Authors

• Marco De Carlo — Pisa, Italy
• Lucia Mazzolai — Lausanne University Hospital, Lausanne, Switzerland
• Eduardo Bossone — University Hospital, Cava de’ Tirreni, Italy
• Marianne Brodmann — Medical University Graz, Graz, Austria
• Antonio Micari — Maria Cecilia Hospital, Cotignola, Italy
• Maria Lorenza Muiesan — University of Brescia, Brescia, Italy
• Jean-Baptiste Ricco — University Hospital of Poitiers, Poitiers, France
• Eugenio Stabile — University of Napoli “Federico II”, Napoli, Italy
• Giancarlo Agnelli — University of Perugia, Perugia, Italy
• Victor Aboyans — Dupuytren University Hospital, Limoges, France

DOI

Full Text

## Preamble In an epidemiological update in 2016, cardiovascular (CV) disease has been estimated as cause of 45% of deaths in Europe, including 12% due to stroke and 14% to other CV diseases, highlighting the major burden of non-coronary artery diseases (i.e. aorta, carotid, and lower extremity arteries) and venous thromboembolism (VTE) in our continent (**Figure 1**). (1) Similar to previous years, (2, 3) relevant scientific evidence in these fields was brought out in 2016 which will affect our daily clinical practice. Figure 1. Proportion of all deaths due to major causes in Europe, latest available year (adapted from Townsend). (1) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. ## Carotid artery disease In the new ‘2016 European guidelines on cardiovascular disease prevention in clinical practice’, the usefulness of carotid intima-media thickness to stratify CV risk has been strikingly challenged, and this marker is no longer recommended due to its high variability, low intra-individual reproducibility, and lack of added predictive value, even in intermediate risk subjects. (4) In opposition, carotid plaque remains a valuable tool for CV risk stratification. In 2016, the long-term clinical equipoise of carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) was confirmed by the 10 year analysis of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), reporting similar rates of death, stroke, or MI within 30 days, or ipsilateral stroke up to 10 years for both strategies (11.8% vs. 9.9%; P = 0.51) (**Table 1**). (5) ### Table 1: Summary of major randomized trials in the aorta, peripheral artery diseases, and venous thrombo-embolic disease in 2016. | **Trial** | **Type and aim** | **Challenger** | **Reference** | **N** | **Setting (indication)** | **Primary endpoint** | **Main hypothesis validated?** | | --- | --- | --- | --- | --- | --- | --- | --- | | **Carotid arteries** | | | | | | | | | ACT-1 (6) | Open: non-inferiority (3% margin) of CAS vs. CEA | CAS | CEA | 1453 | Asymptomatic patients at average surgical risk | Death, stroke, or MI within 30 days, or ipsilateral stroke up to 1 year | Yes | | CREST (10 years) (5) | Open: superiority of CAS vs. CEA | CAS | CEA | 2052 | Symptomatic or asymptomatic carotid stenosis | 10 year composite of any stroke, MI, or death | No | | Aorta | | | | | | | | | AARDVARK (24) | Single blind: perindopril vs. amlodipine vs. placebo to reduce AAA growth | Perindopril 10 mg OD | Amlodipine 5 mg OD or placebo | 224 | Patients with AAA (30–54 mm) | Change in AAA diameter | No | | **Lower extremity artery disease** | | | | | | | | | EUCLID (25) | Double blind: superiority of ticagrelor vs. clopidogrel in PAD patients | Ticagrelor 90 mg BID | Clopidogrel 75 mg OD | 13 885 | ABI ≤0.80 or prior revascularization | Efficacy: composite of CV death, MI, or stroke at 3 years | Efficacy: no | | Safety: major bleeding | Safety: yes | | | | | | | | EUCLID prior revascularization subgroup (26) | Double blind: superiority of ticagrelor vs. clopidogrel in LEAD patients | Ticagrelor 90 mg BID | Clopidogrel 75 mg OD | 7875 | Prior revascularization | Efficacy: composite of CV death, MI, or stroke at 3 years; acute limb ischaemia | Efficacy: no | | Safety: major bleeding | Safety: yes | | | | | | | | TRA2°P—qualifying LEAD subgroup (27) | Double blind: superiority of vorapaxar vs. placebo on top of aspirin and/or thienopyridine | Vorapaxar 2.5 mg OD | Placebo | 3787 | Claudicants with ABI ≤0.85 or prior revascularization | Efficacy: acute limb ischaemia up to 3 years | Efficacy: yes | | Safety: severe bleeding | Safety: yes | | | | | | | | TRA2°P—known LEAD subgroup (28) | Double blind: superiority of vorapaxar vs. placebo on top of aspirin and/or thienopyridine | Vorapaxar 2.5 mg OD | Placebo | 5845 | Claudicants with ABI ≤0.85 or prior revascularization | Efficacy: peripheral revascularization up to 3 years | Efficacy: yes | | Safety: severe bleeding | Safety: yes | | | | | | | | IN.PACT SFA I (3 years) (29) | Open: superiority of DEB vs. PTA for FP lesions | DEB | PTA | 331 | Rutherford class 2 to 4 FP lesions | Efficacy: 3 year primary patency; freedom from CD-TLR | Efficacy: yes | | Safety: death, clinically driven TVR, major amputation, thrombosis | Safety: yes | | | | | | | | ZILVER PTX (5 years) (30) | Open: superiority of DES vs. PTA for FP lesions | DES | PTA | 474 | Rutherford class 2 to 6 FP lesions | 5 year primary patency; freedom from CD-TLR | Yes | | **Venous thrombo-embolic disease** | | | | | | | | | CACTUS (37) | Open; superiority of 6 week nadroparine vs. placebo in low-risk patients with symptomatic calf DVT | nadroparine 171 UI/kg OD | Placebo | 259 | Symptomatic first isolated distal DVT event | Efficacy: composite of proximal DVT extension, contralateral DVT, and PE | Efficacy: no | | Safety: bleedings | Safety: no | | | | | | | [†] AAA, abdominal aortic aneurysm; CAS, carotid artery stenting; CD, clinically driven; CEA, carotid endarterectomy; DEB, drug eluting balloon; DVT, deep vein thrombosis; FP, femoro-popliteal; LEAD, lower-extremity artery disease; MI, myocardial infarction; PE, pulmonary embolism, PTA, percutaneous transluminal angioplasty; TLR, target lesion revascularization; TVR, target vessel revascularization. Peri-procedural stroke during CAS is often related to plaque embolization. The randomized Asymptomatic Carotid Trial (ACT) I compared CAS with embolic protection to CEA in 1453 patients with asymptomatic carotid stenosis, not considered at high surgical risk (**Table 1**). (6) The composite endpoint of death, stroke, or MI at 30 days, or ipsilateral stroke at 1 year, was non-inferior in CAS vs. CEA (3.8% vs. 3.4%; P = 0.01 for non-inferiority); however, peri-procedural stroke rates numerically favoured CEA (1.4% vs. 2.8% for CAS, P = 0.23). Notably, in 2016, three small prospective registries reported peri-procedural stroke rates as low as 0–0.9% with the new dual-layered carotid stents, consisting of a thin-strut nitinol stent covered with a nitinol mesh. (7-9) While surgery remains the procedure of choice, the pending question is the risk stratification of patients with asymptomatic carotid stenosis who would benefit from revascularization. ## Aortic diseases The multicentre Normal Reference Ranges for Echocardiography (NORRE) study provided reference values for echocardiographic measures, taking into account different measurements conventions, and timing of the cardiac cycle. (10) Normal values apply also to athletes, as shown by a study on 3281 healthy elite athletes which reported that 1.8% of men and 1.5% of women had ascending aorta diameters >40 mm and 34 mm, respectively. (11) Important data were recently published regarding the assessment of the risk of aortic dissection (AD) in subjects with moderately dilated ascending aorta. (12) Among 4654 individuals, the 5 year risk of AD and/or rupture was 0.4%, 1.1%, and 2.9% at baseline aortic diameters of 45 mm, 50 mm, and 55 mm, respectively. Therefore, the finding of aortic root dilatation indicates the need for a work-up of underlying conditions and scheduled monitoring. Important steps in the understanding of genetic aortic diseases have been taken. In particular, loss-of-function mutations in lysyl oxidase (LOX) genes, involved the regulation of the stability and integrity of elastin and collagen, were identified in families with inherited predisposition for thoracic aortic diseases. (13) Introducing a human LOX mutation in the mouse genome caused ascending aortic aneurysm and spontaneous haemorrhage in mice that were homozygous for the human allele, likely through insufficient cross-linking of elastin and collagen in the aortic wall. (14) In patients with Marfan syndrome (MFS), the impact of genotype on aortic phenotype severity was demonstrated in the Dutch CONgenital CORvitia registry (**Figure 2**). (15) Among 357 patients with mutations of the fibrillin-1 gene, those with mutations causing reduced amount of fibrillin-1 protein had a worse 8 year prognosis than those with dominant-negative mutations (production of abnormal fibrillin-1 protein), with 2.5-fold, 2.4-fold and 1.6-fold increase in the risk of cardiovascular mortality, death or aortic dissection, and any aortic complication, respectively. Figure 2. Prevalence of genetic abnormalities and outcomes according to subgroups in the Dutch CONgenital CORvitia registry (adapted from Franken). (15) This Figure has been reprinted by permission of Oxford University Press on behalf of the European Society of Cardiology. Other prognostic data were reported from the GenTAC registry, including 1991 patients with genetically associated thoracic aortic aneurysms (TAA). (16) During an average follow-up of 3.6 years, 1.6% of patients experienced type-A AD; however, only 13% met the guideline criteria on aortic size for TAA repair. Importantly, MFS conferred a seven-fold increase in the risk for AD. Another report from the GenTAC registry described the outcome of 94 women with MFS who had a total of 227 pregnancies, reporting 10.6% pregnancy-related aortic complication rates, with eight-fold increased risk for AD. (17) In type-B AD, standard of care is medical management for uncomplicated cases and thoracic endovascular aortic repair (TEVAR) for complicated ones. However, a recent retrospective study on 338 patients with uncomplicated type-B AD comparing immediate TEVAR (n = 184) to medical therapy (n = 154) showed that 30 day mortality was similar, but medically treated patients had significantly higher mortality (P = 0.01) and aortic-related adverse event rate at 5 year follow-up (P = 0.025). (18) Another retrospective study on 156 patients with uncomplicated acute type B-AD identified an aortic diameter >44 mm as independent predictor of mortality during a median follow-up of 3.7 years; an aortic diameter >44 mm and a false lumen diameter >22 mm were associated with decreased intervention-free survival. (19) These data contribute to the identification of high-risk criteria favouring early TEVAR. A frequent complication of TEVAR, the post-implantation syndrome (PIS)—defined as fever >38 °C, white blood cells >12.0/nL and C-reactive protein >10 mg/dL within 72 h after TEVAR despite negative blood culture—was reported in 16% of cases with type-B AD; PIS did not affect in-hospital outcome, but was associated with increased rates of major adverse events (death, aortic rupture and need for reintervention) at 4 year follow-up (62.5 vs. 25.9%; P = 0.004). (20) Ultrasound screening of abdominal aorta aneurysms (AAA) is recommended in all men >65 years (Class I A), and possibly in women >65 years who smoke (Class IIb C). (21) A Finnish study on 585 patients with ruptured AAA, challenged these recommendations, as 21% of men and 3% of women were 250 ug/L) | 5 (abnormal) | 2 | | Obesity [O] | 1 (BMI≥ 30) | 2.5 (BMI> 30) | | | Age [O] [A] | 1 (≥65 years) | 1→6 (10→90 years) | 0.98 | | Genetic thrombophilia [M] | | 5 | | | Varicose veins [V] | | 2.5 | | | Factor VIII activity [E] | | 1.5→10 (50%→400%) | | | Male sex [S] | | 2 | 2 | | Proximal vein thrombosis or pulmonary embolism | | | 5 | | Time between cessation of anticoagulation and D-dimer measurement (days) | | | 0.74 | | Cut-off value for score | ≥2 | ≥11.5 | – | [†] Numbers represent the value attributed to each characteristic in the scores; capital letters in brackets represent the letter chosen for the score acronym. **Numbers represent hazard ratios and not score values. Unprovoked VTE may be an early sign of cancer. It remains unclear whether a subgroup of high-risk patients with unprovoked VTE could potentially benefit from a more extensive screening strategy. The Screening for Occult Malignancy in Patients with Idiopathic Venous Thromboembolism (SOME) trial showed that age, smoking status, and prior provoked VTE may be important predictors of occult cancer in patients with first unprovoked VTE (combined effect HR 3.33; P < 0.001). (36) Whether isolated distal deep vein thrombosis (DVT) requires anticoagulation is still debated. The recent CACTUS trial randomized low-risk outpatients (without active cancer or previous VTE) with a first isolated distal DVT to receive subcutaneous low-molecular-weight heparin (LMWH) or placebo for 6 weeks. (37) Rates of symptomatic VTE were not different between the two groups (3% vs. 5%; P = 0.54), while bleeding risk was higher (4% vs. 0%; P = 0.03) (**Table 1**). Although the trial was largely underpowered given the low event rates, it suggests that not all low-risk outpatients with symptomatic isolated distal DVT should receive full-dose LMWH. Alternative strategies such as prophylactic LMWH doses and direct oral anticoagulants (DOAC) need to be investigated. Following large-scale phase-III clinical trials, real-world data confirm safety and effectiveness of DOACs as alternative to standard anticoagulation in a broad range of patients. Recent data pointed out to increased vaginal and heavy menstrual bleeding in women treated with anti-Xa drugs. (38) However, most of patients could be treated conservatively. Among reversal agents, the antiXa andexanet reduced anti-factor Xa activity in acutely bleeding patients and assured effective haemostasis in 79% of cases. (39) In patients with contraindication to anticoagulation, evidence for inferior vena cava filter use remains elusive. Recent data showed that, in non-cancer acute VTE patients, filter use was associated with a significant reduction in 30 day mortality only in case of contraindication to anticoagulation because of bleeding (HR, 0.68). (40) However, risk of subsequent DVT increased by 135%. Pulmonary embolism (PE) is part of the differential diagnosis of syncope; a recent prospective study on 560 patients hospitalized for syncope reported a 17.3% prevalence of PE in this population, supporting the inclusion of PE imaging in the diagnostic workup of syncope. (41)

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