy.

Surgery or stenting should only be undertaken very rarely in case of stroke recurrence or to restore cerebral perfusion if irreversible infarction has not occurred. Aneurysmal intervention is very rarely needed (up to 50% of aneurysms resolve or shrink in size). Aneurysm enlargement is very rare (Redekop, Can J Neurol Sci 2008). The mechanisms of thrombolysis remain unclear.

Emergency thromboembolectomy: although cardioembolic internal carotid artery occlusion is very rare due to cardiac emboli, some incidents happen during hospitalization. Is there a place for urgent open embolectomy? There is a 100% technical success rate, with clinical improvement in high-risk selected patients. Embolectomy should be considered immediately in patients with atrial fibrillation and a very short clinical course (Murata, Neurosurg Rev 2010).

Mobile/unstable carotid plaques are very rare, could be spontaneous or posttrauma. Although acute thrombosis is rare, it can be treated with a conservative approach (antithrombotic drugs, antiplatelet or anticoagulation, stenting, and CEA). In asymptomatic cases, conservative therapy is the most common approach whereas CEA is recommended in symptomatic patients; CAS could be an option in several cases.

Vascular injuries in the cervico-thoracic region have a 25% mortality rate, so aggressive management of unstable patients is recommended. In stable patients, imaging is mandatory. Urgent surgery is used more frequently in case of penetrating neck trauma, which is characterized by the following hard signs: hemorrhage, expanding hematoma, bruit/thrill, absent pulse, and hemodynamic instability. The surgical principles include damage control, occasional temporary shunt, and balloon tamponade with Foley catheter. In 220 patients, Navsaria (World J Surg 2006) used 17 hemostatic balloons for18 stab wounds and found 3 arterial injuries by arteriography (open surgery on those cases). Balloon removal was successful after 72 hours in 13 cases and 1 patient underwent emergency surgery after removing the Foley.

Anticoagulation is the gold standard to reduce strokes in patients with blunt trauma. Of 643patients screened by angiography for carotid injury, 114 (18%) had carotid lesions. Anticoagulation was used in 73 patients (0 strokes); while in 41 patients, anticoagulation was not used (19 strokes).

False aneurysms are very rare, post-CEA there are less than 0.4% to 1%, and there are anecdotic cases post-CAS or post-trauma. The dangers are rupture, embolization, thrombosis, and compression. Infection occurs in one-third of cases. The recommended treatment is open surgery; CAS can be used as a bridging procedure though it can occasionally be definitive.

A. von Ristow (Brazil)

Atherothrombosis is a multifocal disease, and in a high proportion of cases, carotid occlusive disease and coronary artery disease coexist in the same patient.

In the presence of severe carotid occlusive disease and coronary artery disease, carotid endarterectomy (CEA) and coronary artery bypass graft surgery (CABG) have been employed either in sequence or simultaneously for more than 40 years. There are three traditional strategies. Staged CEA followed by CABG, combined CEA and CABG, or staged CABG followed by CEA. Carotid artery stenting (CAS) can be an alternative to CEA in several cases (usually prior to CABG).

But the additional carotid operation seems to put patients at increased risk of perioperative complications such as stroke and myocardial infarction when patients present with other associated clinical conditions. The risk of stroke in simultaneous CABG and valve replacement ranges from 4.2% to 13.0%. With CABG, the risk of stroke is of 3.0% in patients with unilateral >50% carotid stenosis, 5% in patients with bilateral stenosis, and rises to 7% in case of occlusion. For this reason, most authors favor simultaneous CEA and CABG because stroke and 30- day mortality rates in selected centers range from 2.8% to 5.5% and 3.6% to 6.1%, respectively. However, in a systematic literature review, the combined rate of death, stroke, and myocardial infarction ranged from 9.7% to 17.7%.

In staged procedures, some patients die while waiting for the procedure. In 2006, Randall described that 5.7% of patients died prior to surgery and the total stroke and death rate at 30 days was 19.2% (Randall, Stroke 2006).

At Centervasc, after 2091 carotid revascularization procedures, the approach to the problem is to:

• Treat the symptomatic territory first, whenever possible.

• Perform simultaneous interventions only in unstable angina and severe carotid disease or coronary and cerebrovascular symptoms.

After initiating this strategy in 1988, staged CEA was performed and followed by CABG during the same hospital admission in 27 cases (without carotid operative mortality) and simultaneous CEA and CABG in 65 cases (which only prolonged the mean operative time by 45 min). There was no operative death, 5 cases of postoperative neurologic deficits (2 reversible and 3 irreversible with progression to death). The mortality after 30 days was 4.6%, and in these 3 patients the pump time was over 2 hours.

The overall incidence of stroke in CABG ranges from 1% to 2%; in patients with severe carotid disease, it can be up to 17%, but, despite this important correlation, only half of the strokes that occur during coronary surgery have a carotid etiology.

The etiology of perioperative stroke in CABG is multiple: embolism (air, calcium, aortic atheromatous debris, debris from extracorporeal circuits, thrombi…), aortic dissection, and hypotension.

If carotid stenosis is an important cause of stroke during open heart surgery, cerebral infarctions should be ipsilateral to the severely diseased vessel. Several studies have shown that this is not true. A severely narrowed or occluded carotid may in fact reduce embolization to the affected hemisphere.

The theoretic etiology of strokes during CABG include hypoperfusion (global or focal), and thromboembolic (heart or arterial) and hematologic etiology. During extracorporeal circulation, cerebral embolization seems unlikely. Perioperative hypotension may play an important role. Since hypotension is not totally preventable, all patients with high-grade carotid stenosis would be at risk. But the addition of a carotid intervention puts the patient at increased risk of preoperative complications.

In conclusion:

• Whenever possible, the symptomatic territory should be treated first.

• Simultaneous carotid and coronary revascularization should be undertaken in patients with symptoms in both territories.

• Symptomatic coronary patients with over 70% asymptomatic carotid stenosis, should also be operated simultaneously.

• The combination of CEA and CABG should not be abandoned, but should be restricted to specific situations—patients with unstable angina and severe carotid disease—and take place in centers having excellent results in both carotid and coronary surgery.

1.3. Restenosis

S. Misra (USA)

The author presented his experience in the vascular biology of hemodialysis vascular access restenosis. He described the cost of vascular access–related morbidity (up to 1 billion US $) and the need to study the exact etiology of vascular access failure to determine therapeutic targets.

Vascular access placement induces changes (compliance mismatch, shear stress, hypoxic injury, and inflammatory mediators) that modulate the expression of genes and proteins in the veins (in the adventitia, media, and endothelium) leading to changes in fibroblasts to induce SMC differentiation, migration, and proliferation.

These changes can be studied in animal (pig, mouse, and rat) and human models of arteriovenous fistula stenosis by assessing macrophage infiltration and measuring the expression of HIF-1a, VEGEF-A, MMP-2, TIMP-1, and ADAMTS-1.

Identifying the pathological pathway could help choose the appropriate treatment. The most exciting options at the moment are the “limus” drugs and paclitaxel.

P. Sedivy (Czech Republic)

From 1994 to 2011, the authors performed 4549 open carotid surgical procedures.

Restenoses of >70% were found in 186 cases(4.1%) after follow-up for 2 to156 months (median, 23 months). Restenosis was asymptomatic in 87% of patients and symptomatic in 13%. The authors reported a single TIA event in over 4549 procedures.

1.4. Peripheral arterial disease

T. G. Allison (US)

Exercise was presented as a therapeutic tool in patients with peripheral arterial disease who suffer from intermittent claudication. These patients have a high mortality.

The AHA/ACC Secondary Prevention Guidelines (2006 update) recommendations described peripheral arterial disease rehabilitation (a supervised program of exercise training) as the initial treatment modality for patients with intermittent claudication. (class 1, level A).

The exercise prescription for supervised endurance training in peripheral arterial disease with intermittent claudication must be carried out with a frequency of 3 to 5 times per week, on a treadmill, letting the patients walk until they experience the onset of ischemic pain, and repeating the exercise in successive periods of at least 50 minutes for each session.

The benefits of exercise training include improved walking distance and improved quality of life; however, there is no effect on the ankle brachial index (ABI). There are minimal increases in collaterals, which could demonstrate improved endothelial function, improved myocardial energetics, and reduced markers of systemic inflammation.

A. Nicolaides (UK).

Prof Nicolaides talked about the 10-year cardiovascular risk in the general population according to population studies such as Framingham and PROCAM. He pointed out that this risk is age driven. For example, a 75-year-old male without risk factors is at high risk because of his age and a 40-year-old female with several risk factors may be at lower risk, again because of her age. However, it is this female who needs risk factor modification. Prof Nicolaides pointed out that only 50% of heart attacks occur in high-risk groups and that 40% of the individuals who suffer myocardial infarction (MI) do not have conventional risk factors.

In the PROCAM study only 6.5% of subjects in the general population were at high risk (risk >20% at 10 years), 14% of the population was at intermediate risk (10%-20% risk at 10 years) and the rest of the population (79.5%) was at low risk (risk < 10% at 10 years). However, the percentage of myocardial infarctions was equally distributed in the 3 groups: (33% occurred in the high-risk group, 35% in the intermediate-risk group, and 32% in the low-risk group). It is therefore necessary to develop a methodology and strategy to make better predictions.

There are three methods that can complement the Framingham risk score and can help reclassify patients into higher or lower risk categories: ankle brachial index (ABI), coronary artery calcium score (CACS), and ultrasound arterial scanning.

ABI is not useful below the age of 70 because it will be normal in the vast majority of people. CACS can improve prediction in individuals in the intermediate Framingham risk group, but has several disadvantages: it cannot identify those with noncalcified plaques, it is expensive, and individuals are subjected to high radiation. Ultrasound scanning is the most practical and useful of the three as an initial screening tool. The presence of carotid bifurcation or common femoral bifurcation atherosclerotic plaques allows reclassification of individuals into the high-risk group, even in the absence of risk factors. Its successful prediction has now been demonstrated in many prospective studies

• In individuals aged >40 years and at low Framingham risk should be screened with ultrasonography (both carotid and common femoral bifurcations):
– The absence of plaques will confirm a low risk in 60% of cases. A repeat scan should be carried out 3 to 4 years later.
– The presence of plaques will result in reclassification to a higher risk in 40% of cases. Individuals should be advised about risk factor modification and the presence of nonconventional risk factor (eg, hyperhomocysteinemia) should be investigated.

• Individuals aged >40 years and at intermediate Framingham risk at 10 years should be screened with ultrasonography (both carotid and common femoral bifurcations):
– If plaques are present (in 80% of cases) aggressive risk factor modification is advised. Individuals with plaques should be told that the plaques should not be allowed to progress and that regression with treatment to target, which usually occurs in 28%, is associated with a 50% reduction in risk. Also, advise patients to have an annual ECG stress test.
– If plaques are absent (in 20%) then CACS may be performed. It will allow reclassification to a lower- or higher-risk group with confidence.

Individuals aged >40 years and at high Framingham risk are advised to have aggressive risk factor modification according to current guidelines. Screening with ultrasound in order to follow plaque progression or regression is optional. It can be used to motivate individuals to adhere to prophylactic measures.

J. Belch (UK)

The association between the presence of intermittent claudication (IC) and survival were presented by the author. For the following risk factors the odds ratio are significantly increased: male gender, age, diabetes, hypertension, hypercholesterolemia, and fibrinogen. Alcohol has a protective effect. The author described the different concepts and their relations:

• Peripheral arterial disease and inflammation: importance of the activity of white blood cells, E-selectin, C-reactive protein, and others. However, it is still unclear whether inflammation is a cause or a consequence.

• Genetics: there are studies showing the concordance of the ankle brachial index in twins, which suggests that genetic factors determine 48% of the variability in ankle brachial index scores after risk factor adjustment.

• Infection and peripheral arterial disease risk: smokers have more periodontal disease and H. pylori infection. It is not clear whether this is a cause or a consequence.

• Autoimmune disease: increased mortality in rheumatoid arthritis, sclerosis, and lupus (×3 to ×4) but the actual mechanism is still unclear.

• wInflammation as an acute response to exercise and alteration in skeletal muscle structure are recent findings but with unclear significance.

D. Mikhailibis (UK)

Prof Mikhailibis defended the increased use of aggressive approaches with statin treatment in order to decrease cardiac mortality with evident benefits even after short-term use. This treatment could also be positive in patients with decreased claudication and stroke. He mentioned that carotid plaque composition changes as a result of treatment with statins, and remarked on the significant decrease in intima media thickness and reduction in plaque with atorvastatin.

G. Geroulakos (UK)

The use of exercise as a therapeutic tool was discussed. Leisure time plus activity could decrease the risk in coronary artery disease by 30% to 50% and this effect is linear. The effect of aerobic training is multifactorial: increased HDL-cholesterol, decreased triglycerides, improved glucose tolerance, decreased blood pressure (systolic and diastolic) in normal-weight or overweight normotensive and hypertensive patients. Exercise duration, but not intensity, was the most important element of success. Inflammatory and lipid changes during protracted exercise were studied in a 246-km race (spartathlon). Impressive but reversible changes were observed. In the current climate of global economic recession, physical exercise is perhaps one of the very few nonpharmacological interventions that has a very significant benefit by reducing cardiovascular and all-cause mortality at no or low cost.

R. Cifkova (Czech Republic)

Prof Cifkova stated that the association between peripheral arterial disease and hypertension is underestimated and stressed the importance of hypertension treatment in order to decrease renal artery disease and cardiovascular mortality. She explained that only angiotensin-converting enzyme (ACE) inhibitors could increase walking distance. β-Blockers can be used in patients with peripheral arterial disease and there is no reason to restrict their use in the absence of other contraindications, especially in patients with critical ischemia where acute lowering of blood pressure is contraindicated.

1.5. Critical limb ischemia

N. Angelides (Cyprus)

Critical limb ischemia (CLI) is a severe arterial condition. One year after the initial diagnosis, only 56% of patients were alive with 2 viable legs, 26% had a major amputation, and 18% had died.

Progression of intermittent claudication to CLI occurs in less than 20% of nondiabetic patients whereas it occurs in more than 40% of patients with diabetes.

An initial endovascular attempt could be undertaken for all lesions (Trans-Atlantic Inter-Society Consensus [TASC] classification A to D) prior to any open surgery. Percutaneous catheter procedures are less traumatic, cheaper than surgery, and can be repeated with few complications. However the restenosis rate is still high (up to 30%).

The introduction of drug-eluting stents has partially solved the problem of early restenosis. These stents showed superiority to bare-metal stents in preventing tissue ingrowth even in the long term.

Drug-eluting balloons represent a novel option for the treatment of coronary and peripheral occlusive lesions. These balloons are coated with a drug that can be released when the balloon is expanded. The drug is absorbed in the wall of the vessel and can prevent tissue ingrowth. Drug-eluting balloons are mainly used in case of coronary in-stent restenosis, superficial femoral in-stent restenosis, as well as in distal blocked arteries. Some trials (THUNDER, PACIFIER, and LEVANT) are now in progress. LEVANT 1 and LEVANT 2 evaluated the safety and efficacy of Moxy drug–coated balloons in the treatment of femoro-popliteal segment occlusions and demonstrated that this coat strongly inhibits neointimal hyperplasia.

According to consensus documents, an open reconstructive procedure should be undertaken in patients with CLI when endovascular procedure has been unsuccessful and there is still a 25% of chance of saving the limb for a period of 1 year. The author has performed aorto-iliac bypass in TASC D and TASC C patients with tortuous and atherosclerotic arteries by means of a bifurcated prosthetic graft. The postoperative patency at 1 and 5 years is about 90% and 75%,respectively. Femoral-popliteal bypass grafts were performed in patients with TASC D and C lesions with tortuous arteries with multilevel occlusions. A vein graft is always preferred. Polytetrafluoroethylene (PTFE) grafts are used for abovethe- knee bypass because the results are good and the vein is preserved for a possible repeat surgery or for coronary vein bypass surgery. In case of graft occlusion, thrombolysis should be initiated as soon as possible. When there is no run off below the femoral artery, no tissue loss, nor rest pain, a primary amputation should be considered in order to avoid increased mortality and morbidity.

B. Brodman (Austria)

The value of primary balloon angioplasty in patients with critical limb ischemia (CLI) below the knee has already been reported; however, this is not the case for primary stent implantation.

The author reported a monocenter randomized controlled trial in 54 patients with CLI who had been treated by either percutaneous transluminal angioplasty (PTA) or stenting in the infrapopliteal arteries. They studied the effects of these treatments in terms of clinical benefits and rate of reobstruction at 1 year.

Clinical benefit was improved by at least one Rutherford classification in 81.5% of patients in the PTA group and by only 64.7% in the stent group. Similar positive results were observed for ulcer healing.

Reobstruction occurred in 39.4% of patients in the PTA group, compared with 66.7% in the stent group at 1 year of follow-up. The loss of primary patency as well as secondary patency was higher for the stent group after 1 year.

They concluded that PTA alone with the application of a modern hydrophilic balloon catheter is superior to primary stenting with expandable balloons.

M. Chochola (Czech Republic)

Critical limb ischemia (CLI) can lead to amputation in 25% of cases. Perfusion of bone marrow mononuclear cells (BMMC) is performed in order to achieve better angiogenesis.

In this study, intra-arterial infusion of BMMC was performed in 28 patients with severe CLI. Their clinical status and ankle brachial index (ABI) were evaluated every 6 months and their quality of life was assessed with the SF 36 questionnaire.

Only 2 major amputations were needed, with an improvement on defect healing and clinical status as well as on ankle brachial index (ABI), transcutaneous oxygen (TcpO2), and quality of life. After 5 years of follow-up, 14 patients had died (50%) due to multiple cardiovascular comorbidities. None of the surviving patients underwent major amputation.

This expensive therapeutic option could be suitable for the treatment of CLI in elective patients even if the long-term outcome is unfavorable due to the high mortality caused by cardiovascular comorbidities.

1.6. Stroke / atrial fibrillation

J. Biller (USA).

The pathogenesis of ischemic stroke includes various underlying diseases—large artery atherosclerosis, cardiac disease, small artery diseases, and other diseases such as the so-called cryptogenic stroke. Warfarin is effective in stroke prevention in patients at high risk of cardioembolic stroke, especially in those with nonvalvular atrial fibrillation but also in patients with recent myocardial infarction, dilative cardiomyopathy, mitral stenosis, mechanical prosthesis heart valve, or mechanical valve endocarditis. The risk profile of a patient can be calculated using a scoring system such as the CHADS2 or CHA2DS2VASc scores. Warfarin use significantly reduces the risk of all strokes, ischemic stroke, and all-cause mortality in comparison with antiplatelet therapy. However, there are no other potential indications for warfarin in the prevention of ischemic stroke.

At a high dose (150 mg twice daily), dabigatran was more effective than warfarin for the prevention of ischemic stroke, but at a low dose (110mg twice daily), it was equally as effective. However, the greatest efficacy in comparison with warfarin was reached at sites with poor international normalized ratio (INR) control. Both dabigatran and rivaroxaban have been approved for stroke prevention in patients with nonvalvular atrial fibrillation. Another oral anticoagulant, apixaban, is currently being reviewed by the American and European authorities for this indication.

S. Coccheri (Italy).

We will probably not have a head-to-head comparison of the new anticoagulants in the near future. According to the Euro Heart survey, 30% of high-risk patients with atrial fibrillation are undertreated, which means that the risk of ischemic stroke is twice higher. It is practically impossible to develop an absolutely safe anticoagulant. Attempts to introduce new anticoagulants were made with the goal of avoiding the need for laboratory monitoring and to maintain reasonable costs. The new anticoagulant drugs have some common properties (oral use, predictable dose-response, no need for laboratory monitoring, fixed or weightadjusted dosage). On the other hand, there are also differences in the properties of these new drugs as well as differences in the design of phase3 clinical studies with new anticoagulants in atrial fibrillation patients. Indirect comparison of the new oral anticoagulants has shown that they differ in some aspects. In comparison with warfarin, intracranial bleeding was reduced by all of them, especially by apixaban. Concerning all-cause mortality, superiority to warfarin was proved only for apixaban. When considering the number needed to treat (NNT) to prevent one stroke, high-dose dabigatran was the most effective. Rivaroxaban was less effective in secondary prevention but this finding might have been caused by a higher proportion of high-risk patients in the ROCKET-AF trial than in the other two atrial fibrillation studies.

In conclusion, careful reappraisal of the available data is needed before implementing these new drugs in routine clinical practice.

J. Harenberg (Germany).

The three new anticoagulants proved their superiority or equivalence in comparison with well-controlled warfarin therapy. However, it is highly unlikely that a direct comparison of their efficacy will be performed in the near future due to cost issues and complicated logistics. The author presented a special statistical method for an indirect comparison—a network meta-analysis. The results of three atrial fibrillation studies were evaluated: RE-LY (compared dabigatran at high or low dose versus warfarin), ROCKET-AF (rivaroxaban versus warfarin), and ARISTOTLE (apixaban versus warfarin). They assessed similar outcomes: stroke, systemic embolism, major bleeding, intracranial bleeding, and mortality. Some significant differences were found:

• High-dose dabigatran was superior to low-dose dabigatran as well as rivaroxaban in preventing ischemic stroke.

• High-dose dabigatran was associated with a mild increase in the incidence of myocardial infarction when compared with rivaroxaban.

• Apixaban induced less major bleeding than high-dose dabigatran

• Low-dose dabigatran was associated with less major bleeding, less intracranial hemorrhage, but slightly more myocardial infarction cases than rivaroxaban

• No significant differences were found between low-dose dabigatran and apixaban.

• Apixaban caused less major bleeding and slightly less (borderline significance) intracranial hemorrhage than rivaroxaban.

In conclusion, apixaban and low-dose dabigatran seem to have reached the best risk-benefit ratio.

W. Leong (Canada)

There are many issues remaining concerning the new anticoagulants. Their potential advantage, ie, no need for laboratory monitoring, may lead to very infrequent contact between patients and physicians. Taking a closer look at the results of the RE-LY study, well-controlled warfarin therapy was as good as dabigatran in stroke prophylaxis in patients with atrial fibrillation. In warfarin management, it is crucial to monitor the international normalized ratio (INR) carefully and reach the best possible time in the therapeutic range (TTR). Safety problems with the new anticoagulants are not negligible. In fact, specific patient populations may need laboratory monitoring but no reliable tests are currently available. In addition, no specific antidote has been developed so far. To date, clinical studies have excluded patients with specific problems (serious renal insufficiency, recent stroke). Some potential drug-drug interactions have also been reported with the new anticoagulants and uncertainty remains concerning the perioperative management of patients or the potential risk of combining these drugs with antiplatelet therapy. Therefore, warfarin will probably not become obsolete in the near future.

B. Kaiser (Germany)

In the final discussion of the session, the speaker described the differences among the new anticoagulants—different targets, and different pharmacokinetic and pharmacodynamic properties—and reminded the audience of their safety issues— absence of a specific antidote, possible accumulation in patients with renal impairment or hepatic disease, and potential drug interactions. She came to the conclusion that at present, there is no simple answer to the question of which anticoagulant to choose for stroke prophylaxis in patients with atrial fibrillation.

A Nicolaides (UK)

In the last 5 years the therapeutic attitude toward asymptomatic carotid stenosis patients has changed because with the use of aggressive medical therapy the annual risk of ipsilateral stroke is now close to 1%. This makes routine carotid endarterectomy unjustified. However, if patient subgroups with sufficiently higher than average risk, despite optimal intervention, could be reliably identified, then carotid surgery may still be justified. Three methods can be used to identify patents at increased risk.

(a) The presence of micro-embolic signals (MES) (>2/hour) using transcranial Doppler (TCD).

The ACES multicenter study (467 patients with >70% stenosis with a mean follow-up of 2 years; Marcus, Lancet Neurol 2010) demonstrated an 8% annual ipsilateral stroke risk in patients with MES on TCD, in contrast to 1% in patient without MES. In a meta-analysis of all the published studies MES were present in 15% to 20% of patients with ACS and their presence identified a high-risk group. However, this group contained only 54% of the strokes, thus, 46% of the plaques that produced a stroke were missed. This means that many plaques rupture without producing MES. Perhaps only plaques with a thrombus on their surface produce MES.

(b) The presence of Silent CT-Brain Infarcts.

The prevalence of silent CT-brain infarcts in asymptomatic patients having carotid endarterectomy (>70% NASCET) was 14% in one study (Martin, J Vasc Surg 1991) and 18% in another (Cao, J Vasc Surg 1999). In a prospective study (ACSRS) with 8 years of follow-up in 572 patients with 60-99% NASCET stenosis, the presence of silent embolic infarcts identified a group that had an annual stroke risk of 3.6% in contrast to 1% in those without such infarcts (Kakkos, J Vasc Surg 2009). However, this high-risk group contained only 30% of the strokes. This means that 70% of the plaques that produced a stroke were missed. Perhaps many plaques rupture and produce a stroke without any previous emboli or infarcts.

(c) Texture analysis of ultrasonic images of plaques.

The relationship between hypoechoic plaques and increased risk of stroke was demonstrated in four prospective studies: Polack (Radiology, 1998) showed a relative risk (RR) of 2.8; in the Tromso Study (Mathiesen, Circulation 2001), the RR was 4.6; Gronholdt (Circulation 2001) found a RR of 3.1, and Hashimoto (Cerebrovasc Dis 2009) found a RR of 4.4. The last three studies used gray-scale median (GSM) as a measurement of plaque echodensity.

In the ACSRS study (1121 patients with a 4-year mean follow-up), severity of stenosis, history of contralateral transient ischemic attack/stroke, low GSM, increased plaque area, and discrete white plaque areas (DWA) without acoustic shadowing were independent predictors of risk. These predictors allowed risk stratification from 0.1% per year to 10% per year (Nicolaides, J Vasc Surg 2010).

The presence of juxtaluminal black areas without a visible echogenic cap (JBA) is associated with a necrotic core located at a juxtaluminal position on histology with a sensitivity of 84% and specificity of 75% (Sztajzel, Stroke 2005). In the ACSRS study, this new ultrasonic feature, JBA, could identify a high-risk group with an annual stroke rate of 4.1%. This group consisted of 22% of the population and contained (42/59) 71% of the ipsilateral hemispheric strokes that occurred during the 8-year follow-up (Kakkos, J Vasc Surg 2012).

User-friendly software for image analysis and training is now is available for vascular labs and risk stratification is within the ability of every vascular lab as long as referring doctors request it.

1.7. Others

P. Poredos (Slovenia)

Atherosclerosis may be considered as a systemic (generalized) disease, and therefore:

• Patients with proven atherosclerotic disease are likely to have similar lesions in other vascular beds.

• With the progression of atherosclerosis, more vascular segments are affected and the prognosis worsens.

Advanced atherosclerosis is more widespread, and the prevalence of coronary heart disease (CHD) increases from 18% in patients with mild claudication to 48% in case of severe claudication (da Silva, 1981) and up to 90% if critical limb ischemia is present. The coincidence of peripheral arterial disease (PAD) and CHD depends on the type of diagnostic test. The rate of patients with concomitant PAD and CHD ranges from 20% to 50% if the diagnosis is based on history plus electrocardiogram (ECG) and from 80% to 90% if stress tests or angiography are used (Dormandy, 1992). This is of essential importance for prognosis. All-cause mortality after major vascular surgery depends on the number of vascular beds affected. In a study of 2933 patients, Kuijk (Eur Heart J 2010) showed that mortality increased linearly following parallel slopes (each one with an additional 15% increase in mortality) if 1, 2, or 3 vascular beds are affected. Mortality is mostly caused by cardiovascular events, as the REACH registry has showed.

Then, how to investigate patients with polyvascular disease? A systemic (global) disease may need a systemic (global) investigation, but advanced images of the whole body still have limitations; magnetic resonance imaging is expensive and time-consuming, computed tomography angiography produces radiation and contrast-related complications, and ultrasonography is time-consuming and some areas have limited accessibility. We must therefore choose from a number of basic investigations:

• In PAD patients we must use techniques for the identification of peripheral arterial lesions (Doppler, ultrasonography, angiography,…) and techniques for the recognition of atherosclerosis in other territories (electrocardiogram [ECG] and if necessary scintigraphy, exercise test, carotid ultrasound, and abdominal ultrasound).

• In CHD patients we must identify coronary lesions (ECG, stress test, coronarography) and search for atherosclerosis in other vascular beds (ankle brachial index [ABI], carotid bruit, and ultrasound).

• In cardiovascular disease (CVD) patients we must identify carotid lesions with ultrasonography and angiography and investigate other vascular beds with ECG and ABI.

For all patients we must remember the importance of ABI. This exploration must be performed in all patients with any atherosclerotic disease (CVD, CHD, and peripheral vascular disease [PVD]) particularly in those with polyvascular disease. It may be useful in subjects with no disease but with a high risk score.

What is the treatment for patients with polyvascular disease?

Risk factors should be managed and revascularization should be performed if needed.

The risk factors for atherosclerosis are multiple, and it is important to at least consider lifestyle (smoking, diet, and lack of exercise), hypercoagulable states, homocysteinemia, diabetes, obesity, genetics, hyperlipidemia, hypertension, age, gender, and infection. The REACH registry, with nearly 20 000 patients, has showed us that polyvascular disease patients have more risk factors (more weight for smoking, hypertension, and diabetes) than those with only one affected vascular bed. The control of risk factors in polyvascular disease must be more aggressive. The strategy is similar with medical therapy, so with more vascular beds involved, the treatment should be more aggressive.

There are differences in the relative weights of risk factors in the different vascular diseases:

• In CHD, hypercholesterolemia is the main risk factor, more so than smoking; the third risk factor is hypertension, while diabetes is the fourth.

• The risk factors for CVD are ranked as follows: hypertension > diabetes > dyslipidemia > smoking.

• For PAD, smoking is the main factor, followed by diabetes > hypercholesterolemia > hypertension.

On this basis, is the efficacy of the drugs used for the prevention of atherosclerosis comparable between different territories? Antiplatelet drugs seem to be more effective in the coronary bed (TRAN, JAMA 2004). From the CAPRIE study, we know that clopidogrel seems to be superior to aspirin in PAD, and aspirin is effective for prevention in CHD but not in PAD. Therefore, thienopyridines are probably the drugs of choice in PAD.

Statin trials in CHD have showed that a 1% reduction in LDL-cholesterol levels decreases cardiovascular events by 2%, and that secondary prevention of cardiovascular events in patients with PAD or stroke treated with statins decreases the number of cardiovascular events (Heart Protection Study, Lancet 2002). In fact, statin treatment provides benefits for all the vascular beds.

In patients with intermittent claudication, simvastatin 40 mg improves the painfree walking distance (Mondillo, Am J Med 2003), which could be a pleiotropic effect of statins. Angiotensin-converting enzyme (ACE) inhibitors: the HOPE study data demonstrate the absolute benefits of ramipril treatment in patients with multilevel disease.

β-Blocking agents are no longer contraindicated in patients with PAD, and could be prescribed in those with polyvascular disease.
Polyvascular disease patients undergoing revascularization are at increased risk for intraoperative complications related to atherosclerotic lesions in other territories; they have higher postoperative mortality rates, and invasive procedures may be limited due to multifocal limitations. Validated information is lacking regarding both the efficacy of these procedures in elderly patients and priority of revascularization.

Patients undergoing treatment for myocardial infarction (MI) have a 3-fold increased risk of in-hospital major events (7% to 20.4%) and mortality (3.7% to 13%) in case of associated PAD (Jeremias, AJC 2010), and the REACH registry (JAMA 2007) shows a 2-fold lower mortality for all causes such as CV death, myocardial infarction, and stroke in patients with disease in only one vascular bed compared with those with polyvascular disease .

How can we establish the priority of revascularization in patients with polyvascular disease? Surgical procedures (open or percutaneous) must first be performed in the territories with the most advanced atherosclerotic lesions and when atherosclerosis disease is the most life-threatening.

Revascularization priority should thus be given as follows:

I. Dissecting aortic aneurysm, acute myocardial infarction (ST-segment elevation myocardial infarction).

II. Acute coronary syndrome, symptomatic carotid stenosis, critical limb ischemia.

III. Asymptomatic critical carotid stenosis, asymptomatic AA (>4.5 cm) and limiting intermittent claudication.

When these conditions are concomitant, the priority must be to treat the carotid first, followed by the coronary and peripheral arteries later.

R. F. Shepherd (USA)

Upper extremity arterial disease is less commonly encountered than disease of the lower members, with a wide range of diverse disorders and clinical presentations resulting from the large proximal arteries, smaller digital arteries, or the microvasculature.

Digital ischemia may be constant or episodic due to reversible vasospasm or fixed obstructive disease.

Reversible vasospasm is typical of Raynaud’s phenomenon, persistent cyanosis, etc… but could be permanent in scleroderma and lead to critical ischemia.

To assess circulation deficits, noninvasive methods (laser Doppler, plethysmography, arterial waveforms, segmental blood pressure measurements, finger systolic pressure, basal and thermal challenge, and “cold” or “hot box”) and imaging studies (contrast angiography, duplex ultrasonography, computed tomography angiography, magnetic resonance angiography) can be used.

• The treatment of Raynaud’s remains unsatisfactory because only half of the patients respond to medication and there is poor correlation between the laboratory effect of a medication and clinical response. For this reason, there are multiple therapeutic options and different treatments.

• The few randomized studies that were carried out involved small numbers of patients. In up to 305 cases, the placebo effect was involved. In addition, there are differences in the response of primary and secondary Raynaud’s.

• For the treatment of Raynaud’s, the first step is to prevent vasospasm and improve distal blood flow. A wide range of drugs can be used:

• Direct vasodilators (nitroglycerin), usually in topical form (gel or patches). They can be effective in primary Raynaud’s but their use is limited by side effects (headaches in up to 80% of cases, and hypotension). In a limited number of patients (10 with primary Raynaud’s, 13 with scleroderma, 10 controls), Anderson (Rheumatology 2002) applied 2% topical glyceryl trinitrate to one finger, placebo treatment to a second finger, and left a third finger untreated. Scanning with laser Doppler to measure immediate baseline microvascular blood flow, at 10 and 20 minutes, Anderson found increases in flow in the three treated fingers.

• Calcium channel antagonists (nifedipine, amlodipine). Thompson reviewed18 studies, 13 studies assessing amlodipine vs placebo, and 5 other studies assessing a different CCB vs placebo, including a total of 348 patients with 10.8 attacks/week (Rheumatology 2005). Although he found a 35% reduction in the severity of attacks, the initial benefits were not sustained (tachycardia, headache, edema flushing).

• α-Blockers (a1): Minipress (prazosin), Cardura (doxazocin). Their secondary effects are similar to those of CCBs.

• Prostaglandins (iloprost, prostaglandin E1). They have vasodilatory and antiproliferative effects and inhibit platelet aggregation but they have side effects (headache, flush, nausea, and pulmonary edema). Wigley conducted a multicenter trial (Ann Inter Med 1994) that showed the benefits of iloprost in patients with systemic sclerosis in ulcer healing and improved Raynaud’s scores by 39% (22% in the placebo group). Oral prostaglandins are not effective.

• Phosphodiesterase inhibitors. They inhibit cyclic GMP in vascular smooth muscle. They are useful for erectile dysfunction and pulmonary hypertension. In a single center study with 16 patients with secondary Raynaud’s treated for 4 weeks with 50 mg sildenafil twice a day, laser Doppler showed improved capillary blood flow, a significant reduction in the number of attacks (36 vs 52), and ulcer healing.

• Antiplatelets and anticoagulants (Plavix, heparin).

• Agents improving endothelial function: bosentan, ET-1 receptor antagonist. As endothelin is a potent vasoconstrictor, its antagonist is used in pulmonary hypertension in patients with systemic sclerosis. The RAPID-1 and RAPID 2 trials (Arthritis Rheum 2004) have showed a role in Raynaud’s. RAPID-1 evaluated the use of bosentan in 122 patients with systemic sclerosis in an international, multicenter, placebo-controlled, double-blind trial. Bosentan reduced the onset of new digital ulcers in 48% of patients but did not alter the time of healing. RAPID-2 (188 patients with secondary Raynaud’s) showed a decrease in the number of new ulcers (1.9 vs 2.7). The use of this drug could be limited because it has a black box warning about potential liver toxicity (3-fold increase in liver enzymes in 11% of patients) and FDA pregnancy category X rating because it is very likely to result in major birth defects if used by pregnant women.

• Novel therapies:

– Herbal preparations (Gingko biloba)

– Fish oils (decrease thromboxane a2)

– Losartan (angiotensin receptor blocker [ARB], antifibrotic)

– Biofeedback (to raise digital temperature)

– Traditional Chinese acupuncture

– Spinal cord stimulation

– Pneumatic compression: using an inflatable cuff around the arm with rapid, graduate, sequential, and pulsatile compression. The distal compartment is inflated to 95 mm Hg, 0.3 seconds later, the proximal compartment inflates to 85 mm Hg; after 2 seconds of compression, the cuff deflates and the cycle is repeat every 20 seconds. This device seemed to improve ulcer healing.

– Botox, use of botulinum toxin type A has been reported by Neumeister (Plast Reconstr Surg 2009), in a retrospective study of 19 patients with ischemic hand pain. A total of 16 patients reported pain reduction and 12 (63%) remained free of pain 1 year later. Doppler showed increased tissue perfusion (from 48% to 425%). In a study of 11 patients with nonhealing ulcers, Van Beek (Plast Reconstr Surg 2007) showed healing in 9 of them and pain relief in all of them.

M. G. Costopoulos (USA)

Loeys-Dietz syndrome can be confused with Marfan disease. The author presented the clinical case of a man aged 48 years with previous thromboembolic strokes currently treated with oral anticoagulation. The patient needed urgent repair of the ascending aorta due of a Stanford type A dissection from the origin of the artery to the iliac arteries with a St Jude aortic valve conduit. Genetic testing was positive for the presence of the TGFBR-2 gene mutation. The patient was left with renal insufficiency. Physical examination was positive for thoracic kyphosis, pectus excavatum, and dolicocephaly.

This syndrome was described by Loeys and colleagues in 2008. It is transmitted genetically as an autosomal dominant disease and shows four specific features: aneurysm and dissection throughout the arterial tree, generalized arterial tortuosity, hypertelorism, and bifid uvula. These signs could be associated with sinus of Valsalva aneurysm, patent ductus arteriosus, atrial septal defects, bicuspid aortic valve, and other features (mental retardation, craniosynostosis, arachnocdactyly, joint laxity, malar hypoplasia, retrognathia, arched palate, blue sclera, easy bruising, dystrophic scars, translucent skin, cervical spine instability, scoliosis, and club foot deformity).

If there is cranio-facial involvement, the disease is named type I, as opposed to type II, which does not show cranio-facial involvement.

Phenotype similarities exist with Marfan disease, but in Loeys-Dietz syndrome, the aneurysms are more aggressive (ruptured and of smaller size) and biosynthesis of fibrillin-1 is normal. The explanation for the similar features between both diseases could be that both TGF-β and fibrillin-1 have a functional role in the synthesis of microfibrils.

There are also similarities with the Ehlers-Danlos type IV phenotype but type III collagen biochemistry is normal.

Treatment has poor results. Early intervention for aneurysmal disease and aggressive control of blood pressure must be performed.

Only two treatments are promising:

• Losartan (which could control arterial pressure and have a secondary effect by blocking TGF-β activity).

• Dexamethasone (which induces a beneficial upregulation in the expression of specific mRNAs leading to the normalization of elastic fiber production in fibroblasts with TGFBR-1 mutations and corrects the abnormal secretion of type 1 collagen in fibroblasts with TGFBR-2 mutations).

J. Bultas (Czech Republic)

More than 30% of patients treated with dual antiplatelet therapy are cotreated with proton pump inhibitors (PPIs), but when these two types of drugs are combined, they are associated with reduced therapeutic effect and with increased cardiovascular risk (hazard ratio, 1.4 for cardiovascular mortality, myocardial infarction, or stroke). This effect seems to be smaller with rabeprazole and pantoprazole and could even disappear in as little as 12 hours if the drugs are discontinued. Another possibility is the use of new drugs that do not need bioactivation with CYP2C19, like ticagrelor, or have a pro-drug with PPI-resistant bioactivation, like prasugrel.

There is another question: do PPIs also interact with aspirin? The answer is yes. Aspirin needs an acid pH (<3.5) for its bioavailability and PPIs interact with its absorption. The antiplatelet effect of comedication is unpredictable. Thus, patients with a high risk of bleeding could be treated by prasugrel or ticagrelor; Helicobacter pylori should be eradicated and PPI comedication should not be used. H₂ Inhibitors should be considered instead of a PPI. Pantoprazole could be an alternative.

C. Thalhammer (Switzerland)

Central venous pressure is a very important factor in the management of some intensive care patients, eg, patients with cardiac failure, volume overload, and sepsis. Until now, only invasive measurement has been possible. The authors presented a new noninvasive and simple method. They used a special device in connection with compression ultrasound. They compressed a superficial vein of the forearm with an ultrasound probe. They measured the lowest possible pressure necessary to fully compress the venous lumen, and based on this value and on the vertical distance between the site of measurement and the heart level, they calculated the central venous pressure.

They tested this method for peripheral venous pressure measurement in healthy volunteers with experimentally induced venous hypertension as well as for central venous pressure measurement in 50 intensive care patients with a central venous line. In both groups, they found a very good correlation between the results of invasive and noninvasive venous pressure measurements.

M. Aschwanden (Switzerland)

Both the feasibility and the accuracy of the above described methods of noninvasive central venous pressure measurement with the use of compression ultrasound were tested. The results obtained with a high-end ultrasound machine and with portable ultrasound were compared. Further on, the differences in results between 2 groups of investigators were also compared: vascular specialists and nonvascular physicians who had completed a short training on this method. Both groups performedmeasurements in 50 patients in an intensive care unit. The maximal time of measurement was 8 minutes, and feasibility ranged from 88% to 92%. No significant differences were found between the two types of ultrasound machines and the two groups of investigators. The authors concluded that compression ultrasound seems to be an effective method for noninvasive central venous pressure measurement in clinical practice.

P. Sedivy (Czech Republic)

The author related his experience in 990 cases of endovascular abdominal surgery.

Patients with special conditions were treated: 4% after open surgery and 3%with infected aneurysms.

In the patients with infected aneurysms, antibiotic therapy was given 2 to 4 weeks before the procedure and 4 to 6 weeks after. In the patients presenting Salmonella infection, the antibiotic was maintained in the long term after the procedure (12 months).

P. Stadler (Czech Republic)

Robots represent the next step in minimally invasive surgery.

The authors used the Da Vinci robotic system between November 2005 and November 2011, performing 225 robotic-assisted laparoscopic aorto-iliac procedures.The clamping time was between 21 and 120 minutes according to the learning curve (ie, decreasing with experience). Conversion was made in 9 cases (3.8%)

The authors demonstrated the feasibility of this technique on aorto-iliac and hybrid procedures and in case of a difficult approach as for some visceral aneurysms, mammary artery aneurysms, and endoleak II – treatment.