Online sample Vasa 2019 by Hogrefe

Volume 47 / Number 1 / 2018

Vasa European Journal of Vascular Medicine

Editor-in-Chief Andreas Creutzig Editors Beatrice Amann-Vesti Erich Minar Pavel PoredoĹĄ Omke Teebken

Soziale Ungleichheit im Gesundheitswesen

Johann Behrens / Markus Zimmermann (Hrsg.)

Sozial ungleich behandelt? A. Sens und P. Bourdieus Theorien und die soziale Ungleichheit im Gesundheitswesen – am Fallbeispiel präventiver Rehabilitation 2017. 278 S., 113 Abb., 30 Tab., € 39,95 / CHF 48.50 ISBN 978-3-456-84765-8 Auch als eBook erhältlich

Seit mindestens 2400 Jahren, seit den hippokratischen Schriften, schwören ärztliche und andere Gesundheitsberufe, ihre Patienten nicht nach Kaufkraft und Stand, sondern allein nach ihren Bedürfnissen zu behandeln – und wenn sie dafür auf jedes Honorar verzichten müssten.

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Seit mindestens 70 Jahren hilft ihnen die solidarische Finanzierung durch Steuern oder Sozialversicherung, ihren Schwur einzuhalten. Kann die Finanzierungsgarantie eine gleiche Behandlung sichern? Im Anschluss an die Theorien von A. Sen und P. Bourdieu wird diese Frage empirisch am Beispiel präventiver Rehabilitation erörtert.

Vasa European Journal of Vascular Medicine

Volume 47 / Number 1 / 2018

Editor-in-Chief Andreas Creutzig Editors Beatrice Amann-Vesti Erich Minar Pavel PoredoĹĄ Omke Teebken

Editor-in-Chief

A. Creutzig, Hannover, andreas@creutzig.de

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A. Blinc, Ljubljana H. Bounameaux, Geneva R. Brandes, Frankfurt M. Brodmann, Graz A. Broulíková, Prague M. Bulvas, Prague L. Caspary, Hannover A. Chraim, Lviv M. Czihal, Munich E. S. Debus, Hamburg F. Dick, St. Gallen N. Diehm, Aarau C. Espinola-Klein, Mainz P. Fitzgerald, Dublin A. Gottsäter, Lund V. Hach-Wunderle, Frankfurt U. Hoffmann, Munich M. Husmann, Zurich C. Jeanneret, Bruderholz M. Lichtenberg, Arnsberg F. Khan, Dundee P. Klein-Weigel, Berlin K. Kröger, Krefeld P. Kuhlencordt, Hamburg

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Vasa (2018), 47 (1), 2

Contents Editorial

Do we have to change therapeutic considerations in peripheral arterial disease? Robert Berent and Helmut Sinzinger

Reviews

Carotid stenosis – basing treatment on individual patients’ needs. Optimal medical therapy alone or accompanied by stenting or endarterectomy

Ralf Langhoff Surgical and endovascular venous arterialization for treatment of critical limb ischaemia

Michael Lichtenberg, Michiel A. Schreve, Roberto Ferraresi, Daniel A. F. van den Heuvel, Çagdas Ünlü, Vincent Cabane, and Steven Kum 23

Posterior nutcracker syndrome – a systematic review Jae Hyon Park, Gi Hoon Lee, Seul Mi Lee, Michael Eisenhut, Andreas Kronbichler, Keum Hwa Lee, and Jae Il Shin Original communications

Sensitivities of in vivo markers of arterial organ damage in patients with peripheral atherosclerosis

Martina Frick, Frederic Baumann, Beate Sick, Ian B. Wilkinson, Beatrice Amann-Vesti, and Marc Husmann 36

Gender differences in abdominal aortic aneurysms in Germany using health insurance claims data Konstanze Stoberock, Henrik Christian Rieß, Eike Sebastian Debus, Thea Schwaneberg, Tilo Kölbel, and Christian-Alexander Behrendt Mortality in endovascular and open abdominal aneurysm repair – trends in Germany

Olga von Beckerath, Sebastian Schrader, Marcus Katoh, Bernd Luther, Frans Santosa, and Knut Kröger 49

Treatment of femoropopliteal lesions with the AngioSculpt scoring balloon – results from the Heidelberg PANTHER registry Ira Lugenbiel, Michaela Grebner, Qianxing Zhou, Anna Strothmeyer, Britta Vogel, Rita Cebola, Oliver Müller, Bernadett Brado, Marc Mittnacht, Benedikt Kohler, Hugo Katus, and Erwin Blessing Early clinical outcomes of a novel rheolytic directional thrombectomy technique for patients with iliofemoral deep vein thrombosis

Jörn F. Dopheide, Tim Sebastian, Rolf P. Engelberger, Axel Haine, and Nils Kucher Case reports

Laser-assisted transprosthesial coil embolization combined with thrombin injection for treatment of an endoleak type II after endovascular aneurysm repair

Tanja Boehme, Aljoscha Rastan, Elias Noory, Peter-Christian Fluegel, and Thomas Zeller Journal club

Drug coated ballons for femoro-popliteal interventions

Luca Tamburrini, Markus Vosseler, and Christine Espinola-Klein From the societies

Vasa (2018), 47 (1), 3

Umfassend und aktuell – das komplette Wissen der Psychologie

Markus Antonius Wirtz (Hrsg.)

Dorsch – Lexikon der Psychologie Unter Mitarbeit von Janina Strohmer. 18., überarb. Auﬂ. 2017. 1952 S., Gb € 74,95 / CHF 95.00 ISBN 978-3-456-85643-8

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Editorial

Do we have to change therapeutic considerations in peripheral arterial disease? Robert Berent1 and Helmut Sinzinger2 1 2

HerzReha Bad Ischl, Center for Cardiovascular Rehabilitation, Bad Ischl, Austria Institute for Diagnosis and Treatment of Lipid Disorders and Atherosclerosis, Vienna, Austria

In patients with symptomatic or asymptomatic peripheral arterial disease (PAD), there is an increased risk of cardiovascular (CV) mortality and morbidity regarding myocardial infarction (MI) and stroke, even after adjustment for conventional risk factors [1–3]. Fowkes FG et al. revealed that a low ankle brachial index of ≤ 0.90 is indicative of the 10-year rates of total mortality, cardiovascular mortality, and major coronary events that have more than doubled [1]. Moreover, in patients with intermittent claudication, the annual rate of CV events like myocardial infarction, stroke, or death is 5 to 7 % because of its ongoing atherogenesis in other vascular beds. The five-year mortality for patients with symptomatic PAD is approximately 25 % [2]. Therefore, treatment of claudication and PAD should result in improving of walking distance and, much more importantly, reducing CV risk. Aspirin, statins, and ACE-inhibitors are effective and widely used as standard treatment in patients with PAD. In comparison to aspirin, patients receiving clopidogrel revealed a lower risk of cardiovascular events [3]. The combination of aspirin and clopidogrel vs. aspirin alone did not reduce major adverse CV events in patients at high risk of atherothrombotic occurrence [4]. However, in a subgroup of patients with documented prior MI, ischaemic stroke, or symptomatic PAD, a benefit was evident [5]. Yet, in patients with symptomatic PAD, ticagrelor, an oral reversible ADP (P2Y12) receptor antagonist (90 mg twice daily), was as effective as clopidogrel for the reduction of CV events [6]. Long-term treatment with the combination of aspirin and ticagrelor compared with aspirin alone in patients after MI reduced major adverse CV events (MACE), such as CV death, MI, or stroke, with a large absolute risk reduction and major adverse limb events [7]. Treatment with a combination of aspirin and dipyridamole compared with aspirin alone or the combination of vorapaxar, a PAR-1 antagonist, with standard antiplatelet therapy also yielded benefits, but none of these approaches reduced mortality [8, 9]. The combination of aspirin and warfarin compared with aspirin alone always increased the risk of bleeding © 2018 Hogrefe

complications but reduced the risk of recurrent MI in patients with a recent acute coronary syndrome. In contrast, in patients with PAD, the combination of aspirin and warfarin did not reduce ischaemic events [10, 11]. Moreover, use of warfarin promotes systemic calcification, including the coronary and peripheral vasculature as a concealed side effect of vitamin K antagonists, which may result in adverse clinical effects [12]. As PAD is associated with an increased risk of bleeding as well as an increased risk of ischaemic events, due to shared comorbidities, antithrombotic therapy in combination with anticoagulation is risky but encouraging at the same time. Rivaroxaban is a direct FXa inhibitor without any effect on platelet function. Rivaroxaban was tested as an addon therapy to standard of care (most participants received the combination of aspirin and clopidogrel) in patients with a recent acute coronary syndrome in the ATLAS ACS 2–TIMI 51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome – Thrombolysis In Myocardial Infarction-51) [13]. Rivaroxaban at a dose of 2.5 mg bid reduced total mortality, and we know from previous trials that it is safer than warfarin in terms of bleeding complications [14]. The recently published COMPASS trial, comparing rivaroxaban twice daily 2.5 mg together with aspirin (100 mg once daily (od)) vs. aspirin od or rivaroxaban 5 mg bid, was presented at the ESC in August 2017 in Barcelona by Eikelboom [15]. The primary outcome (CV death, stroke or MI (MACE)) in a PAD subpopulation of peripheral or carotid artery disease (7,470 patients, 4,129 with symptomatic PAD, 1,919 with carotid artery disease, and 1,422 with coronary artery disease and an ABI < 0,90) was statistically highly reduced (RRR 28 %, p = 0.005). However, the study was not designed to demonstrate a statistical significant difference in the primary outcome components, although there was a clear trend in favour of the combination of rivaroxaban and aspirin. Overall mortality (CV death) was not reduced in this particular cohort in comparison to the whole COMPASS study population. Vasa (2018), 47 (1), 5–6 https://doi.org/10.1024/0301-1526/a000673

R. Berent and H. Sinzinger, Do we have to change therapeutic considerations in PAD?

Furthermore, it has to be taken into account that the COMPASS trial was stopped prematurely when only one half of the primary endpoint events had occurred because of the clear evidence of the efficacy in rivaroxaban/aspirin group. As a secondary outcome measure, a highly significant decrease in major adverse limb events and major amputations were demonstrated in the rivaroxaban/aspirin group. The key composite outcome, including MACE, major adverse limb events or major amputation, was also highly significant. The primary safety outcome was major bleeding (defined according to modified International Society on Thrombosis and Haemostasis (ISTH) criteria), which was significantly higher in the rivaroxaban group compared to the aspirin-alone group but with low rates of fatal or intracranial bleeding. Other major bleeding was mostly driven by gastrointestinal bleeding complications. The role of warfarin in PAD is very limited. The WAVE trial (Warfarin Antiplatelet Vascular Evaluation), which compared warfarin and aspirin vs. aspirin alone in patients with symptomatic PAD, showed no benefit of warfarin regarding CV death, MI, and stroke but a dramatic increase in life-threatening bleeding (4.0 vs. 1.2 %, p < 0.001) [16]. However, there are only limited data on rivaroxaban in PAD available [17]. In PAD patients in ROCKET AF, there was a treatment interaction in the post-hoc subgroup analysis with a higher risk of major bleeding or non-major clinically relevant bleeding with rivaroxaban when compared with warfarin (interaction p = 0.037) that was not observed in non-PAD patients [18]. However, risk of fatal and intracranial bleeding was very low among rivaroxaban-treated patients. Such results could not be confirmed in a post-hoc analysis with apixaban; no differences existed concerning rates of stroke, systemic embolism, and major bleeding compared with patients without PAD after adjustment [19]. As rivaroxaban/ASA was associated with a 1.8 % absolute risk reduction in the combined CV endpoint at the expense of a 1.2 % increased rate of major bleeding in the COMPASS PAD group, this trial seems to be an important step forward in antiplatelet therapy in combination with a direct-acting factor Xa inhibitor for peripheral arterial disease and critical limb ischaemia. Such results will probably change our practice guidelines.

References 1. Fowkes FG, Murray GD, Butcher I, et al. Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JAMA. 2008;300: 197–208. 2. Hankey GJ, Norman PE, Eikelboom JW. Medical treatment of peripheral arterial disease. JAMA. 2006;295(5):547–53. 3. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–39. 4. Bhatt DL, Fox KA, Hacke W, et al. CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16): 1706–17. Vasa (2018), 47 (1), 5–6

5. Bhatt DL, Flather MD, Hacke W, et al. CHARISMA Investigators. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49(19):1982–8. 6. Hiatt WR, Fowkes FG, Heizer G, et al. EUCLID Trial Steering Committee and Investigators. Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease. N Engl J Med. 2017; 376(1):32–40. 7. Bonaca MP, Bhatt DL, Storey RF, et al. Ticagrelor for Prevention of Ischemic Events After Myocardial Infarction in Patients With Peripheral Artery Disease. J Am Coll Cardiol. 2016; 67(23):2719–28. 8. Li X, Zhou G, Zhou X, et al. The efficacy and safety of aspirin plus dipyridamole versus aspirin in secondary prevention following TIA or stroke: a meta-analysis of randomized controlled trials. J Neurol Sci. 2013;332(1–2):92–6. 9. Moon JY, Franchi F, Rollini F, et al. Role for Thrombin Receptor Antagonism With Vorapaxar in Secondary Prevention of Atherothrombotic Events: From Bench to Bedside. J Cardiovasc Pharmacol Ther. 2017 Jan 1:1074248417708617. doi: 10.1177/1074248417708617, epub ahead of print. 10. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol. 2003;41(4 suppl S): 62S–9S. 11. Anand S, Yusuf S, Xie C, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med. 2007; 357:217–27. 12. Poterucha TJ, Goldhaber SZ. Warfarin and Vascular Calcification. Am J Med. 2016;129(6):635.e1–4. 13. Mega JL, Braunwald E, Wiviott SD, et al. ATLAS ACS 2–TIMI 51 Investigators. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9–19. 14. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423–34. 15. Eikelboom JW, Connolly SJ, Bosch J, et al. COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017; 377(14):1319–30. doi: 10.1056/NEJMoa1709118. 16. Azarbal A, Clavijo L, Gaglia MA Jr. Antiplatelet therapy for peripheral arterial disease and critical limb ischemia: guidelines abound, but where are the data? J Cardiovasc Pharmacol Ther. 2015;20(2):144–56. 17. Whayne TF. A Review of the Role of Anticoagulation in the Treatment of Peripheral Arterial Disease. Int J Angiol. 2012;21: 187–94. 18. Jones WS, Hellkamp AS, Halperin J, et al. Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF. Eur Heart J. 2014;35(4):242–9. 19. Hu PT, Lopes RD, Stevens SR, et al. Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation and Peripheral Artery Disease: Insights From the ARISTOTLE Trial. J Am Heart Assoc. 2017 Jan 17;6(1). pii: e004699. doi: 10.1161/JAHA.116.004699.

There are no conﬂicts of interest existing.

Review

Carotid stenosis – basing treatment on individual patients’ needs. Optimal medical therapy alone or accompanied by stenting or endarterectomy Ralf Langhoff Department of Angiology, Sankt Gertrauden-Krankenhaus, Berlin, Germany

Summary: Though carotid artery stenosis is a known origin of stroke, risk assessment and treatment modality are not yet satisfactorily established. Guideline updates according to latest evidence are expected shortly. Current clinical weakness concerns in particular the identiﬁcation of “at-risk” patients. Beside the symptomatic status and the degree of stenosis, further signs of unstable plaque on carotid and cerebral imaging should be considered. Moreover, medical and endovascular therapy are continuously improving. Randomized trials and meta-analyses have shown similar long-term results for protected carotid artery stenting and endarterectomy. However, endovascular revascularization was associated with an increased 30-day rate of minor strokes. Newly developed embolic protection devices could possibly compensate for this disadvantage. Furthermore, high-level optimal medical therapy alone is currently being evaluated comparatively. We assume that a comprehensive evaluation of plaque vulnerability, serious consideration of advanced embolic protection, and more space for optimal medical therapy alone according to latest evidence, will beneﬁt patients with carotid stenosis. Keywords: Carotid artery stenosis, carotid artery stenting, carotid endarterectomy, optimal medical therapy

Introduction

Risk of stroke

Carotid artery disease is a major cause of ischaemic stroke. Up to one-third of acute significant intracranial occlusions are caused by extracranial carotid stenosis [1]. However, patient risk depends on various factors such as comorbidities, lesion characteristics, and even the kind of treatment. In the recent past, all treatment modalities, including optimal medical therapy (OMT), carotid artery stenting (CAS), and endarterectomy (CEA) improved considerably and, even in clinical diagnostic, further progress is to be expected in the near future. As a result, treatment recommendations are still controversial. Anyway, the underlying aim is to prevent stroke and death. Therefore, the balance of the respective benefit and harm arising from disease or treatment should be carefully evaluated, based on individual patient and lesion characteristics and latest evidence.

In neurologically symptomatic patients with carotid artery stenosis, in particular in those with a recent stroke or transient ischaemic attack (TIA), severe atherosclerosis is known to be associated with a high risk of recurrent stroke. In a recently published study [2], the recurrence rate of ipsilateral ischaemic stroke in patients with a degree of 50–99 % stenosis increased from 2.7 % within the first day, to 5.3 % within three days, to 11.5 % within 14 days and finally to 18.8 % within 90 days after occurrence of neurologic symptoms. Advanced age and cerebral vs. ocular symptoms were associated with a higher recurrence rate. The survey did not reveal associations between the recurrence of neurological events and the degree of stenosis, additional vascular risk factors or medication. However, a large pooled data analysis [3] on symptomatic patients showed an increased benefit from endarterectomy compared to medical treatment alone,

Vasa (2018), 47 (1), 7–16 https://doi.org/10.1024/0301-1526/a000668

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

depending on stenosis severity (absolute risk reduction of ipsilateral stroke and operative stroke or death at five years of –2.2 %, 3.2 %, 4.6 %, and 15.9 % in patients with < 30 %, 30–49 %, 50–69 %, and ≥ 70 % stenosis, respectively). In contrast, for patients without a history of stroke or TIA who are on OMT of current standard, the annual risk of cerebral infarction is low (0.3–2.9 % [4–7]). A severe stenosis of ≥ 70 % might increase the annual risk for asymptomatic patients (ipsilateral neurologic symptoms 7.3–18.3 %; ipsilateral stroke 2.1–11.1 % [8, 9].

At-risk patients Lesion properties For both, symptomatic and asymptomatic patients, the degree of stenosis on its own is not necessarily a reliable determinant of cerebral infarction. This needs to be considered in the context of signs of unstable plaque such as progressively worsening of plaque formation and plaque expansion. Progressing stenosis is known to predict vascular events (HR 1.92) [7–10]. It occurs in about a fifth of asymptomatic patients. Finally, often unnoticed, it might come to plaque rupture and downstream cerebral infarction. • Vulnerability of plaques can potentially be determined by advanced carotid imaging [11–13]. Irregular stenosis and plaques with endothelial defects are found to be associated with an increased risk of stroke, even in the long term [14–17]. Endothelial defects were detected in 14– 31 % of asymptomatic and 36–48 % of symptomatic plaques [18, 19]. In addition, probably triggered by inflammation, adventitial vasa vasorum may proliferate into the plaque. These immature vessels increase the risk of intraplaque haemorrhage and plaque rupture. Therefore, intraplaque neovascularization is a reliable marker for plaque vulnerability [13]. A lipid rich necrotic core, intraplaque haemorrhage, and a thinning or rupture of the fibrous cap were found to be strongly associated with the risk of stroke or TIA (HR 3.0, 4.6, and 5.9, respectively) [20]. Even nonstenosing plaques with signs of intraplaque haemorrhage are suspected to be vulnerable [21]. − Ultrasonography (ideally B-mode) provides a limited sensitivity (48 %) and specificity (90 %) for the detection of an irregular plaque surface. Echolucency indicates a lipid-rich necrotic core or intraplaque haemorrhage [22]. Advanced techniques such as contrast enhanced ultrasound (CEUS) and high-resolution 3D ultrasound, ideally together with quantification software, improve the accuracy and help to identify intraplaque neovascularization [23] and plaque surface motion [22, 24], respectively. − Computed tomography angiography (ideally multidetector-row CT) can reliably detect endothelial defects. Sensitivity and specificity is > 90 %. It differentiates between calcification, lipid rich necrotic core, and intraplaque haemorrhage. Molecular imaging Vasa (2018), 47 (1), 7–16

•

(F-fluorodeoxyglucose-PET/CT) can detect inflammation and hypoxia. − Magnetic resonance angiography (MRA), particularly contrast-enhanced, allows to identify endothelial defects, thickness of the fibrous cap, lipid-rich necrotic core, intraplaque haemorrhage, inflammation, and neovascularization with moderate to good sensitivity and specificity [11, 25]. Silent cerebral microemboli and infarctions, detected by transcranial Doppler ultrasonography (TCD), computed tomography scanning, or diffusion-weighted MR imaging (DW-MRI) are proposed to be surrogate risk markers of future symptomatic strokes or TIA. Dempsey et al. [26] determined microemboli in 26 % of patients (stenosis > 60 %) classified as asymptomatic according to classic criteria. Kakkos et al. (ACSRS trial [27]) found a rate of 18 % silent embolic infarctions in asymptomatic patients with 50–99 % carotid stenosis. The annual rate of TIA or stroke in patients with moderate stenosis of 60– 79 % was 4.4 % in the presence and 1.3 % in the absence of embolic infarctions (p = 0.005). Additionally, in the ACES trial [28], embolic signals in combination with plaque echolucency (6.3 % of asymptomatic patients with ≥ 70 % stenosis) increased the risk of ipsilateral late stroke (HR 10.6). The annual risk of ipsilateral stroke in these patients was 8.9 % vs. 0.8 % in the remaining patients. Gupta et al. [29] reported on a silent cerebral microemboli and an infarction prevalence of 18 % in adults over 60 years of age, with a twofold increased stroke risk. Finn et al. [30] found a significant association of ipsilateral silent cerebral microemboli and infarctions with both carotid stenosis and nonstenosing carotid intimamedia thickening. This is not always necessarily directly causal but may also be linked to the generalized elevated cardiovascular risk of concerned patients. Even patients considered asymptomatic for stroke or TIA may suffer from subtle vascular cognitive decline, possibly attributed to cerebral microvascular disease from advanced atherosclerosis or perhaps due to silent cerebral infarctions. Our approach therefore is to put more effort into identifying those asymptomatic patients who might be at high risk of stroke by advanced imaging techniques that allow for a closer look at or even inside the plaque.

Symptomatic status According to the ESC guidelines [31], symptomatic status is defined by medical history of stroke or TIA in the last six months affecting the corresponding territory. A recently published meta-analysis of five large randomized trials [32] showed a higher 30-day (periprocedural) rate of stroke, death, myocardial infarction (MI), or ipsilateral stroke for symptomatic patients with CAS compared with CEA (11.4 % versus 8.3 %, P = 0.001, mean follow-up 5.3 years). Even after excluding one of the studies (ICSS) from the analysis because of its comparably low embolic protection © 2017 Hogrefe

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

rate, this trend remained. No significant difference was seen in asymptomatic patients (6.0 % CAS vs. 8.2 % CEA, P = 0.62). However, in the randomized CREST study, the symptomatic status of the patient did not interact with the treatment effect. Additionally, Meschina et al. [33] derived from CREST that time from onset of symptoms to CAS or CEA (< 15, 15–60, > 60 days) did not alter the periprocedural safety. This was confirmed for CEA by results from Tsantilas et al. [34] (CEA 0–2, 3–7, 8–14, or 14 till 180 days after neurologic event). However, Rantner et al. [35] concluded from several randomized trials that the periprocedural risk of CAS compared to CEA is larger within one week after the onset of symptoms than after the first week (P for interaction with time interval 0.06). It is assumed that a freshly ruptured plaque might be particularly susceptible to mechanical impairment from the catheter. Whether OMT alone for patients, deemed to be at low risk, compares favourably to revascularization, remains to be proven.

Age Along with age, incidence of concomitant systemic diseases increases. As a consequence, due to general anaesthesia, periprocedural risk with CEA might be higher as compared to CAS. In comparison, regional anaesthesia was found to be associated with lower rates of in-hospital strokes or death [36] as well as periprocedural myocardial infarction [37] and therefore could be considered an alternative. However, with CEA, diastolic hypertension has proven to be an independent risk factor of stroke. On the other hand, with CAS, vascular tortuosity and calcification may contribute to an increased procedural risk of death or stroke in patients older than 70 years of age [38]. However, 10-year results from CREST showed no significant treatment interaction with age [39]. Although in CREST, efficacy of CAS decreased in patients above 70 years of age. Therefore, it seems reasonable to base treatment decisions on patient’s systemic disease and vessel characteristics rather than on age in general. Overall, for younger patients (< 70 years of age), a trend emerges from several trials showing a greater benefit from CAS than from CEA.

Beneﬁt and harm from treatment Both invasive treatment methods, protected CAS and CEA are effective to prevent strokes, even if entailing the risk of therapy-related periprocedural complications. CEA proved to be superior to OMT in asymptomatic (ACAS [40], ACST [41]) and in symptomatic patients (ECST [3], NASCET [42]). Protected CAS was noninferior to CEA in the SAPPHIRE [43] and the ACT I trial [44]. In case of atherosclerotic vascular cognitive decline, cognitive improvement is most likely to take place between six and 12 months, regardless of the method of revascularization [45, 46]. © 2017 Hogrefe

The direct comparison of protected CAS and CEA in the randomized CREST study showed a significantly increased rate of periprocedural minor strokes and periprocedural deaths or stroke with CAS (3.2 % and 4.4 % vs. 1.7 % and 2.3 % with CEA). Hitchner et al. observed a higher rate of new microemboli after CAS compared to CEA with a significantly related cognitive decline at 30 days. Six months after intervention, an association between emboli and decline could no longer be demonstrated [47]. For CEA, CREST showed a significantly increased rate of periprocedural MI and cranial nerve palsy (2.3 % and 4.7 % vs. 1.1 % and 0.3 % with CAS). It should be noted that cranial nerve injuries rarely cause disabilities lasting longer than one year [48]. Nevertheless, after the periprocedural period, the annual rate of major or minor stroke over 10 years of follow-up was equally low in both groups (0.7 % with CAS vs. 0.6 % with CEA, P = 0.96) [38, 39]. For asymptomatic patients with severe carotid stenosis of ≥ 70 %, the ACT I investigators found protected CAS to be noninferior to CEA with regard to the primary composite endpoint of death, stroke, or MI within 30 days, or ipsilateral stroke within one year after the procedure (3.8 % with CAS versus 3.4 % with CEA, P = 0.01 for noninferiority). Even at five years, there was no significant difference in rates of death and stroke between the treatment groups [44]. A meta-analysis, which included CREST [38, 39], ACT I [44], EVA-3S [49], ICSS [50], and SAPPHIRE [43] (Table I and II) confirmed the abovementioned findings: The composite of periprocedural death, stroke, MI, or nonperiprocedural stroke within a mean of 5.3 years was similar across groups (8.1 % CAS vs. 7.5 % CEA, P = 0.14), but with CAS, periprocedural stroke was higher (P < 0.001, number needed to harm 47 patients) and periprocedural MI was lower (P = 0.002, number needed to treat 99 patients). Periprocedural and long-term death did not differ significantly between groups [32]. Within the first 30 days after intervention, both CAS and CEA rarely lead to the hyperperfusion syndrome (1.2 and 1.9 %, respectively); however, in some patients, they are followed by intracerebral haemorrhage (0.7 and 0.4 %, respectively) with life-threatening consequential damages [51]. Multiple factors such as impaired auto-regulation, baroreceptor dysfunction, chronic hypertension, and chronic hypoperfusion probably play a causal role. Therefore, periprocedural blood pressure control, timing of the procedure (within two weeks after stroke or TIA, only after a period of three months after contralateral revascularization), and the type of anaesthetic are considered to be preventive [52]. Periprocedural TCD may predict hyperperfusion [53]. However, results from a direct comparison of OMT alone, according to current standards, with CAS and CEA, respectively, are still pending [54]. Therefore, particularly with regard to severe complications within 30 days, CAS or CEA should only be considered if the patient is at a relatively elevated high risk of stroke or death from the disease itself, and if OMT alone is not suspected to be sufficiently effective. At the same time, meaningful assignment of patients to each treatment along with advanced technologies Vasa (2018), 47 (1), 7–16

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

Table I. Primary composite end point from large randomized trials on protected CAS vs. CEA. Trial

ACT I [44]

CREST [38, 39]

EVA-3S [49]

ICSS [50]

Pat. (N)

EPD (%)

1453

2502

100

527

1710

Primary pomposite end point*

Asymptomatic (%)

1-Year outcome (%)

3-Year out- 4-Year out- 5-Year outcome come come (%) (%) (%)

CAS

CEA

CAS

3.8

3.4

CAS

CEA

Periprocedural death, stroke, or MI, or ipsilateral stroke within four and 10 years

7.2

6.8

Periprocedural stroke or death, or ipsilateral stroke within 30 days

11.1

Periprocedural death, stroke, or MI, or ipsilateral stroke within one year

CEA

CAS

P = 0.51

334

Periprocedural death, stroke, or MI, or death or ipsilateral stroke within one year

CAS

CEA

11.8

9.9

P = 0.51

6.2

11.0

3.9

12.2

6.3

11.5

P = 0.04

3.2

6.4

P = 0.77 SAPPHIRE [43]

CEA

P = 0.01 for noninferiority

P = 0.03

Fatal or disabling stroke after randomization

10-Year outcome (%)

7.6

P = 0.07

6.5

P = 0.77

20.1

24.6

26.9

P = 0.71

P = 0.004 for noninferiority P = 0.053 for superiority

*There are various definitions for myocardial infarction. In ACT I, MI is defined by creatinine kinase level and pathological ECG changes. In CREST, MI is defined by creatinine kinase or troponin level in addition to symptoms or ECG evidence of ischaemia. In SAPPHIRE, MI is defined by creatinine kinase level only. ACT I: Asymptomatic carotid trial I; CAS: carotid artery stenting; CEA: carotid endarterectomy; CREST: carotid revascularization endarterectomy vs. stenting trial; EPD: embolic protection device; EVA-3S: endarterectomy vs. angioplasty in patients with symptomatic severe carotid stenosis; ICSS: International Carotid Stenting Study; MI: myocardial infarction; SAPPHIRE: stenting and angioplasty with protection in patients at high risk for endarterectomy.

Table II. Periprocedural* outcome from randomized large trials on protected CAS vs. CEA. Periprocedural death (%)

ACT I [44]

CEA

CAS

CEA

CAS

CEA

CAS

CEA

0.1

0.3

2.8

1.4

2.4

1.1

0.5

0.9

0.1

1.1

0.7

0.3

0.8

1.1

1.3

0.5

P = 0.117 SAPPHIRE [43]

Cranial-nerve injury (%)

CAS

P = 0.685 ICSS [50]

Periprocedural MI (%)

CEA

P = 0.18

EVA-3S [72]

Periprocedural minor stroke (%)

CAS

P = 0.43 CREST [38, 39]

Periprocedural all stroke (%)

1.2

2.5

P = 0.39

P = 0.23 4.1

2.3

P = 0.20 3.2

P = 0.01

9.1

3.4

3.2

6.0

3.1

P = 0.77

1.1

2.3

4.3

0.4

0.3

4.7 HR 0.07 95 % CI: 0.02 – 0.18

0.8 P = 1.0

1.4

0.4

P = 0.001 2.4

2.3

P = 0.02

P = 0.03

P = 0.045

P = 0.001 3.6

1.7 P = 0.01

P = 0.011 7.0

P = 0.41

0.6

P = 0.507 0.6

2.4

P = 0.18 (ipsilateral)

6.1

P = 0.10

0.1

5.4 all (0.1 disabling)

P < 0.0001 disabling P = 1.0 0.0

4.9 P = 0.04

*Periprocedural is deﬁned as within 30 days after randomization. Abbreviations as in Table I. Vasa (2018), 47 (1), 7–16

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

may prevent complications and increase benefits, even for patients at a lower risk. Nowadays, the risk from intervention should fall below 1.0 % for asymptomatic patients, which is the achievable magnitude of annual risk for vascular events with OMT alone.

•

Guideline recommendations Currently available guideline recommendations (e. g. ESC 2011 [31], ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/ CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS (ECVD) 2011 [55], AHA/ASA 2014 [56, 57]; Table III) are partially based on outdated scientific knowledge. It can be assumed that meanwhile medical treatment and diagnostic methods have been improved significantly. Therefore, it might be reasonable to abandon revascularization in low-risk patients more frequently and instead decide based on OMT alone. First, however, reliable results on the direct comparison of OMT with CAS or CEA have to be attained. The CREST-2 trial currently makes this enquiry. Estimated primary completion date is December 2020 (ClinicalTrials.gov Identifier: NCT02089217). Furthermore, current guidelines largely confine risk assessment to symptomatic status and degree of stenosis. In the future, ancillary diagnostic beyond grading of carotid stenosis, such as cerebral TCD and refined plaque analysis using B-mode ultrasonography, CEUS, and/ or CT/MRA, should be recommended to reliably identify unstable plaques and thus patients at risk. While awaiting planned updates, current guidelines shall apply.

•

Decision according to patient’s need •

Optimal medical therapy consists of lipid lowering therapy (statin and, where appropriate, ezetimib and/or PCSK-9-inhibitor), antihypertensive therapy, antiplatelet therapy, diabetes control, and lifestyle modifications such as smoking cessation, dietary counselling, and physical activity. Guidelines [31, 55–57] provide the following recommendations. − Lipid-lowering treatment: LDL cholesterol < 100 mg/ dl, and optimally < 70 mg/dl for all patients with carotid stenosis (ESC 20111). LDL cholesterol < 70 mg/ dl for patients with ischaemic stroke (ECVD 2011). Statin medication for primary prevention of ischaemic stroke for patients who are at a high 10-year risk of cardiovascular events and intensive lipid lowering for patients with stroke and TIA (AHA/ASA 2014). − Blood pressure control: ≤ 140/90 mmHg (ESC 2011); < 40/90 mmHg (AHA/ASA 2014, ECVD 2011). − Antiplatelet therapy: Low dose aspirin daily is recommended for patients with carotid stenosis regardless of symptoms and dual antiplatelet therapy for patients undergoing CAS (ESC 2011). Clopidogrel and aspirin are recommended before and for a minimum

•

of 30 days after CAS. Ticlopidine may be substituted for patients intolerant to clopidogrel (ECVD 2011). OMT alone is considered appropriate for the treatment of patients with stable plaque and no evidence of cerebral microemboli. In addition, at least initially, OMT alone might be an option in case of a particularly high risk of any revascularization due to: − reduced cerebrovascular reserve (contralateral or intracranial occlusive disease, incomplete circle of Willis), − post-stenotic collapse of the distal lumen > 1 cm in length due to diminished antegrade flow with or without thrombus (string sign), − and severe systolic hypertension, angina, and heart failure. Carotid artery stenting in addition to OMT should mandatorily be conducted with embolic protection to prevent cerebral embolism. Embolic release of atherosclerotic debris due to catheterization mainly occurs during post-dilation, but might also occur at any time during the intervention and within the first weeks after the procedure. Meanwhile, a series of advanced embolic protection devices are available or under development. − Distal filters are advanced in closed condition through the lesion and opened distally to the lesion. They allow a continuous antegrade blood flow. At the end of the procedure, captured debris are removed within the filter. − Proximal occlusion devices occlude the common and external carotid artery and induce reversed flow in the internal carotid artery. Thus, crucial manoeuvres of lesion crossing and stenting are already protected. Debris is aspirated retrogradely. − Mesh-covered stents, equipped with a fine-pored mesh inside or outside, are to prevent debris prolapse through the large open cells of the stent into the lumen. Kotsugi et al. [58] found an incidence of plaque protrusion with CAS of 2.9 %, strongly associated with ischaemic stroke. The mesh should retain particles ≥ 200 μm, which potentially induce brain damage [59, 60]. Mesh-covered stents could possibly close the safety gap caused by removal of the protection system up to complete endotheliasation. Nevertheless, 48 hours after distal filter or proximal occlusion, Cano et al. [61] found new ischaemic cerebral lesions in > 60 % of patients. The vast majority of these lesions was small and did not result in clinical symptoms. Proximal balloon occlusion has proven to be accompanied by significantly fewer and smaller new insults than distal filter protection [62]. However, inhospital stroke or death rates did not differ and were similarly low in both strategies [63]. Protected CAS is considered appropriate when revascularization is indicated, vascular anatomical characteristics and plaque morphology are eligible for catheterization, and periprocedural risk with carotid endarterectomy would most probably be equally hazardous or even riskier, which applies to: Vasa (2018), 47 (1), 7–16

Vasa (2018), 47 (1), 7–16

Symptomatic

AHA/ASA 2014 [57]

Effectiveness of revascularization vs. medical therapy alone is not well established.

Effectiveness of either CEA or CAS vs. OMT in patients with high risk of complications is not well established.

IIb

Optimally within two weeks of onset of symptoms. No revascularization for stenosis of < 50 % or chronic total occlusion. Except in extraordinary circumstances. Reasonable to consider in patients with > 70 % stenosis + risk of perioperative stroke, MI, and death < 3 %. – > 70 % stenosis by noninvasive imaging – > 50 % stenosis by angiography or corroborated noninvasive imaging – Patients older than ~70 years – Anatomy unfavourable for CAS – anticipated periprocedural stroke and death risk < 6 % Within two weeks of the index event in case of TIA or minor stroke

IIa

III

IIb

IIa

Optimally within two weeks of the onset of symptoms. No revascularization for stenosis of < 50 % or chronic total occlusion. Except in extraordinary circumstances.

Indicated alternatively to CEA in patients with – >70 % stenosis by noninvasive imaging – > 50 % stenosis by angiography or corroborated noninvasive imaging – anticipated periprocedural stroke and death risk < 6 % – Increased risk for surgery

Might be considered in highly selected patients with ≥ 60 % stenosis by angiography and ≥ 70 % by DUS.

Older patients with unfavourable arterial pathoanatomy for CAS

IIa

Patients with unfavourable neck anatomy for CEA

*Class of recommendation; †recent (< 6 months) symptoms of stroke/TIA; CAS: carotid artery stenting; CEA: carotid endarterectomy; OMT: optimal medical therapy; MI: myocardial infarction.

Asymptomatic

Asymptomatic or symptomatic

Reasonable in patients with > 70 % stenosis + low risk of perioperative stroke, MI, and death.

– Recommended for 70–99 % stenosis. – Should be considered for 50–69 % stenosis depending patient-speciﬁc factors. Optimally within two weeks of onset of symptoms.

– > 70 % stenosis by noninvasive imaging – > 50 % stenosis by angiography + perioperative risk of stroke and death < 6 % + average or low risk of CEA complications

IIb

IIa

– > 70 % stenosis by noninvasive imaging – > 50 % stenosis by angiography + perioperative risk of stroke and death < 6 % + average or low risk of CAS complications

Might be considered in highly selected patients with – ≥ 70 % stenosis by noninvasive imaging – ≥ 60 % stenosis by angiography.

Effectiveness of prophylactic CAS (ste- IIb nosis ≥ 70 % by Doppler, ultrasound or ≥ 60 % by angiography) compared with OMT is not well established.

Asymptomatic

Symptomatic†

– Should be considered in patients at high surgical risk. – May be considered in centres with documented stroke and death rate < 6 %. Optimally within two weeks of onset of symptoms.

– Stenosis < 50 %

IIa

III

IIa

I IIa

IIa

Should be considered in patients with ≥ 60 % stenosis + perioperative stroke and death risk < 3 % + life expectancy > 5 years.

IIb

May be considered in patients with ≥ 60 % stenosis + periinterventional risk of stroke and death <3% + life expectancy > 5 years.

Symptomatic†

Class*

CEA + OMT

Class*

CAS + OMT

– Stenosis < 60 % – Occlusion or near-occlusion – Stenosis 60–99 % + unfavourable anatomy or life expectancy ≤ 5 years

Class*

Asymptomatic

AHA/ASA 2014 [56]

2011 ASA/ACCF/AHA/ AANN/AANS/ACR/ASNR/ CNS/SAIP/SCAI/SIR/SNIS/ SVM/SVS (ECVD) Guideline [55]

ESC Guidelines 2011 [31]

OMT alone

Table III. Extract from guideline recommendations for the treatment of carotid artery stenosis.

12 R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

− surgically inaccessible lesions (proximal to the

•

clavicle or distal to the C2 vertebral body), − prior ipsilateral neck surgery, − prior ipsilateral radiation therapy, − restenosis after CEA and CAS, − hostile neck, − prior cranial nerve injury, − tracheal stoma, − and comorbidities such as severe coronary artery disease, congestive heart failure, and chronic obstructive pulmonary disease which increase the risk of CEA. Carotid endarterectomy in addition to OMT is considered appropriate when revascularization is indicated and CAS would most probably be associated with a relatively increased periprocedural risk. This might be the case with: − calcified and severely ulcerated plaques, which are particularly emboligenic, − severe angulation or tortuosity of innominate and common carotid artery (sheath placement hindered), − severe angulation or tortuosity of internal carotid artery within 4 cm of target lesion (place for embolic protection device), − severe tortuosity, calcification or atherosclerosis of access vessels, whether or not associated with older age (≥ 70 years), − disadvantaged aortic arch anatomy, and patients on chronic anticoagulation and/or contraindication for dual antiplatelet therapy. Eversion CEA (plaque removal following transection of the distal internal carotid artery) and conventional longitudinal CEA (patch angioplasty or direct closure) proved to be similar in regard to freedom from neurologic morbidity, death, and reintervention. However, eversion CEA has a significantly lower rate of late stenosis [64, 65]. By meta-analysis, Demirel et al. [66] found moderate evidence for an increased rate of post-CEA hypertension (OR 2.8) with eversion CEA. Patch angioplasty is considered to reduce the combined periprocedural and long-term risk of stroke and restenosis compared to primary closure, due to less narrowing from the suture [65, 67]. However, the technique requires a longer clamp time than direct closure or eversion CEA and might be associated with graftspecific complications. Märtens et al. [68] found the periprocedural safety of primary closure to be equivalent to patch angioplasty in case of: − carotid artery diameter > 5 mm, − high carotid bifurcation, − or occlusion of the contralateral carotid artery. For CEA, thoroughly preoperative cardiovascular evaluation and advanced anaesthesia are mandatory. Local vs. general anaesthesia and perioperative antiplatelet medication are advantageous [36]. Early clamping of the internal carotid artery and accurate dissection of the carotid bulb may help to prevent cerebral embolism. However, patients have to be informed on possible risks due to surgery, such as cranial nerve deficits, vocal cord

paralysis, dysphagia, hoarseness, scarring, and increased risk for local wound infection. Complete recovering time is two to four weeks. In case of a crescendo TIA or a stroke-in-evolution, a careful evaluation of the patient by an experienced neurologist and additional dedicated imaging techniques such as cerebral computed tomography (not to run into cerebral bleeding) are the mainstay to decide if a rescue-revascularization is indicated.

Research and development The CREST-2 trials are comparing medical management with CAS or CEA alone, each combined with OMT, for severe carotid stenosis of ≥ 70 % in asymptomatic patients [54]. Estimated primary completion is December 2020. The ACST-2 trial is being conducted to compare the periprocedural risk and the long-term prevention of stroke between CEA and CAS in patients with severe asymptomatic carotid stenosis (70–99 %). The interim analysis of the first 691 patients revealed an overall rate of periprocedural stroke, fatal myocardial infarction, and death of 1 %. For CAS, eight types of stent and eight types of cerebral protection devices were used. Patch angioplasty was performed in 50 % of the CEA patients. The trial is currently recruiting and aims to enrol up to 5,000 participants [69]. Estimated primary completion is December 2019. The ECST-2 trial (ISRCTN 97744893) is comparing OMT alone with CEA or CAS in combination with OMT in symptomatic and asymptomatic patients with carotid stenosis of at least 50 %. Patients have to be at low or intermediate risk of stroke, determined by a new measure, the carotid artery risk score (CAR Score). The CAR score predicts the five-year risk of stroke in patients with carotid stenosis who are treated with OMT alone. Eligibility lies at < 20 %. Patients have cerebral MRI randomly and during follow-up at 30 days, two, and five years. The overall trial end date is March 2022. The SPACE-2 Trial was designed to investigate efficacy and safety of OMT for asymptomatic patients with a 70– 99 % carotid stenosis [70]. Initially, it was planned to compare OMT alone vs. OMT plus CAS vs. OMT plus CEA in a three-arm study design, but due to slow recruitment, the design was changed to two parallel-randomized trials comparing OMT alone with the combination of OMT plus CAS or OMT plus CEA. Despite all efforts to improve recruitment, the trial had to be stopped prematurely with 513 patients randomized. The 30-day stroke rate was 2.0 % with CEA and 2.5 % with CAS. No event occurred in the OMT group. The Paladin trial investigated a dedicated micropore filter device (pore size of 40 μm) to be applied during postdilation in CAS (106 patients with severe stenosis). The filter is integrated distally into the post-dilation balloon catheter. Currently available EPDs are beneficial in preVasa (2018), 47 (1), 7–16

R. Langhoff, Carotid stenosis – basing treatment on individual patients’ needs

venting large embolic particles from reaching the brain. However, MRI and TCD data show that despite the use of EPD, microemboli reach the middle cerebral artery in almost every intervention. Results from the Paladin trial, recently presented at LINC 2017 (Leipzig Interventional Course), pointed out that the incidence of new lesions on DW-MRI after CAS decreased. The rate of the composite endpoint of 30-day death, stroke, or MI was relatively low (0.95 %). The Paladin system therefore appears to be a promising addition to the field of carotid intervention and seems worth being validated in subsequent studies. Remote ischemic preconditioning (RIPC) within a randomized sham-controlled trial led to promising results. Fife cycles of bilateral upper arm ischaemia for five minutes followed by reperfusion were applied twice daily for two weeks before CAS. Although, the underlying mechanism of RIPC is not entirely known, the strategy aimed to reduce ischaemic brain lesions from distal embolization due to CAS. Patients with severe asymptomatic or symptomatic carotid artery stenosis were treated with CAS after RIPC or with CAS alone [71]. With RIPC, the incidence of newly ischaemic brain lesions was lower than with CAS alone (15.9 vs. 41.3 %, P < 0.002). Single and total lesion volume was significantly decreased in the RIPC group compared to the control and the sham group. However, underlying mechanisms remain unexplained. The study intended to proof the concept but was not able to detect differences in clinical outcomes. More evidence would be highly appreciated, as RIPC is probably free of any negative side effects.

Acknowledgement I want to express my gratitude to Maja Ingwersen for her professional support and assistance during article preparation and medical writing.

References 1. Berkhemer OA, Fransen PS, Beumer D, et al. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11–20. 2. Johansson E, Cuadrado-Godia E, Hayden D, et al. Recurrent stroke in symptomatic carotid stenosis awaiting revascularization: A pooled analysis. Neurology. 2016;86(6):498–504. 3. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooled data from the randomised controlled trials of endarterectomy for symptomatic carotid stenosis. Lancet. 2003;361(9352):107–16. 4. den Hartog AG, Achterberg S, Moll FL, et al. Asymptomatic carotid artery stenosis and the risk of ischemic stroke according to subtype in patients with clinical manifest arterial disease. Stroke. 2013;44(4):1002–7. 5. Marquardt L, Geraghty OC, Mehta Z, et al. Low risk of ipsilateral stroke in patients with asymptomatic carotid stenosis on best medical treatment: a prospective, population-based study. Stroke. 2010;41(1):e11–7. 6. Conrad MF, Boulom V, Mukhopadhyay S, et al. Progression of asymptomatic carotid stenosis despite optimal medical therapy. J Vasc Surg. 2013;58(1):128–35 e1. Vasa (2018), 47 (1), 7–16

7. Kakkos SK, Nicolaides AN, Charalambous I, et al. Predictors and clinical signiﬁcance of progression or regression of asymptomatic carotid stenosis. J Vasc Surg. 2014;59(4):956–67 e1. 8. Conrad MF, Michalczyk MJ, Opalacz A, et al. The natural history of asymptomatic severe carotid artery stenosis. J Vasc Surg. 2014;60(5):1218–25. 9. Hadar N, Raman G, Moorthy D, et al. Asymptomatic carotid artery stenosis treated with medical therapy alone: temporal trends and implications for risk assessment and the design of future studies. Cerebrovasc Dis. 2014;38(3):163–73. 10. Balestrini S, Lupidi F, Balucani C, et al. One-year progression of moderate asymptomatic carotid stenosis predicts the risk of vascular events. Stroke. 2013;44(3):792–4. 11. Brinjikji W, Huston J, 3rd, Rabinstein AA, et al. Contemporary carotid imaging: from degree of stenosis to plaque vulnerability. J Neurosurg. 2016;124(1):27–42. 12. Rafailidis V, Chryssogonidis I, Tegos T, et al. Imaging of the ulcerated carotid atherosclerotic plaque: a review of the literature. Insights Imaging. 2017;8(2):213–25. 13. Schinkel AF, Kaspar M, Staub D. Contrast-enhanced ultrasound: clinical applications in patients with atherosclerosis. Int J Cardiovasc Imaging. 2016;32(1):35–48. 14. Nakamura T, Tsutsumi Y, Shimizu Y, et al. Ulcerated carotid plaques with ultrasonic echolucency are causatively associated with thromboembolic cerebrovascular events. J Stroke Cerebrovasc Dis. 2013;22(2):93–9. 15. Naylor AR, Sillesen H, Schroeder TV. Clinical and imaging features associated with an increased risk of early and late stroke in patients with symptomatic carotid disease. Eur J Vasc Endovasc Surg. 2015;49(5):513–23. 16. Jashari F, Ibrahimi P, Bajraktari G, et al. Carotid plaque echogenicity predicts cerebrovascular symptoms: a systematic review and meta-analysis. Eur J Neurol. 2016;23(7):1241–7. 17. Huibers A, de Borst GJ, Bulbulia R, et al. Plaque Echolucency and the Risk of Ischaemic Stroke in Patients with Asymptomatic Carotid Stenosis Within the First Asymptomatic Carotid Surgery Trial (ACST-1). Eur J Vasc Endovasc Surg. 2016;51(5):616–21. 18. Golledge J, Greenhalgh RM, Davies AH. The symptomatic carotid plaque. Stroke. 2000;31(3):774–81. 19. Fisher M, Paganini-Hill A, Martin A, et al. Carotid plaque pathology: thrombosis, ulceration, and stroke pathogenesis. Stroke. 2005;36(2):253–7. 20. Gupta A, Baradaran H, Schweitzer AD, et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. Stroke. 2013;44(11):3071–7. 21. Gupta A, Gialdini G, Giambrone AE, et al. Association Between Nonstenosing Carotid Artery Plaque on MR Angiography and Acute Ischemic Stroke. JACC Cardiovasc Imaging. 2016;9(10): 1228–9. 22. Muraki M, Mikami T, Yoshimoto T, et al. Sonographic Detection of Abnormal Plaque Motion of the Carotid Artery: Its Usefulness in Diagnosing High-Risk Lesions Ranging from Plaque Rupture to Ulcer Formation. Ultrasound Med Biol. 2016;42(2):358–64. 23. van den Oord SC, Akkus Z, Bosch JG, et al. Quantitative contrast-enhanced ultrasound of intraplaque neovascularization in patients with carotid atherosclerosis. Ultraschall Med. 2015;36(2):154–61. 24. Harloff A. Carotid plaque hemodynamics. Interv Neurol. 2012;1 (1):44–54. 25. den Hartog AG, Bovens SM, Koning W, et al. Current status of clinical magnetic resonance imaging for plaque characterisation in patients with carotid artery stenosis. Eur J Vasc Endovasc Surg. 2013;45(1):7–21. 26. Dempsey RJ, Varghese T, Jackson DC, et al. Carotid atherosclerotic plaque instability and cognition determined by ultrasoundmeasured plaque strain in asymptomatic patients with signiﬁcant stenosis. J Neurosurg. 2017:1–9. doi:10.3171/2016.10. JNS161299. [Epub ahead of print]. 27. Kakkos SK, Sabetai M, Tegos T, et al. Silent embolic infarcts on computed tomography brain scans and risk of ipsilateral hemispheric events in patients with asymptomatic internal carotid artery stenosis. J Vasc Surg. 2009;49(4):902–9. © 2017 Hogrefe

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28. Topakian R, King A, Kwon SU, et al. Ultrasonic plaque echolucency and emboli signals predict stroke in asymptomatic carotid stenosis. Neurology. 2011;77(8):751–8. 29. Gupta A, Giambrone AE, Gialdini G, et al. Silent Brain Infarction and Risk of Future Stroke: A Systematic Review and MetaAnalysis. Stroke. 2016;47(3):719–25. 30. Finn C, Giambrone AE, Gialdini G, et al. The Association between Carotid Artery Atherosclerosis and Silent Brain Infarction: A Systematic Review and Meta-analysis. J Stroke Cerebrovasc Dis. 2017;26(7):1594–601. 31. Tendera M, Aboyans V, Bartelink ML, et al. ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries: the Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(22):2851–906. 32. Sardar P, Chatterjee S, Aronow HD, et al. Carotid Artery Stenting Versus Endarterectomy for Stroke Prevention: A Meta-Analysis of Clinical Trials. J Am Coll Cardiol. 2017;69(18):2266–75. 33. Meschia JF, Hopkins LN, Altafullah I, et al. Time From Symptoms to Carotid Endarterectomy or Stenting and Perioperative Risk. Stroke. 2015;46(12):3540–2. 34. Tsantilas P, Kuhnl A, Kallmayer M, et al. A short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery. J Vasc Surg. 2017; 65(1):12–20e1. 35. Rantner B, Kollerits B, Roubin GS, et al. Early Endarterectomy Carries a Lower Procedural Risk Than Early Stenting in Patients With Symptomatic Stenosis of the Internal Carotid Artery: Results From 4 Randomized Controlled Trials. Stroke. 2017;48(6):1580–7. 36. Knappich C, Kuehnl A, Tsantilas P, et al. Intraoperative Completion Studies, Local Anesthesia, and Antiplatelet Medication Are Associated With Lower Risk in Carotid Endarterectomy. Stroke. 2017;48(4):955–62. 37. Hye RJ, Voeks JH, Malas MB, et al. Anesthetic type and risk of myocardial infarction after carotid endarterectomy in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST). J Vasc Surg. 2016;64(1): 3–8e1. 38. Brott TG, Hobson RW, 2nd, Howard G, et al. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med. 2010;363(1):11–23. 39. Brott TG, Howard G, Roubin GS, et al. Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis. N Engl J Med. 2016;374(11):1021–31. 40. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. JAMA. 1995;273(18):1421–8. 41. Halliday A, Mansfield A, Marro J, et al. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet. 2004;363(9420):1491–502. 42. Barnett HJ, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med. 1998;339(20):1415–25. 43. Gurm HS, Yadav JS, Fayad P, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572–9. 44. Rosenfield K, Matsumura JS, Chaturvedi S, et al. Randomized Trial of Stent versus Surgery for Asymptomatic Carotid Stenosis. N Engl J Med. 2016;374(11):1011–20. 45. Kim JJ, Schwartz S, Wen J, et al. Comparison of Neurocognitive Outcomes after Carotid Endarterectomy and Carotid Artery Stenting. Am Surg. 2015;81(10):1010–4. 46. Kougias P, Collins R, Pastorek N, et al. Comparison of domainspecific cognitive function after carotid endarterectomy and stenting. J Vasc Surg. 2015;62(2):355–61. 47. Hitchner E, Baughman BD, Soman S, et al. Microembolization is associated with transient cognitive decline in patients undergoing carotid interventions. J Vasc Surg. 2016;64(6):1719–25. © 2017 Hogrefe

48. Hye RJ, Mackey A, Hill MD, et al. Incidence, outcomes, and effect on quality of life of cranial nerve injury in the Carotid Revascularization Endarterectomy versus Stenting Trial. J Vasc Surg. 2015;61(5):1208–14. 49. Mas JL, Arquizan C, Calvet D, et al. Long-term follow-up study of endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis trial. Stroke. 2014;45(9):2750–6. 50. Bonati LH, Dobson J, Featherstone RL, et al. Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial. Lancet. 2015;385(9967):529–38. 51. Moulakakis KG, Mylonas SN, Sfyroeras GS, et al. Hyperperfusion syndrome after carotid revascularization. J Vasc Surg. 2009;49(4):1060–8. 52. Farooq MU, Goshgarian C, Min J, et al. Pathophysiology and management of reperfusion injury and hyperperfusion syndrome after carotid endarterectomy and carotid artery stenting. Exp Transl Stroke Med. 2016;8(1):7. 53. Fujimoto S, Toyoda K, Inoue T, et al. Diagnostic impact of transcranial color-coded real-time sonography with echo contrast agents for hyperperfusion syndrome after carotid endarterectomy. Stroke. 2004;35(8):1852–6. 54. Howard VJ, Meschia JF, Lal BK, et al. Carotid revascularization and medical management for asymptomatic carotid stenosis: Protocol of the CREST-2 clinical trials. Int J Stroke. 2017: 1747493017706238. doi:10.1177/1747493017706238. [Epub ahead of print]. 55. Brott TG, Halperin JL, Abbara S, et al. 2011 ASA/ACCF/AHA/ AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on the management of patients with extracranial carotid and vertebral artery disease: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. J Am Coll Cardiol. 2011;57(8):1002–44. 56. Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(12):3754–832. 57. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45(7):2160–236. 58. Kotsugi M, Takayama K, Myouchin K, et al. Carotid Artery Stenting: Investigation of Plaque Protrusion Incidence and Prognosis. JACC Cardiovasc Interv. 2017;10(8):824–31. 59. Diaz O, Lopez G, Roehm JOF, Jr., et al. The Casper carotid artery stent: a unique all metal micromesh stent designed to prevent embolic release. J Neurointerv Surg. 2017. doi:10.1136/neurintsurg-2016-012913. [Epub ahead of print]. 60. Speziale F, Capoccia L, Sirignano P, et al. 30-day results from prospective multi-specialty evaluation of carotid artery stenting using the CGuard micronet-covered embolic prevention stent system in real world multicenter clinical practice: the IRON-GUARD study. EuroIntervention. 2017. doi:10.4244/EIJD-17-00008. [Epub ahead of print]. 61. Cano MN, Kambara AM, de Cano SJ, et al. Randomized comparison of distal and proximal cerebral protection during carotid artery stenting. JACC Cardiovasc Interv. 2013;6(11):1203–9. 62. Bijuklic K, Wandler A, Hazizi F, et al. The PROFI study (Prevention of Cerebral Embolization by Proximal Balloon Occlusion Compared to Filter Protection During Carotid Artery Stenting): a prospective randomized trial. J Am Coll Cardiol. 2012;59(15): 1383–9. Vasa (2018), 47 (1), 7–16

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63. Giri J, Parikh SA, Kennedy KF, et al. Proximal versus distal embolic protection for carotid artery stenting: a national cardiovascular data registry analysis. JACC Cardiovasc Interv. 2015;8(4): 609–15. 64. Schneider JR, Helenowski IB, Jackson CR, et al. A comparison of results with eversion versus conventional carotid endarterectomy from the Vascular Quality Initiative and the Mid-America Vascular Study Group. J Vasc Surg. 2015;61(5):1216–22. 65. Eckstein HHK, Kühnl A, Berkefeld J, et al. S3-Leitlinie zur Diagnostik, Therapie und Nachsorge der extracraniellen Carotisstenose (AWMF-register-no.004/028). 2012. 66. Demirel S, Goossen K, Bruijnen H, et al. Systematic review and meta-analysis of postcarotid endarterectomy hypertension after eversion versus conventional carotid endarterectomy. J Vasc Surg. 2017;65(3):868–82. 67. Rerkasem K, Rothwell PM. Systematic review of randomized controlled trials of patch angioplasty versus primary closure and different types of patch materials during carotid endarterectomy. Asian J Surg. 2011;34(1):32–40. 68. Maertens V, Maertens H, Kint M, et al. Complication Rate after Carotid Endarterectomy Comparing Patch Angioplasty and Primary Closure. Ann Vasc Surg. 2016;30:248–52. 69. Halliday A, Bulbulia R, Gray W, et al. Status update and interim results from the asymptomatic carotid surgery trial-2 (ACST2). Eur J Vasc Endovasc Surg. 2013;46(5):510–8. 70. Eckstein HH, Reiff T, Ringleb P, et al. SPACE-2: A Missed Opportunity to Compare Carotid Endarterectomy, Carotid Stenting,

and Best Medical Treatment in Patients with Asymptomatic Carotid Stenoses. Eur J Vasc Endovasc Surg. 2016;51(6):761–5. 71. Zhao W, Meng R, Ma C, et al. Safety and Efﬁcacy of Remote Ischemic Preconditioning in Patients With Severe Carotid Artery Stenosis Before Carotid Artery Stenting: A Proof-of-Concept, Randomized Controlled Trial. Circulation. 2017;135(14): 1325–35. 72. Mas JL, Trinquart L, Leys D, et al. Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial. Lancet Neurol. 2008;7(10):885–92. Submitted: 14.06.2017 Accepted after revision: 14.08.2017 There are no conﬂicts of interest existing. Published online: 24.10.2017 Correspondence address Ralf Langhoff, M. D. Department of Angiology Sankt Gertrauden-Krankenhaus Paretzerstr. 12 10713 Berlin Germany ralf.langhoff@sankt-gertrauden.de

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Vasa (2018), 47 (1), 7–16

Review

Surgical and endovascular venous arterialization for treatment of critical limb ischaemia Michael Lichtenberg1, Michiel A. Schreve2, Roberto Ferraresi3, Daniel A. F. van den Heuvel4, Çagdas Ünlü2, Vincent Cabane5, and Steven Kum5 1 2 3 4 5

Vascular Centre Arnsberg, Arnsberg Clinic, Arnsberg, Germany Department of Surgery, Northwest Clinics, Alkmaar, the Netherlands Peripheral Interventional Unit, Humanitas Gavazzeni, Bergamo, Italy Department of Radiology, St. Antonius Hospital, Nieuwegein, the Netherlands Vascular Service, Department of Surgery, Changi General Hospital, Changi, Singapore

Summary: Patients with critical limb ischaemia have a poor life expectancy. Aggressive revascularization is accepted in order to preserve their independence in the ﬁnal phase of their lives. Bypass surgery and more recently endovascular interventions with angioplasty and stenting have become the treatment of choice to prevent amputation and to resolve pain. However, as many as 20 % of patients with critical limb ischaemia are unsuitable candidates for a vascular intervention because of extensive occlusions of outﬂow in the crural and pedal vessels. Such “no-option critical limb ischaemia” may be treated with venous arterialization. In the present review, we discuss the history of the venous arterialization procedure, the mechanisms, the different techniques, and complications of venous arterialization. Keywords: Critical limb ischemia, venous arterialization, wound management, endovascular therapy

Introduction Critical limb ischaemia (CLI) is the clinical end stage of peripheral artery disease and continues to be a challenge. CLI will develop within five years in 5–10 % of patients older than 50 years of age diagnosed with PAD [1]. Patients with CLI have a poor life expectancy, with a mortality rate of 20 % after one year and 40–70 % after five years [2]. Only 40 % of patients are mobile two years after a below-knee amputation [3]. A bypass operation in crural and pedal arteries may salvage the limb but depends on the presence of patent arterial outflow vessels. Endovascular interventions with angioplasty and stenting have become the treatment of choice and are believed to be associated with a lower risk of morbidity and mortality [4]. New treatment options have been explored for patients with CLI; these include stem-cell therapy, spinal cord stimulation, and prostanoid therapy. A meta-analysis of placebo-controlled trials showed no advantageous effect of stem-cell therapy on the primary outcome measures of amputation, survival, and amputation-free survival in patients with CLI [5]. Another meta-analysis showed no ben© 2017 Hogrefe

efit of prostanoid therapy or other types of medical treatment [6]. A Cochrane review concluded that spinal cord stimulation may be of some benefit in preventing amputation. However, evidence of these benefits are considered low, mainly because of imprecision and bias [7]. For CLI patients with no revascularization options, venous arterialization could be an alternative for limb salvage. Theoretical explanations for venous arterialization include direct nutrition of tissue [8] from reversed perfusion and increased flow in existing collaterals, which stimulates angiogenesis [9]. The exact mechanism of action remains unclear. Attempts have been made to monitor these changes in microperfusion and pressure induced by reverse flow. It has been suggested that small connections between peripheral veins and arteries may open in response to the increased pressure [10]. Patients with CLI who are not suitable candidates for a vascular intervention are treated conservatively on a wait-and-see basis, with a 55 % amputation-free survival rate after one year. In these patients, one-year mortality and amputation rates are both approximately at 20 % and spontaneous wound healing at 10–20 %, while 35 % have persisting wounds [11, 12]. Patients who need amputation Vasa (2018), 47 (1), 17–22 https://doi.org/10.1024/0301-1526/a000669

and those with persisting wounds – jointly comprising 55 % – could benefit from a suitable intervention but are not easily identified.

M. Lichtenberg et al., Venous arterialization techniques

Surgical techniques Given the presence of a superficial and a deep venous system, two surgical approaches may be used for venous arterialization.

Historical background of venous arterialization Superﬁcial venous arterialization The first attempt to reverse flow was suggested and demonstrated by Carell and Guthrie in 1906; the authors performed a series of canine experiments to explore the possibility of an arteriovenous anastomosis in the groin [13]. The concept of using the disease-free venous bed as an alternative conduit for the perfusion of peripheral tissues with arterial blood was first proposed by Halstead and Vaughan in 1912 [14]. The authors reviewed 42 cases and found only one patient in whom pulsation of the foot veins were observable on the day of surgery. The failure of the approach was primarily attributed to the formation of fistulae in the groin. The expectation of distal valves being destroyed by arterial pressure was proven incorrect. The operation was unpopular because of the difficulties of high-output cardiac failure, severe limb swelling, and progressive distal ischaemia associated with proximal fistulae. In 1951, Szilagyi et al. [15], using the technique of Halstead, reported failure in nine patients. Szilagyi et al. showed that arterial pressure did not effectively destroy the valves, even if the latter were incompetent. As a result, this operation received very little interest until the end of the 1970s. In 1977, Sheil [16] reported on six patients who underwent venous arterialization of the great saphenous vein, highlighting the need for distal valve destruction and noting the lack of adequate perfusion to the forefoot when this step is omitted. In 1984, Lengua et al. [17] reported a new concept with a more distal anastomosis in the deep venous system, which yielded better results. Lengua et al. described the outcome of the procedure in a series of 59 patients who were followed for 15 years [18]. Since then, the principle of arterialization has been used in different variations and under various conditions to improve tissue oxygenation in retrograde fashion. The key aspects of the success of the procedure are valve destruction and adequate perfusion to the forefoot. Many reports on venous arterialization have been published since then, but with small numbers of patients. In a systematic review and meta-analysis of these studies in 2017, it was concluded that venous arterialization could be a valuable treatment option in patients facing amputation, with a limb salvage rate of 75 % after one year [19]. The clinician’s ability to identify patients with CLI and recommend an optimal technique is rendered difficult by the variety of venous arterializations and low-volume studies on them. One of the aims of the present review is to inform clinicians about the history, mechanisms, outcomes, and complications of the different techniques of venous arterializations as well as to describe various open techniques and new percutaneous procedures. Vasa (2018), 47 (1), 17–22

The superficial venous arch of the foot is used for arterialization. Separate incisions are performed to expose the infragenual great saphenous vein at the suitable site for the anastomosis and the median marginal vein of the foot for the treatment of valves. An anastomosis is created between the great saphenous vein and the appropriate inflow artery, which is usually the popliteal artery. A valvulotomy is performed by inserting an expandable valvulotome through a transverse venotomy at the median marginal vein. A small plastic probe or metal olive destroys, in antegrade fashion, the distal valves of the hallux and the superficial venous arch. After the venotomy has been closed and all tributaries of the great saphenous vein have been ligated, a final angiogram is performed to visualize the perfusion of the foot through the superficial venous arch.

Deep venous arterialization This technique differs in that the outflow is directed toward one of the deep veins of the foot. An anastomosis to one of the concomitant veins of the posterior tibial artery at the malleolar level or even one of the concomitant veins of the plantar artery are commonly used. One of the advantages of deep venous arterialization is that it does not rely on communication between the saphenous vein and the deep system below the ankle to perfuse the foot because blood flow is directed to the foot through the deep venous system. A second advantage is that fewer valves will be destroyed compared with superficial venous arterialization, as the last valve is located halfway to the foot. However, the distal anastomosis may prove to be a technical challenge.

Alternative hybrid approach Another possibility is the hybrid approach, in which a distal anastomosis of an infragenual bypass is created at the level of the popliteal veins or another tibial vein, followed by endovascular embolization of the venous branches and or covered stent placement [20]. Previously, the valves of veins on the foot were destroyed separately by a foot incision, but new techniques allow to achieve this via endovascular approach. A hybrid technique may be considered at any level below the knee.

M. Lichtenberg et al., Venous arterialization techniques

The endovascular technique of venous arterialization Percutaneous deep vein arterialization is based on an endovascular method to achieve venous arterialization. The endovascular system consists of four main components: an arterial ultrasound catheter with a needle, a venous ultrasound catheter, a series of covered nitinol stents, and an ultrasound system with a laptop computer. After standard preparation, a 7F sheath is placed in the femoral artery. In a first step, the arterial catheter is placed over a standard 0.014-inch guidewire, using a monorail system, and advance it distally into the tibial artery to the point of the intended crossing. The handle of the catheter has a pusher ring that advances the crossing needle from the artery to the vein. A standard 0.014-inch guidewire can be inserted through the needle from the proximal hub and is used as the crossing wire. With ultrasound guidance, the venous access is achieved by puncturing the tibial vein around the ankle. The choice of target vein arterialization/access depends on the size of the vein and the location of the wound based on the angiosome/venosome concept. A 5F sheath is positioned in the target vein over a standard 0.014-inch guidewire, through which the venous catheter is advanced from the ankle to the crossing point. The venous ultrasound catheter receives an ultrasound signal from the arterial catheter and acts as a target in the vein for aligning the needle of the arterial ultrasound catheter. Once the peak ultrasound signal indicates optimal alignment of the arterial and venous catheter, the needle of the arterial ultrasound catheter is advanced into the tibial vein. This is referred to as the crossover procedure at the crossover point. A standard guidewire is inserted through the crossing needle, which after predilatation allows for the deployment of a covered stent (the crossover stent), thus creating the arteriovenous fistula. The covered crossover stent creates deep vein arterialization, prevents leakage at the crossover point and also drives blood distally, therefore preventing the return of blood to the heart. The wire is lowered from the proximal aspect to the deep venous arch and loops the foot. The medial posterior vein is followed. The crossover stent is subsequently extended with multiple 5-mm self-expanding covered stents (extension stents) to the level of the ankle. The extension stents serve as an endoconduit and address the issue of multiple valves in the tibial veins that may impede flow as well as cover the multiple venous collaterals that may “bleed off ” flow to the ankle. Extension stents also ensure a large calibre of flow to the ankle. Distal to the covered stents at the ankle, a novel 4F over-the-wire forward-cutting valvulotome destroys the valves distal to the covered stent, some occurring as distal as the midfoot. This is in contrast to a conventional surgical valvulotome, which is pulled rather than pushed. Balloon dilatation follows within the stent and is some© 2017 Hogrefe

times needed distally. Post-procedural therapy include one antiplatelet medication plus anticoagulation (preferred Vitamin K antagonist).

Patient selection Patient selection is a key aspect of the success of this procedure. Not all patients are candidates for venous arterialization. Even without intervention, a significant number of patients with CLI will be able to preserve their limb [11, 12]. Comparative studies are lacking, although Matzke et al. [21] showed that wound care and pain relief were followed by a 50 % limb salvage rate after 12 months. This suggests that not all patients need revascularization. However, Djoric et al. [22, 23] registered a limb salvage rate of 13 % in patients treated conservatively, and 83– 93 % in the venous arterialization group. These data and the differences in limb salvage rates suggest that patient selection is important. Patient selection should be determined by clinical and radiologic criteria. Patients with CLI and no arterial revascularization options are candidates for the procedure. If no pedal artery is available and the superficial or deep venous arch of the foot is patent, a venous arterialization can be performed. Clinically, the necrosis should not have advanced to the metatarsal bones.

Outcome A recent meta-analysis [19] assessed the clinical effectiveness of open venous arterialization for lower limb salvage in CLI patients with no revascularization options. Fifteen articles met the inclusion criteria. The studies included in the meta-analysis comprised 768 patients. Limb salvage was reported in all of these studies. However, the exact definition of limb salvage varied and was not specifically defined in some studies. Seven studies reported limb salvage rates of 57–79 % at one year [18, 20, 21, 24–27]. Engelke et al. [28] registered a limb salvage rate of 75 % at two years and an overall limb salvage rate of 83 % with a mean follow-up of 25 months (range nine to 48 months). The remaining seven studies reported limb salvage rates without specifying the postoperative interval at which limb salvage was measured [22, 23, 29–31]. In these studies, limb salvage was 30–100 %, and the mean duration of follow-up was four to 23 months. Wu et al. [31] reported a limb salvage rate of 100 % in 156 patients (212 limbs), with a mean follow-up of 10 months (range three to 27 months). A comparison of conventional surgical pedal bypass and superficial venous arterialization revealed equivalent limb salvage rates [28].

Vasa (2018), 47 (1), 17–22

Survival The 30-day or in-hospital mortality was reported in 12 studies and ranged from zero to 10 % [18, 20–22, 26, 30]. Survival at 12 months was reported in three studies and ranged between 85 and 93 % [26, 27, 29]. Overall survival was reported in 10 studies and ranged between 54 and 100 % with a mean follow-up of five to 60 months [20, 22–24, 26, 27, 29, 30].

Patency Six studies reported on the patency of venous arterialization. Mutirangura et al. [26] registered a primary patency rate of 59.0 % ± 1.1 % at 12 months and 49.2 % ± 1.3 % at two years. Alexandrescu et al. [20] reported only secondary patency, which was 66 % ± 9 % at 12 months and 48 % ± 14 % at three years. Engelke et al. [28] reported primary and secondary patency rates of 66 and 72 %, respectively, with a mean follow-up of 25 months (range nine to 48 months). Two studies reported mean patency rates of 8.5 and 15 months, respectively [24, 25], while another study reported a patency rate of 71 % at 12 months [27]. The latter three studies did not specify the type of patency (i. e. primary, primary assisted, or secondary patency). The meta-analysis revealed no difference in outcomes between superficial and deep venous arterialization.

Percutaneous deep vein arterialization In a case series, Kum et al. [32] performed percutaneous deep vein arterialization in seven patients with no-option CLI, defined as CLI with no traditional endovascular or

M. Lichtenberg et al., Venous arterialization techniques

surgical revascularization options. The primary safety endpoint was achieved in 100 %, with no deaths, aboveankle amputations, or major reintervention at 30 days. The technical success rate was 100 %. Two adverse cardiac events occurred within 30 days. All patients showed symptomatic improvement with the formation of granulation tissue, resolution of rest pain, or both. Complete wound healing was achieved in four of seven patients (57.1 %) at six months and in five of seven patients (71.4 %) at 12 months, with a median healing time of 138 days (95 % confidence interval 84–192 days). The median postprocedural maximum transcutaneous oxygen (TcPo2) measurement was 62 mmHg, compared with a pre-procedure level of 8 mmHg (p = 0.046). Two major amputations were needed (28.9 %): one above the knee because of infection and the other below the knee after a percutaneous deep vein arterialization graft thrombosis. This resulted in limb salvage rates of 85.7 % at six months and 68.6 % at 12 months. The 12-month mortality rate was 42.9 % and none of the deaths were related to the procedure or the study device [32]. One of our cases is presented in Figure 1.

Discussion Objectively, CLI may be interpreted as the presence of a non-healing wound or distal gangrene associated with no distal pulse and a TcPo2 below 40 mmHg in the absence of confounding factors such as oedema or infection which may falsely depress the TcPo2 [33]. No-option CLI is a poorly defined clinical condition that implies the absence of surgical or endovascular revascularization options in a patient who presents with

Figure 1. A 75-year-old male diabetic patient with critical limb ischaemia in the right foot (left) and a transcutaneous oxygen pressure (TcPo2) of 2–8 mmHg in the forefoot. Corresponding diagnostic angiography showing no option for endovascular or surgical arterial revascularization (middle). Sufﬁcient inﬂow is seen after deep venous arterialization (right). The TcPo2 increased to 56 mmHg. Vasa (2018), 47 (1), 17–22

M. Lichtenberg et al., Venous arterialization techniques

CLI. The fact that the interpretation of the condition is subject to bias makes it difficult to compare published studies. Surgically, the condition implies the impracticality of performing a conventional distal bypass, usually because of the absence of an appropriate target vessel for the bypass. This can be due to the size of the surgical target or the quality of the vessel, which may be affected by severe calcification. For endovascular revascularization, it implies small distal target vessels of poor quality, resistant calcification, recoil, and the lack of an option for frequent below-the-knee restenosis. Before a patient is labelled as a case of no-option CLI, a surgeon, experienced in contemporary techniques, must attempt an endovascular intervention. Venous arterialization is a valuable treatment option for this purpose. The majority of patients with CLI are in the final stage of their lives. A recent meta-analysis of no-option CLI studies reported mortality rates of 10 to 54.3 %; 19.2–54 % of the patients were diabetic [11]. Since the patients’ functional reserves are poor, it would be essential to optimize their medical comorbidities as well as assess the risk-benefit ratio of revascularization in the individual case. Some patients have wounds that cannot be salvaged or extensive infection that would preclude a reasonable attempt at limb salvage. These patients are better served with a primary amputation. With regard to technical aspects, an understanding of the venous anatomy of the foot and correct orientation is essential. The surgeon must refrain from twisting the target vein segments, ensure meticulous handling of the segments, and pay careful attention to the anastomosis. Valves constitute another crucial technical aspect. The simplicity of their construction may be deceptive. The surgeon should have a thorough knowledge of valve anatomy before attempting to pass through or treat them. Venous arterialization is a low-resistance bypass that permits high flow. Appropriate flow is essential to ensure the patency of the bypass. Perfusion of the venous arch of the foot is regarded as the key aspect of successful wound healing. A combination of probes, wires, balloons, and even forward cutting over the wire push valvulotome help to achieve this. Swelling of the leg is a common occurrence after the procedure. In our experience, the swelling can be managed conservatively with elevation and, occasionally, diuresis. Subsequently, the patient can be nursed with their legs lowered in order to permit hydrostatic pressure for the formation of further venous collaterals. Wound healing after venous arterialization takes longer than after conventional revascularization. In some reports, the patients underwent amputation with an open bypass [21, 27, 34]. Ongoing ischaemia is seen in the beginning and may be the result of arteriovenous shunting. Inadequate forward pressure appears to be the cause of failed wound healing. In some cases, arteriovenous formation is seen even when the graft is occluded; arterial flow is marked by a persistently high TcPo2 [26, 32]. © 2017 Hogrefe

Conclusions Chronic CLI continues to be a challenge. With the rise of diabetic patients, improved life expectancy, greater awareness, and wider adoption of endovascular techniques, amputation rates continue to fall [35–37]. In the future, we expect patients to be older, have more advanced comorbidities, and several prior interventions that will limit their current options. This may translate into more numerous patients with no-option CLI. Venous arterialization may be a viable alternative for the preservation of limbs but the technique is not fully developed yet. Forward pressure seems to be a key factor. The percutaneous approach helps to reduce surgical stress in this vulnerable patient group.

References 1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1–75. 2. Dormandy J, Heeck L, Vig S. The fate of patients with critical leg ischemia. Semin Vasc Surg 1999;12:142–7. 3. Dormandy J, Heeck L, Vig S. Major amputations: clinical patterns and predictors. Semin Vasc Surg 1999;12:154–61. 4. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366(9501):1925–34. 5. Peeters Weem SM, Teraa M, de Borst GJ, Verhaar MC, Moll FL. Bone marrow derived cell therapy in critical limb ischemia: a meta-analysis of randomized placebo controlled trials. Eur J Vasc Endovasc Surg. 2015;50(6):775–83. 6. Abu Dabrh AM, Steffen MW, Asi N, Undavalli C, Wang Z, Elamin MB, et al. Nonrevascularization-based treatments in patients with severe or critical limb ischemia. J Vasc Surg. 2015;62(5): 1330–9.e13. 7. Ubbink DT, Vermeulen H. Spinal cord stimulation for non- reconstructable chronic critical leg ischaemia. Cochrane Database Syst Rev 2005:CD004001. 8. Ozek C, Zhang F, Lineaweaver WC, Chin BT, Newlin L, Eiman T, et al. Arterialization of the venous system in a rat lower limb model. Br J Plast Surg 1997;50:402–7. 9. Baffour R, Danylewick R, Burdon T, Sniderman A, Common A, Graham A, et al. An angiographic study of ischaemia as a determinant of neovascularisation in arteriovenous reversal. Surg Gynaecol Obstet 1988;166:28–32. 10. Johnston CG, Jordan P Jr, Cloud T. Arteriovenous anastomosis in traumatic vascular lesions. Am J Surg 1950;80:809–12 11. Benoit E, O’Donnell TF Jr, Kitsios GD, Lafrati MD. Improved amputation-free survival in unreconstructable critical limb ischemia and its implications for clinical trial design and quality measurement. J Vasc Surg 2012;55(3)781–9. 12. Abu Dabrh AM, Steffen MW, Undavalli C, Asi N, Wang Z, Elamin MB, Conte MS, Murad MH. The natural history of untreated severe or critical limb ischemia. J Vasc Surg 2015 dec;62(6): 1642–51. 13. Carrel A, Guthrie CC. The reversal of the circulation in a limb. Ann Surg 1906;43:203. 14. Halstead AE, Vaughan RT. Arteriovenous anastomosis in the treatment of gangrene of the extremities. Surg Gynecol Obstet 1912;14:1. 15. Szilagyi DE, Jay GE, Munnel ED. Femoral arteriovenous anastomosis in the treatment of occlusive arterial disease. AMA Arch Surg 1951;63:435. Vasa (2018), 47 (1), 17–22

16. Sheil AGR. Treatment of critical ischaemia of the lower limb by venous arterialisation: an interim report. Br J Surg 1977;64: 197–9. 17. Lenqua F, Nuss JM, Lechner R, Kunlin J. Arterialization of the venous network of the foot through a bypass in severe arteriopathic ischemia. J Cardiovasc Surg 1984;25:357–60. 18. Lengua F, Cohen R, L’Huiller B, Buffet JM. Arteriovenous revascularization for lower limb salvage in unreconstructible arterial occlusive disease (long term outcome). Vasa. 1995;24(3):261–9. 19. Schreve MA, Vos CG, Vahl AC, de Vries JP, Kum S, de Borst GJ, Unlu C. Venous arterialization for salvage of critically ischaemic limbs: a systematic review and meta-analysis. Eur J Vasc Endovasc Surg. 2017;53(3):387–402. 20. Alexandrescu V, Ngongang C, Vincent G, Ledent G, Hubermont G. Deep calf veins arterialization for inferior limb preservation in diabetic patients with extended ischaemic wounds, unﬁt for direct arterial reconstruction: preliminary results according to an angiosome model of perfusion. Cardiovasc Revasc Med. 2011;12(1):10–9. 21. Mätzke S, Pitkänen J, Lepäntalo M. Does saphenous vein arterialisation prevent major amputation in critical leg ischaemia? A comparative study. J Cardiovasc Surg (Torino). 1999;40(6):845–7. 22. Djoric P. Early individual experience with distal venous arterialization as a lower limb salvage procedure. Am Surg. 2011;77(6):726–30. 23. Djoric P, Zeleskov-Djoric J, Stanisavljevic DM, Markovic ZD, Zivkovic V, Vuletic M, Djuric D, Jakovljevic V. Distal venous arterialization and reperfusion injury: focus on oxidative status. Eur Surg Res. 2012;48(4):200–7. 24. Gavrilenko AV, Skrylev SI. Long-term results of venous blood ﬂow arterialization of the leg and foot in patients with critical lower limb ischemia. Angiol Sosud Khir. 2007;13(2):95–103. 25. Lengua F, La Madrid A, Acosta C, Vargas J. Temporal venous arterialization of the diabetic foot. Jornal Vascular Brasileiro. 2010;9(1):14–20. 26. Mutirangura P, Ruangsetakit C, Wongwanit C, Sermsathanasawadi N, Chinsakchai K. Pedal bypass with deep venous arterialization: the therapeutic option in critical limb ischemia and unreconstructable distal arteries. Vascular. 2011;19(6):313–9. 27. Schreve MA, Minnee RC, Bosma J, Leijdekkers VJ, Idu MM, Vahl AC. Comparative study of venous arterialization and pedal bypass in a patient cohort with critical limb ischemia. Ann Vasc Surg. 2014;28(5):1123–7. 28. Engelke C, Morgan RA, Quarmby JW, Taylor RS, Belli AM. Distal venous arterialization for lower limb salvage: angiographic appearances and interventional procedures. Radiographics. 2001;21(5):1239–48. 29. Busato CR, UtraboII CAL, Gomes RZ, Hoeldtke E, HousomeII JK, Costa DMM, Busato CD. The great saphenous vein in situ for

Vasa (2018), 47 (1), 17–22

M. Lichtenberg et al., Venous arterialization techniques

the arterialization of the venous arch of the foot. Jornal Vascular Brasileiro. 2010;9(3):119–23. 30. Vira Reddi HT, Nath LS. New concepts in the management of ischaemic lower extremities. Int Angiol. 1990;9(2):97–104. 31. Wu ZQ, Jiang XP, Wu ZP, Zhang L, Liu XM, Xia GH, Zhang PH. Experimental and clinical studies on one-stage arterialization of the venous channels for revascularization of severely ischemic limbs. Chin Med J (Engl). 1993;106(11):814–20. 32. Kum S, Tan YK, Schreve MA, Ferraresi R, Varcoe RL, Schmidt A, et al. Midterm Outcomes From a Pilot Study of Percutaneous Deep Vein Arterialization for the Treatment of No-Option Critical Limb Ischemia. J Endovasc Ther. 2017;24(5):619–26. 33. Faglia E, Clerici G, Caminiti M, Quarantiello A, Curci V, Morabito A. Predictive values of transcutaneous oxygen tension for above-the-ankle amputation in diabetic patients with critical limb ischemia. Eur J Vasc Endovasc Surg. 2007;33(6):731–6. 34. Houlind K, Christensen J, Hallenberg C, Jespen JM. Early results from an angiosome-directed open surgical technique for venous arterialization in patients with critical limb ischemia. Diabet Foot Ankle 2013;17:4. 35. Egorova NN, Guillerme S, Gelijns A, Morrissey N, Dayal R, McKinsey JF, Nowygrod R. An analysis of the outcomes of a decade of experience with lower extremity revascularization including limb salvage, lengths of stay, and safety. J Vasc Surg. 2010;51: 878–85. 36. Nowygrod R, Egorova N, Greco G, Anderson P, Gelijns A, Moskowitz A, McKinsey J, Morrissey N, Kent KC. Trends, complications, and mortality in peripheral vascular surgery. J Vasc Surg. 2006;43:205–16. 37. Goodney PP, Beck AW, Nagle J, Welch HG, Zwolak RM. National trends in lower extremity bypass surgery, endovascular interventions, and major amputations. J Vasc Surg. 2009;50:54–60.

Submitted: 15.07.2017 Accepted after revision: 14.08.2017 There are no conﬂicts of interest existing. Published online: 25.10.2017

Correspondence address Dr. Michael Lichtenberg, MD Vascular Centre Arnsberg Arnsberg Clinic Stolte Ley 5 D-59759 Arnsberg Germany klichte@gmx.net

Review

Posterior nutcracker syndrome – a systematic review Jae Hyon Park1,a, Gi Hoon Lee2,a, Seul Mi Lee3,4, Michael Eisenhut5, Andreas Kronbichler6, Keum Hwa Lee3,4, and Jae Il Shin3,4,7 1 2 3 4 5 6 7 a

Yonsei University College of Medicine, Severance Hospital, Seoul, Republic of Korea Yonsei University Wonju College of Medicine, Wonju, Republic of Korea Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea Division of Pediatric Nephrology, Severance Children‘s Hospital, Seoul, Republic of Korea Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton, United Kingdom Department of Internal Medicine IV, Medical University Innsbruck, Innsbruck, Austria Institute of Kidney Disease Research, Yonsei University College of Medicine, Seoul, Republic of Korea These authors contributed equally to this paper

Summary: Posterior nutcracker syndrome (PNCS) is the entrapment of the left renal vein between the aorta and the vertebral column. Although uncommon, it is still an important diagnosis due to the high morbidity associated with the risk of secondary anaemia from haematuria, from long-term left renal vein hypertension, vascular thrombosis, and even blood clots in the urinary system. A literature search of PubMed and EMBASE databases was performed and 27 publications containing 27 cases were included for the final analysis. The following frequency of clinical signs and symptoms was noted: twenty-five patients had haematuria, 13 patients had flank pain, and two had hypertension. Overall, male-female distribution was balanced and there were more adult than paediatric (age < 18 years) patients. All symptoms of patients with conservative treatment were either well-controlled or under spontaneous resolution. Conservative management instead of surgical treatment should be preferred in most cases. Taken together, despite the low incidence of PNCS, its recognition and management are highly important. This systematic study explores the evidence base for conservative and medical options. Keywords: Posterior nutcracker syndrome (PNCS), systematic review, haematuria, conservative management

Introduction Entrapment of the left renal vein also known as the nutcracker syndrome (NCS) is a rare cause of both microscopic and macroscopic haematuria [1]. Two types of left renal vein entrapment can possibly exist: anterior NCS is the compression of the left renal vein between abdominal aorta and superior mesenteric artery, while the posterior NCS (PNCS) is the compression of the retroaortic left renal vein between the abdominal aorta and vertebral column. The latter is a rarer condition and, given its paucity, little is known about the patient’s demographic profile, clinical presentation, method of diagnosis, and treatment outcome since not one single systematic review has yet analysed patients diagnosed with PNCS. Since the incidence of PNCS is supposed to be low, its clinical manifestations are often mistaken as presentations of other more common illnesses [1]. Venostasis or the distension of the left ovarian or spermatic vein caused by left renal vein entrapment often results in flank and back pain, which may lead to misdiagnosis [2]. In addition, haematuria and proteinuria caused by the rupture of venous sinuses can be presentations and may be misdiag© 2017 Hogrefe

nosed as glomerulonephritis [1]. In contrast to potential differential diagnoses, absence of specific clinical features necessitates a high suspicion for the diagnosis of PNCS, where noninvasive imaging followed by invasive imaging may be needed for the confirmation of PNCS.

Methods Two investigators independently identified published case reports of PNCS that were indexed in PubMed and EMBASE database using the search terms “posterior nutcracker syndrome” or “left renal vein entrapment” up to 3 April 2017. The identification of relevant literatures was performed in accordance with the items of the PRISMA (Preferred Reporting Items for Systematic Reviews and Metaanalyses) statement (ESM 2, Table) [3]. Case reports that were (1) not associated with PNCS, (2) reviews, comments, and letters, and (3) reports solely consisting of radiologic findings were excluded. Moreover, a case report of an adolescent patient with both anterior and PNCS was excluded Vasa (2018), 47 (1), 23–29 https://doi.org/10.1024/0301-1526/a000670

from our final analysis to exclusively select reports of patients with only PNCS [2]. Cases of haematuria secondary to renal vein thrombosis were also excluded and articles reporting haematuria due to superimposition of other diseases that could possibly cause haematuria (i. e. glomerulonephritis, hypercalcemia, ureter stone, etc.) were also excluded. Through our search methods, a total of 114 articles were retrieved, of which 27 case reports were used for the final analysis (ESM 1, Figure). From each case report, data regarding the case-reported patient’s age, sex, clinical presentation, diagnostics and radiological findings, treatment, and patient outcomes were tabulated and are summarized in ESM 3, Table. One case report did not disclose the patient’s gender [4], while four case reports did not reveal the means of treatment and the outcome of the patients [5–8]. As for clinical presentation, microhaematuria herein refers to more than two red blood cells (RBCs) per high-power field from two of three properly collected urine specimens as defined by the American Urological Association (AUA). Gross haematuria that is visible without the need of microscopic evaluation was considered as macrohaematuria. Presence of a cast was also recorded if this was reported in the case report.

Results Demographic characteristics and clinical features Out of the total of 27 patients who had a final diagnosis of PNCS, 25 patients exhibited signs of haematuria (ESM 3, Table). Two patients who did not show any signs of haematuria exhibited flank pains with one also exhibiting hypertension due to secondary hyperaldosteronism [9]. Nine patients exhibited isolated haematuria while others presented additional clinical signs and symptoms such as proteinuria, pyuria, pain (i. e. flank, loin and left upper quadrant pain), abdominal mass, and hypertension. Interestingly, more than half (n = 9) of the patients who showed isolated haematuria also exhibited macrohaematuria. The second most common symptom among patients with PNCS was flank pain. Nearly half of the patients (n = 13) exhibited flank pain with two patients also exhibiting pain in the back and loin, respectively. Only two patients showed signs of hypertension and two other patients exhibited both haematuria and proteinuria. The diagnosis of PNCS was made most frequently using computed tomography (CT) in 23 patients. In addition, seven patients were diagnosed using renal ultrasound doppler flow, while three were diagnosed via magnetic resonance imaging (MRI). Nine patients showed significant increase in the left renal vein pressure (LRVP), with a mean (7.0 ± 2.2 mmHg) above the normal value of less than 1–2 mmHg. Different combinations of symptoms are depicted in Table I; various radiologic investigations used for the diagnosis of each patient are summarized in Table II. Vasa (2018), 47 (1), 23–29

J. H. Park et al., Posterior nutcracker syndrome

Only one patient was diagnosed using a single radiologic exam (i. e. CT with contrast). Most patients (n = 10) were diagnosed using three exams, although seven and four patients required four and five radiologic investigations, respectively. The radiologic examinations that were most frequently used for the diagnosis of PNCS in decreasing order were: ultrasound or CT with contrast (n = 14), cystoscopy (n = 12), renal ultrasound doppler flow (n = 8), renal venogram (n = 7), and CT angiography or CT (including multidetector CT (MDCT)) without contrast (n = 5) (Table III). All other investigations (i. e. arteriogram, intravenous urogram (IVU), kidney-ureter-bladder X-ray (KUB), MDCT angiography) were used in less than five cases. Among the radiologic examinations that were used most frequently, renal ultrasound doppler flow and renal venogram results revealed abnormality in all cases, while CT with contrast and cystoscopy gave abnormal results in 92.9 % and 100.0 % of the patients, respectively. Interestingly, abnormal findings were found in only 28.6 % of patients using renal ultrasound, although this examination was most frequently used alongside CT with contrast. Moreover, in five cases where no contrast was used, normal findings were given via CT in two patients but abnormal findings were found using MDCT in three patients. Examinations that were used in less than five cases revealed that only MDCT angiography showed abnormal findings in patients. Renal biopsy was not performed in any of the patients.

Table I. Different combinations of symptoms shown by patients with posterior nutcracker syndrome. Speciﬁc symptoms

Haematuria

Microhaematuria

Macrohaematuria

Haematuria, unspeciﬁed

Flank pain

–

Abdomen lump

Haematuria

# of patients

Hypertension

Proteinuria

Flank pain

– Pelvic congestion syndrome

Back pain

Loin pain

Proteinuria

–

Flank pain

Loin pain

–

Flank pain

–

Left upper quadrant pain

Flank pain

Pyuria

Proteinuria

Hypertension Total

1 27

J. H. Park et al., Posterior nutcracker syndrome

Table II. Different combinations of radiologic test performed for the diagnosis of posterior nutcracker syndrome. Radiologic test performed Ultrasonography

CT without contrast CT with contrast

# of patients

Cystoscopy

CT angiography

Cystoscopy

Left renal venogram Doppler

MRI

Doppler

Cystoscopy CT with contrast

Doppler

CT with contrast

–

MRI

Phlebography

Cystography

MDCT angiography IVU

CT with contrast

Cystoscopy

CT with contrast

Phlebography

CT with contrast

–

Cystoscopy –

Left renal arteriogram Doppler

Left renal venogram

MDCT without contrast IVU

2 Ultrasonography

MDCT without contrast

CT with contrast

Arteriography

Cystoscopy Renal arteriogram Cystoscopy

CT angiography

KUB

Ultrasonography

Left renal venogram CT with contrast

1 2

MDCT angiography

Voiding cystourethrogram Doppler Gynaecological and urological work up Doppler

CT angiography

1 Left renal venogram

Selective angiography*

1 1

Total

CT: Computed tomography; MRI: magnetic resonance imaging; IVU: intravenous urogram; KUB: kidney-ureter-bladder X-ray; MDCT: multi-detector computed tomography. *Selective angiography refers to angiography performed on internal iliac veins, right and left ovarian veins, and left renal vein. Here, left renal venogram refers to retrograde venogram.

Among 23 patients who exhibited retroaortic left renal vein in CT and MDCT, 10 patients showed additional radiologic abnormalities, including anomalous anatomy, three of which exhibited abnormalities in the kidney (i. e. L-shaped type left cross fused renal ectopia (CFRE), mass in upper pole of the left kidney with arteriovenous fistula, multiple renal abscesses), four in the arteries and veins (i. e. renal arteriovenous malformation, anomalous communication between azygos vein and inferior vena cava (IVC), left renal vein duplication), and three in the aorta (i. e. atherosclerotic change of aorta and infrarenal aortic aneurysm) (Table II). The age distribution of 27 patients was found to follow a bimodal distribution with most patients diagnosed in their mid-twenties (Figure 1). In terms of age, only seven pa© 2017 Hogrefe

tients were less than 18 years old and thus overall there was a smaller number of paediatric patients than adult patients. In general, there were more male patients than female patients regardless of age, although this was not the case for patients in the first or third decade of their lives. However, overall, the male-female distribution was roughly the same (n = 14 vs. n = 13).

Course and management Twenty-two patients received treatment, thereof 13 received a surgical procedure, including open surgery and minimally invasive or endovascular approaches. Overall, Vasa (2018), 47 (1), 23–29

J. H. Park et al., Posterior nutcracker syndrome

five patients underwent conservative treatment (i. e. transfusion of packed RBC if serum haemoglobin level < 7 g/dL, flank/loin/back pain management, etc.), while two and eleven patients underwent stent and open surgical procedures (i. e. left renal vein bypass, left renal vein transposition with and without polytetrafluoroethylene (PTFE) stent, superior mesenteric artery transposition, left radical nephrectomy, wrapping of the left renal vein with ringed PTFE stent, etc.), respectively. All patients who received conservative treatment had either well-controlled symptoms or they were under spontaneous resolution

Table III. Various radiologic tests used for the final diagnosis of posterior nutcracker syndrome and the number of normal and abnormal findings for each corresponding radiologic test. Normal findings Ultrasonography

Abnormal ﬁndings 4 (28.6 %)

2 (16.7 %)

10 (83.3 %)*

2 (100.0 %)

0 (0.0 %)

CT with contrast

1 (7.1 %)

13 (92.9 %)

MDCT without contrast

0 (0.0 %)

3 (100.0 %)

CT angiography

0 (0.0 %)

5 (100.0 %)

MDCT angiography

0 (0.0 %)

2 (100.0 %)

Doppler

0 (0.0 %)

8 (100.0 %)

Venogram

0 (0.0 %)

7 (100.0 %)

Arteriogram

1 (33.3 %)

2 (66.7 %)

IVU

3 (75.0 %)

1 (25.0 %)

KUB

1 (50.0 %)

Total

20 (26.3 %)

CT without contrast

Discussion To the best of our knowledge, this is the first systematic review analysing the clinical and demographic characteristics, methods of diagnosis, and treatment and outcome of

Total

10 (71.4 %)

Cystoscopy

(Table IV). In contrast, patients who received an operation had mixed outcomes. Seven patients had complete resolutions and three partial resolutions (i. e. reduced episodes of haematuria and improvement of anaemia, etc.) Three patients who refused treatment showed mixed outcomes: spontaneous resolution, persistent asymptomatic haematuria, and death, respectively.

Table IV. Treatment and outcome of patients with posterior nutcracker syndrome. Treatment

Treatment outcome

# of patients

Refused treatment

Free of haematuria

Intermittent painless haematuria

Death

–

Spontaneous resolution

Well controlled

Antibiotics, LMWH, conservative

Partial resolution

Stent

Complete resolution

1 (50.0 %)

Operation

–

56 (73.7 %)

Partial resolution

Complete resolution

Conservative

CT: computed tomography; MDCT: multidetector computed tomography; IVU: intravenous urogram; KUB: kidney-ureter-bladder x-ray. * 10 abnormal ﬁndings from cystoscopy were all patients with haematuria. Two patients without haematuria showed normal ﬁndings.

LMWH: Low-molecular-weight heparin

Total

No. of patients

Age < 18

7 6

Number of patients

Female Male 5 4 3 2

Age 18 +

0 5 0 5

1 0

0 < 10

10–19

20–29

30–39

Age of patient

40–49

50–59

59 <

No. of patients

Female

Male

Gender Distribution of patients

Figure 1. (A) Age distribution of patients with PNCS with the number of male and female patients in each age group. (B) Male-female distribution of patients and distribution of pediatric and adult patients with PNCS. PNCS: posterior nutcracker syndrome. Vasa (2018), 47 (1), 23–29

J. H. Park et al., Posterior nutcracker syndrome

patients with PNCS. Since the posterior entrapment of the left renal vein is a rarer condition among NCS patients, little is known about the disease. While the clinical features of patients with PNCS vary from asymptomatic haematuria to pelvic congestion, our results indicate that, similar to anterior NCS, typical renal presentations (i. e. micro- and macrohaematuria, proteinuria) are by far the most common, followed by atypical presentations such as flank pain and secondary hypertension. However, contrary to a previous report [4] of left renal vein entrapment emphasizing proteinuria as a feature in adolescents and children, our results indicate that PNCS results in isolated haematuria (rarely linked with proteinuria) from the ipsilateral collecting system as revealed by blood arising in the left ureteral orifice via cystoscopy in 83.3 % of the patients. Haematuria observed in patients with PNCS is thought to occur due to elevated LRVP that causes the rupture of the thin-walled septum between the varices and the collecting system in the renal fornix. Previously, one study has reported that the amount of haematuria follows a direct relationship with the increase in the LRVP [10]. However, such a correlation was not evident in our study as one patient with LVRP of 4.4 mmHg [5] showed macrohaematuria and another patient with LVRP of 8 mmHg [11] showed microhaematuria. Moreover, not a single case report reported the presence of a varicocele, although the development of a varicocele has been commonly noted in NCS patients due to elevated LVRP and collateral circulation. Furthermore, as opposed to patients with anterior NCS who exhibited microhaematuria four times more than macrohaematuria [12], the number of patients with microhaematuria and macrohaematuria was equivalent in PNCS. As for pain, most patients (n = 7, 77.8 %) with increased LRVP on renal venogram exhibited either left flank pain or discomfort. This phenomenon was consistent with the report of a previous study, where pain was found to result from an inflammatory cascade triggered by venous hypertension [13]. Moreover, 12 out of 25 patients who exhibited haematuria also had left flank pain, which is thought to be ureteral-colic related to blood clots passing down the left ureter [14]. As for demographic profiles of PNCS patients, a male preponderance has been reported which is in contrast to anterior NCS that affects mainly females [15]. Affected patients were diverse in age, ranging from children and adolescent to middle-aged and even elderly in the seventh decade of life, similar to the age distribution of anterior NCS [14]. Moreover, most symptomatic patients were in the second and third decades of their lives and a second peak occurred near the fifth decade for both men and women, similar to anterior NCS, thus indicating that the PNCS is not a hereditary phenomenon with genetic aetiology [16]. Previously, anterior NCS has been reported to occur mostly during puberty in the first decade of life when the angle between the aorta and superior mesenteric artery reduces due to rapid increase in body height and sharp reduction in body mass index [15]. Other than in anterior NCS, our results indicate that PCNS occurs mostly in adults (age ≥ 18 years). This finding is consistent © 2017 Hogrefe

with the fact that a retroaortic entrapment of the left renal vein is unaffected by a change in a person’s body mass index, mainly because there is less perinephric fat and no peritoneal fat anatomically in front of the psoas muscle and vertebral column. Confirmation of a variation in the normal anatomy is essential for the diagnosis of PNCS. Overall, the first diagnosis of PNCS should be made through past medical history and various clinical examinations especially via physical examinations to check for symptoms such as flank pains, voiding abnormalities, and palpable mass followed by routine lab investigations such as venous blood sampling and urinalysis for signs of secondary hyperaldosteronism, and haematuria and proteinuria, respectively. After the abovementioned routine examinations, renal ultrasound with doppler should be the preferred first radiologic examination to investigate presence of an anatomic change followed by either CT with contrast or MDCT without contrast, if the former is not diagnostic. However, it should be noted that the renal doppler flow may not be as sensitive as could be expected, mainly because NCS can also exist without the left renal vein dilatation and a normal flow can exist even in the presence of a dilatation [19]. Our result shows that a majority of patients with PNCS were subjected to three or more noninvasive and invasive procedures before a proper diagnosis was made. While there is currently no standardized diagnostic method, the use of either a renal ultrasound or CT as an imaging examination was previously recommended by one study to observe the entrapment of the left renal vein for patients with NCS [17]. However, according to our results, CT and renal ultrasound were able to diagnose 92.9 % and 28.6 % of the patients respectively, suggesting that CT should be the preferred method for making the final diagnosis, whereas renal ultrasound should be used for screening of patients who are sensitive to or intolerable of radiation hazard. Moreover, CT without contrast was unable to diagnose PNCS in three patients. Only CT with contrast and MDCT without contrast were able to properly diagnose PNCS, suggesting that either the use of a contrast agent or a high-resolution imaging using multi-detectors are needed to fully visualize the variation in the left renal vein. Invasive diagnostic tools such as CT and MDCT angiography were able to diagnose PNCS in all patients; in one patient, the tools were used for the confirmation of PNCS, as CT without contrast could not reveal any abnormal findings. These radiologic examinations certainly have the advantages of providing a real-time visualization of the “beak point” or an abrupt narrowing point and even a prestenotic dilation of the left renal vein. However, their availability at the level of a local healthcare facility, their costs, and invasiveness should be considered before appliance to a paediatric and adolescent patient [18]. Similarly, the retrograde venogram is useful to confirm the anatomic change, measure the pressure gradient near the area of entrapment, and check the reflux of contrast into adrenal and gonadal veins. But this test is also invasive and is not the Vasa (2018), 47 (1), 23–29

diagnostic method of choice for patients with mild or moderate symptoms [1]. Cystoscopy, while being an invasive procedure, provides very little information other than the confirmation of the haematuria’s ureteral origins and should only be used when other examinations reveal to be non-diagnostic. In regards to managing PNCS, while the treatment option may vary from surveillance to nephrectomy, treatment decision should ideally be based on the severity of symptoms, patient’s age, stage of the syndrome, and the expected reversibility from management. Our results indicate that a patient who refuses any sort of treatment has an equal probability of dying and achieving partial or complete spontaneous resolution. In general, for anterior NCS, a conservative approach with observation for a minimum of two years is recommended for paediatric and adolescent (age < 18 years) patients because studies have previously reported on spontaneous resolution via physical development during childhood with 75 % of haematuria resolved during this period [14, 17, 20]. Consistent with this finding, our team also reported that an increase in BMI negatively correlates with the peak velocity at the aortomesenteric portion and positively with spontaneous resolution of haematuria in children with anterior NCS [21]. However, it should be noted that four out of five of these patients were adolescent cases in the first and second decades of their life, which may be the reason why conservative treatment might have turned out to be highly efficacious. Still, one middle-aged (52 years old) male with flank pain and microhaematuria also recovered via conservative treatment [22] and thus, a careful follow-up should be the first step, unless there is a serious indication for an intervention. Moreover, though signs of proteinuria were rarely observed in patients in our study, angiotensin inhibitors should be administered in cases of severe and persistent proteinuria as recommended by a previous investigation [13]. However, surgical approaches should be considered in cases when there is (1) a severe, persistent or recurrent haematuria that leads to haemodynamic instability, anaemia or blood clots causing abdominal or flank pain and (2) when the patient’s symptoms do not alleviate via conservative treatment or after physical development during childhood. In our study, patients who received surgical treatment had mixed outcomes and only seven out of the total eleven patients showed spontaneous resolutions. In fact, one five-yearold patient with PNCS continued to exhibit signs of haematuria two weeks after receiving the operation and only after a year of postoperative follow-up had it completely resolved [7]. However, considering the age of the patient, one could question as to whether the patient would not have undergone a spontaneous resolution simply through years of conservative treatment and follow-up without operation. Overall, though some clinicians may consider surgical repair as the gold standard, expectant management should be first administered to patients with PNCS. The decision to conduct a particular type of surgery is entirely at the surgeon discretion but in cases where the Vasa (2018), 47 (1), 23–29

J. H. Park et al., Posterior nutcracker syndrome

patient’s left renal vein is anatomically short and there is a subsequent possibility of high pressure, left renal vein bypass was used instead of transposition [9]. However, in a previous study, renal vein transposition was found to demonstrate a better long-term result with a high rate of resolution in flank pain, hypertension and haematuria [13]. As for endovascular stent placement, two patients who received this treatment showed complete resolution. Patients who had a long period of renal congestion, additional anastomoses, and required extensive dissections via open surgery can clearly benefit from endovascular stenting but the possibility of stent migration, thrombosis, and restenosis, though rare, should always be considered [23, 24].

Limitations Foremost, due to the very low incidence of the disease, a relatively small number of case reports have been used for the analysis. Secondly, due to the limited number of published case reports, both diagnostic and therapeutic recommendations do not arise from scientific or statistical analyses but rather from author’s opinions or reported past experiences. Lastly, our analysis includes information from single case reports or small case series that are often retrospective and without follow-ups or with very short follow-ups. Not all case reports disclosed patient’s profiles, method of diagnosis, treatment, and outcome; we were only able to analyse information provided by these reports.

Conclusions Our findings still suggest that whenever there is an unexplained haematuria with or without abdominal or flank pain, the diagnosis of NCS should always be considered and, while renal ultrasound with doppler flow is a reliable initial tool of screening, CT with contrast or MDCT without contrast should be considered if the results of the initial set of investigations turn out to be non-diagnostic. CT scans could be performed for the anatomic special case of a left renal vein located behind the aorta; in addition, duplex sonographic investigations can detect a possible reversible compression in standing position. Our results indicate that, similar to the anterior NCS, an expectant management such as monitoring of weight gain and close observation should be preferred over surgical treatment, especially for paediatric and adolescent patients with PNCS. For adult patients, conservative management should still be the treatment of choice but, depending on the clinical presentation and duration of symptoms, surgical management should be considered. In addition, we suggest a prospective study addressing the issue of the specificity of the imaging findings of PNCS in the future. © 2017 Hogrefe

J. H. Park et al., Posterior nutcracker syndrome

Acknowledgements J. H. P, G. H. L, and J. I. S designed the study and coordinated data acquisition. J. H. P, S. M. L, M. E, A. K, K. H. L, and J. I.S analysed and interpreted the data and drafted the manuscript. All authors read and approved the final manuscript.

Electronic supplementary material The electronic supplementary material is available with the online version of the article at https://doi.org/10.1024/0301-1526/a000670 ESM 1. Figure. Flowchart of literature search using search terms ‘posteriornutcracker’ and ‘left renal vein entrapment’ in EMBASE and PubMed database searches. ESM 2. Table. Checklist summarizing compliance with PRISMA guidelines. ESM 3. Table. Demographic summary of patient characteristics including presenting symptoms as well as test results, treatment outcomes, and comorbidities.

References 1. Noorani A, Walsh SR, Cooper DG, Varty K. Entrapment syndromes. Eur J Vasc Endovasc Surg. 2009;37:213–20. 2. Özkan MB, Ceyhan Bilgici M, Hayalioglu E. Anterior and posterior nutcracker syndrome accompanying left circumaortic renal vein in an adolescent: case report. Arch Argent Pediatr. 2016;114:e114–6. 3. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Acad Emerg Med. 2009;151:264–9. 4. Muller Arteaga C, Martín Martín S, Cortiñas González JR, González Fajardo JA, Fernández del Busto E. Posterior nutcracker syndrome: retroaortic renal vein associated with arteriovenous ﬁstula and renal cancinoma. Report of a case and review of literature. Actas Urol Esp. 2009;33:101–4. 5. Sato Y, Yoshimura A, Sakai H, Yogi S, Kai Y, Ideura T. A case of posterior nutcracker syndrome occurring in pregnancy. Nihon Jinzo Gakkai Shi. 1997;39:790–3. 6. Pupca G, Miclăuş GD, Bucuraş V, Iacob N, Sas I, Matusz P, et al. Left crossed fused renal ectopia L-shaped kidney type, with double nutcracker syndrome (anterior and posterior). Rom J Morphol Embryol. 2014;55:1237–41. 7. Quinones Baldrich WJ. Posterior nutcracker syndrome in a child. J Vasc Surg. 2015;61:511. 8. Jang YB, Kang KP, Lee S, Kim W, Kwak HS, Park SK. Posterior nutcracker phenomenon. Nephrology, Dialysis, Transplantation. 2005;20:2573–4.

9. Deser SB, Onem K, Demirag MK, Buyukalpelli R. Surgical treatment of posterior nutcracker syndrome presented with hyperaldosteronism. Interact Cardiovasc Thorac Surg. 2016; 22:682–4. 10. Daily R, Matteo J, Loper T, Northup M. Nutcracker syndrome: symptoms of syncope and hypotension improved following endovascular stenting. Vascular. 2012;20:337–41. 11. Granata A, Clementi A, Floccari F, Di Lullo L, Basile A. An unusual case of posterior nutcracker syndrome. Clin Exp Nephrol. 2014;18:670–1. 12. Shin JI, Park JM, Lee JS, Kim MJ. Effect of renal Doppler ultrasound on the detection of nutcracker syndrome in children with hematuria. Eur J Pediatr. 2007;166:399–404. 13. He Y, Wu Z, Chen S, Tian L, Li D, Li M, et al. Nutcracker syndrome--how well do we know it? Urology. 2014;83:12–7. 14. Kurklinsky AK, Rooke TW. Nutcracker phenomenon and nutcracker syndrome. Mayo Clin Proc. 2010;85:552–9. 15. Kaan Gulleroglu BG, Esra Baskin. Nutcracker syndrome. World J Nephrol. 2014;3:277–81. 16. Rudloff U, Holmes RJ, Prem JT, Faust GR, Moldwin R, Siegel D. Mesoaortic compression of the left renal vein (nutcracker syndrome): case reports and review of the literature. Ann Vasc Surg. 2006;20:120–9. 17. Wang L, Yi L, Yang L, Liu Z, Rao J, Liu L, et al. Diagnosis and surgical treatment of nutcracker syndrome: a single-center experience. Urology. 2009;73:871–6. 18. Bhanji A, Malcolm P, Karim M. Nutcracker syndrome and radiographic evaluation of loin pain and hematuria. Am J Kidney Dis. 2010;55:1142–5. 19. Takebayashi S, Ueki T, Ikeda N, Fujikawa A. Diagnosis of the nutcracker syndrome with color Doppler sonography: correlation with ﬂow patterns on retrograde left renal venography. AJR Am J Roentgenol. 1999;172:39–43. 20. Shin JI, Lee JS. Nutcracker. The Lancet. 2005;365:2177–8. 21. Shin JI, Park JM, Lee SM, Shin YH, Kim JH, Lee JS, et al. Factors affecting spontaneous resolution of hematuria in childhood nutcracker syndrome. Pediatr Nephrol. 2005;20:609–13. 22. Rassi I, Khabbaz Z, Chelala D, Jebara VA. A new variant of the posterior nutcracker phenomenon. J Vasc Surg. 2010;51:1279. 23. Chen S, Zhang H, Shi H, Tian L, Jin W, Li M. Endovascular stenting for treatment of Nutcracker syndrome: report of 61 cases with long-term followup. J Urol. 2011;186:570–5 24. Jeanneret C, Beier K, von Weymarn A, Traber J. Pelvic congestion syndrome and left renal compression syndrome – clinical features and therapeutic approaches. Vasa. 2016;45: 275–82.

Submitted: 23.06.2017 Accepted after revision: 05.09.2017 There are no conﬂicts of interest existing. Published online: 22.11.2017

Correspondence address Jae Il Shin, M. D., Ph. D. Department of Pediatrics Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu C. P.O. Box 8044 Seoul 120–752 Republic of Korea shinji@yuhs.ac

Vasa (2018), 47 (1), 23–29

Original communication

Sensitivities of in vivo markers of arterial organ damage in patients with peripheral atherosclerosis Martina Frick1, Frederic Baumann1, Beate Sick2, Ian B. Wilkinson3, Beatrice Amann-Vesti1, and Marc Husmann1,4 1 2 3 4

Division of Angiology, University Hospital Zurich, Zurich, Switzerland Institute for Biostatistics, University Zurich, Zurich, Switzerland Clinical Pharmacology Unit, University of Cambridge, Cambridge, United Kingdom Centre for Vascular Diseases, Zurich-Stadelhofen, Zurich, Switzerland

Summary: Background: Biomarkers of vascular diseases such as ankle-brachial index (ABI), peripheral pulse pressure (pPP), central pulse pressure (cPP), and pulse wave velocity (PWV) allow assessment of arterial organ damage (AOD). However, the utility of markers other than ABI in patients with peripheral arterial disease (PAD), which are also associated with a signiﬁcant increase of cardiovascular events, remains unclear. Patients and methods: Asymptomatic (n = 21) and symptomatic patients (n = 46) with a positive sonography for PAD or history of lower limb revascularization were included. ABI, pPP, cPP, and PWV were assessed. PWV were performed using a brachial cuff-based method (aortic PWV (aPWV)) and oscillography (carotid-femoral pulse wave velocity (cfPWV)), respectively. The two methods for PWV were compared using Bland Altman analysis. Sensitivities of ABI, pPP, cPP, cfPWV, and aPWV for AOD were calculated. Results: Sixty-seven patients (35.8 % female, mean age 69, range 39–91 years) had a signiﬁcantly higher aPWV than cfPWV (median 10.5 m/s (IQR: 8.8–12.65 m/s) vs. median 9.0 m/s (IQR: 7.57–10.55 m/s), p = 0.0013). There was no correlation between cfPWV and age (r = 0.311, p = 0.116). Bland Altman analysis revealed a mean difference of -1.04 (-2SD; -6.38 to + 2SD; 4.31). The sensitivities for AOD were 68.7 % for ABI, 61.2 % for aPWV, 40.3 % for cfPWV, 31.3 % for peripheral PP, and 10.4 % for central aortic PP (p < 0.001). Conclusions: Brachial-derived aPWV differs from the gold standard assessment (cfPWV), which may be underestimated in PAD due to atherosclerotic obstructions along the aorto-iliac segment. The sensitivities of noninvasive in vivo markers of AOD vary widely and tend to underestimate the actual presence of AOD. Keywords: Pulse wave velocity, arterial organ damage, peripheral arterial disease, pulse pressure

Introduction Arterial stiffness is an important and independent risk factor for cardiovascular events (CV) [1–3]. The assessment of arterial stiffness has gained substantial importance mostly in primary but also secondary prevention as it may guide therapy and predict the outcome [4–6]. A current large meta-analysis has reported that carotid-femoral pulse wave velocity (cfPWV) predicts future cardiovascular risk and improves risk classification in addition to established risk factors in low and intermediated risk patients in a primary prevention setting [7]. Aortic stiffness can be assessed in a number of ways. Carotid-femoral pulse wave travelling time currently is regarded as the gold standard and has been related to increased cardiovascular risks. However, aortic pulse wave velocity (aPWV), derived from [8, 9] carotid-femoral pulse wave travelling time, has not been studied extensively. PWV can be assessed in a rouVasa (2018), 47 (1), 30–35 https://doi.org/10.1024/0301-1526/a000664

tine clinical setting using a number of commercially available devices, making it an attractive in vivo marker of vascular disease. In addition, assessment of arterial organ damage (AOD), for example through ABI and PWV, has been proposed in asymptomatic individuals by the latest guidelines of the European Societies of Hypertension and Cardiology (ESH/ESC) [9]. A large body of evidence indicates that AOD plays a crucial role in determining the CV risk of asymptomatic individuals [8–10]. Vascular in vivo markers such as ABI index (ABI < 0.9), peripheral/ central pulse pressure (pPP/cPP > 60 mmHg) and cfPWV (> 10m/s) are used to assess AOD according to guidelines [9, 10]. Atherosclerosis is irreversible. Early atherosclerosis is asymptomatic and associated with a markedly increased risk for coronary and cerebrovascular events [11]. Hence, peripheral arterial disease (PAD) is an overt AOD, which should be detectable by the assessment of the abovementioned markers of vascular disease. We hypoth© 2017 Hogrefe

M. Frick et al., Markers of arterial organ damage

esized that cfPWV may not be appropriate to detect AOD in PAD due to atherosclerotic obstruction along the aortoiliac segments. We therefore assessed PWV with two different commercially available devices and tested and compared sensitivities of PWV, cPP, pPP, and ABI to detect AOD in selected, well-defined patients with PAD.

Patients and methods The study was conducted at the University Hospital of Zurich, which serves as a tertiary referral centre. ABI, PP (peripheral and central), and PWV (aortic and carotid-femoral) were assessed in consecutive patients with PAD who were either referred for clinical evaluation or follow-up. Only patients with chronic and stable PAD were eligible for the study. Inclusion criteria were colour-coded duplex sonography with plaques > 15 mm or a history of lower limb revascularization, which defined presence of PAD. Exclusion criteria were critical limb ischaemia (Fontaine IV), cardiac arrhythmia, and chronic inflammatory vascular disorders. Patients continued to take their regular medications. The presence of coronary and cerebrovascular diseases was defined by clinical history of either events or interventions. The study was approved by the local ethics committee and was conducted according to clinical practice standards [12]. Measurements were part of the standard care, including pulse volume recordings for oscillometric assessment of PWV and brachial blood pressure assessment for brachial derived PWV. The following data were collected: anthropometric data (height, weight), comorbidities and medications, major vascular risk factors (arterial hypertension, diabetes mellitus, dyslipidaemia, and smoking), peripheral systolic and diastolic blood pressures, heart rate, central blood pressures, ABI, cfPWV, and aPWV.

Pulse wave velocity Pulse wave velocity was measured in all patients using a brachial cuff-based method (Mobil-O-Graph; I. E.M., Stolberg, Germany) and an oscillometric device (Vicorder; Skidmore Medical, Bristol, UK). Patients rested in a supine position for 10 Minutes in a quiet room. AOD was defined according to the ESH/ESC guidelines for the management of arterial hypertension as a PWV > 10 m/s [9]. All measurements were carried out in triplicate by the same vascular technicians and mean values of the triplicate measurements were calculated and used for analysis.

Mobil-O-Graph The ARCSolver method, on which the Mobil-O-Graph measurement is based, performs pulse wave analysis based on oscillometric blood pressure measurements with a common blood pressure cuff. The method was developed © 2017 Hogrefe

by the Austrian Institute of Technology in Vienna and uses the pulse waves assessed at the brachial artery level [13]. Simplification of the signal processing is performed using a three level algorithm. In a first step, the single brachial pressure waves are verified for their plausibility, using pulse wave analysis and impedance wave separation. Thereafter, an aortic pulse wave is generated by means of a generalized transfer function [13–18]. The required flow is approximated by a model-based approach using methods described by Wassertheurer and Parragh [13, 19]. This is an operator-independent method for 24-hour ambulatory peripheral and central blood pressure and aortic PWV monitoring, invasively validated by Hametner et al. [15].

Vicorder The Vicorder device allows measurement of carotid to femoral PWV. A collar is placed on the patient’s neck, equipped with a photoplethysmographic sensor, which is able to record carotid pressure waves. A second cuff is placed around the right upper thigh. The carotid and femoral waveforms are recorded simultaneously and estimate the transit time by means of the foot-to-foot method [16]. The foot point in the pressure wave was defined as the beginning of systole that was identified by an inbuilt algorithm that was centred on the peak of the second derivative of pressure [17, 18]. Path length was defined as the distance from the suprasternal notch to the top of the thigh cuff [17]. The cfPWV was calculated as path length divided by the transit time: cfPWV (m/s) = path length (m)/transit time (s).

Ankle-brachial index, peripheral and central pulse pressure Standard brachial systolic and diastolic blood pressures on both arms with traditional cuff manometer were measured in triplicate according to the Riva Rocci method. Systolic ankle blood pressures of the anterior and posterior tibial artery on both legs were obtained using a hand-held 6-MHz Doppler probe. For each leg, ABI was calculated as the ratio of the highest ankle systolic blood pressure divided by the highest brachial systolic blood pressure, the lower ABI was taken as the study reference [20]. The AOD was defined as an ABI of < 0.9 or > 1.3 (incompressible tibial and peroneal arteries due to mediacalcinosis) according to the ESH/ESC guidelines for the management of arterial hypertension [9]. Pulse pressure represents the blood pressure amplitude, i. e. the difference of systolic blood pressure and diastolic blood pressure. We applied the peripheral pulse pressure and the noninvasive measurements of the central pulse pressure derived from the Mobil-O-Graph [15, 21]. The blood pressure (peripheral and central) was carried out in triplicate and mean values of the triplicate measurements were calculated and used for analysis. The AOD was defined according to the ESH/ESC guidelines for the management of arterial hypertension as a peripheral or central PP > 60 mmHg [9, 15]. Vasa (2018), 47 (1), 30–35

Statistical analysis Descriptive statistics for continuous variables are given as median and interquartile range (IQR). For categorical variables, results are presented as number and percentages. Age, ABI, and pulse pressure were considered as independent variables and PWV as a dependent variable. Univariate linear regression by Spearman Rank correlation was used to determine the association between cfPWV and age and pulse pressure. The two methods for PWV were analysed by univariate correlation and by Bland-Altman plot. Values of two-sided tests with p < 0.05 were considered statistically significant. The McNemar’s test was applied to test for sensitivity [22]. Difference of sensitivity between in vivo markers of vascular organ damage (ABI, cfPWV, aPWV, pPP, cPP) was assessed by Cochran’s Q test [23]. All analyses were performed using StatView software (Abacus, Berkeley, CA, U. S.A.) and R: a language and environment for statistical computing (the R Foundation for Statistical Computing, Vienna, Austria).

M. Frick et al., Markers of arterial organ damage

of aPWV and cfPWV remained significant (p = 0.008). Cochran’s Q test confirms that there is strong evidence that the five diagnostic tests do not have the same sensitivity (p < 0.001) [23].

Discussion In this study we determined the sensitivities of five relevant arterial disease indices or in vivo markers of AOD that are all easily applied, noninvasive, and in part automated in their use. We found that currently used in vivo markers of AOD have a much lower sensitivity to detect vascular damage in patients with PAD than expected. This may result in insufficient detection or underdiagnosed vascular damage in PAD using each measurement modality. These in vivo markers have gained great attention as screening tools for AOD mostly in asymptomatic patients with cardiovascular risk factors in a primary care setting. All parameters are based on blood pressure relations (ABI, central and peripheral PP) or pulse wave characteristics (aortic

Results Table I. Characteristics of 67 patients with peripheral arterial disease.

Sixty-seven patients (24 women (35.8 %)) with PAD and a mean age of 69 years (range 39–91 years) were studied. The characteristics of the study population are summarized in Table I. The PWV from the Mobil-O-Graph (median 10.5 m/s; IQR 8.8–12.7 m/s) were significantly different (p = 0.0013) from the Vicorder (median 9 m/s; IQR 7.6– 10.6 m/s). Figure 1 shows the univariate correlation and the Bland-Altman plot for the two devices. The mean difference was -1.04 (-2SD, -6.38; + 2SD, 4.31). Correlation with age was found for aPWV (Mobil-O-graph) with r = 0.935 (p = < 0.0001) but not for the cfPWV (Vicorder) (r = 0.311 (p = 0.116)). Figure 2A/2B shows the correlation between PWV and peripheral pulse pressures. The correlation coefficients were r = 0.606 (p = < 0.0001) for pulse pressure and aPWV (by Mobil-O-Graph) and r = 0.248 (p = 0.442) for pulse pressure and cfPWV (by Vicorder). Twenty-one (31 %) of a total of 67 patients had a normal ABI ranging from 0.9 to 1.3 with a median of 0.98 (IQR 0.93–1). Forty-one (62 %) patients had an ABI lower than 0.9 (median 0.6 (IQR: 0.46–0.74), and five (7 %) patients had mediacalcinosis with a median ABI of 1.4 (IQR: 1.38– 1.4). Sensitivities for the presence of AOD in relation to each of the in vivo markers of arterial organ injury are shown in Figure 3. Sensitivities to detect AOD in PAD patients ranged from 10.4 % (central pulse pressure) to 68.7 % (ABI). The carotid-femoral PWV, the current gold standard, had a sensitivity of 40.3 % for AOD. The sensitivities for AOD between aPWV and cfPWV differed significantly (p = 0.043) with better sensitivity of aPWV for AOD. The difference in sensitivities between aPWV and ABI were not significant (p = 0.3173). After correction for multiple testing, the differences between the sensitivities Vasa (2018), 47 (1), 30–35

Age, (yrs) BMI, (kg/m2) Blood pressure (mmHg) * Systolic

69 (39–91) 27(17–44) 136 (125–153)

Diastolic

82 (75–89)

Peripheral pulse pressure

55 (44–65)

Central pulse pressure

53 ( 42–63)

Ankle brachial index *

0.79 (0.96–0.58)

Pulse wave velocity (m/s) * Mobil-O-Graph® Vicorder® Cardiovascular risk factor **

10.5 (8.8–12.7) 9 (7.6–10.6)

Diabetes mellitus

21 (31)

Dyslipidaemia

36 (53)

Hypertension

51 (76)

Ever smoking

51 (76)

Positive family history

18 (27)

Cardiovascular comorbidities**

Coronary artery disease

24 (36)

Cerebrovascular disease

13 (19)

M. Frick et al., Markers of arterial organ damage

Figure 1. A) Regression plot for aortic pulse wave velocity by Mobil-O-Graph® and carotid-femoral pulse wave velocity by Vicorder® in PAD (r = 0.339; p = 0.0058). B) Bland-Altman graph of pulse wave velocity (m/s) Mobil-O-Graph® (aortic) vs. Vicorder® (carotid-femoral).

Figure 2. Regression plots for pulse wave velocities and peripheral pulse pressures in patients with peripheral arterial disease by A) Mobil-OGraph® (r = 0.606; p = < 0.0001) and B) Vicorder® (r = 0.248; p = 0.442).

and carotid-femoral PWV). As expected, ABI revealed the highest sensitivity for AOD. Accordingly, the difference between upper to lower extremity blood pressure per se is the noninvasive diagnostic tool of choice for PAD. We also included PAD patients with an ABI within the normal range following lower limb angioplasty and found that ABI was not pathologic and hence not sensitive to AOD. Unexpectedly, cfPWV had a low sensitivity for AOD in PAD and even lower than aPWV. As a consequence, aPWV and cfPWV measurements did not correlate, revealing higher values for PWV derived from the brachial artery (aPWV). This might be explained by the fact that the brachial artery is mostly free of atherosclerotic plaque and thus pulse wave Vasa (2018), 47 (1), 30–35

analysis may be more accurate. Unexpectedly, cfPWV was not associated with age. This may be explained by the fact that atherosclerosis and obstructive lesions along the aortic and iliac arterial segments cause delay in systolic upstroke of the wave at the femoral level resulting in a false low cfPWV [24]. Therefore, cfPWV can only be reliably assessed if relevant atherosclerotic disease is absent between the carotid and femoral artery. Thus, a comprehensive vascular assessment including imaging prior to a simple cfPWV assessment, especially in elderly patients and those with cardiovascular risk factors, is necessary due to the high prevalence of PAD. Alternatively, measurements could be performed with the Mobil-O-Graph for the brachial measurement using the ARCSolver, a novel method to noninvasively estimate aortic PWV from a single brachial cuff waveform [13, 25, 26]. Hametner and Wassertheurer showed a significant linear correlation between the noninvasive assessment and the intraaortic pressure measurement [15]. This suggests that the combination provides an easily gained approximation for aortic PWV with promising results compared to other methods and that it might be of use in PAD [23]. Other studies, which investigated PWV in PAD using the SphygmoCor device, support our findings. Brand et al. investigated 136 patients with critical limb ischaemia and 194 controls. They demonstrated that PWV is markedly lower in patients with critical limb ischaemia (PWV = 5.72 m/s) when compared to healthy controls (PWV = 8.62m/s). Similarly, there was no correlation between PWV and age [24]. In contrast, Catalano et al. reported higher PWV assessed by SphygmoCor in PAD patients than in the control group (11 ± 3 m/s vs. 9.8 ± 1.8 m/s), which negatively correlated with ABI in the PAD group and had no correlation with age (r = 0.13, p = 0.06) [27]. Although these findings can be considered conflicting, they indicate that cfPWV should be assessed with caution in presence of PAD. Other parameters that are derived from blood pressure measurements are the central aortic and peripheral pressure amplitudes. Arterial stiffening resulting from aortic atherosclerosis or loss of Windkessel function increases systolic arterial blood pressure and decreases diastolic blood pressures, resulting in an increase in blood pressure amplitude, which is a recognized pressure pattern in PAD [28, 29]. Despite the fact that the pathophysiology of these changes is well understood and documented, the suggested cut-off at > 60 mmHg in amplitudes was not sufficient to identify AOD in the majority of our population, irrespectively of whether values were calculated as peripheral or central blood pressure amplitudes. In our population, the sensitivities of cPP or pPP higher than 60 mmHg were as low as 10 % and 30 %, respectively. The findings of the present study have a number of relevant implications for both clinical and scientific evaluation of in vivo arterial disease markers. First, the results show that a marker currently considered as gold standard (cfPWV) for disease detection has some drawbacks in the presence of atherosclerotic arterial diseases. Atherosclerotic vascular changes along the aortic and iliac arterial conduit Vasa (2018), 47 (1), 30–35

M. Frick et al., Markers of arterial organ damage

may result in false low velocities, suggesting less or even absence of AOD. Even ABI, the gold standard assessment for PAD, may be not sensitive for atherosclerotic damage in case of non-significant arterial stenosis. In this case, AOD can only be detected by noninvasive or invasive imaging, such as duplexsonography, intraarterial angiography or computed angiograms. In our patient selection, we diagnosed PAD prior to inclusion in the study. Second, our findings indicate that cut-off values presented in current guidelines for the management of arterial hypertension, that recommend assessment of cfPWV in hypertensive patients [9], can only be advocated after exclusion of PAD and suggest that single assessment such as cfPWV should not be performed in settings without proper medical knowledge or training. Third, devices for measurement of PWV differ in their sensitivity to detect AOD and some methods might have advantages over the current gold standard.

Limitations The sample size of our study was limited. More work is needed to evaluate the differences of cfPWV dependent on the stage and localization of the stenosis/obstruction.

Conclusions In conclusion, in vivo markers of AOD do not offer satisfying sensitivities in presence of peripheral arterial disease and even the current gold standard to assess PWV has to be used with caution, specifically in PAD patients. Given that advanced age is an independent determinant of generalized atherosclerosis, markers of AOD in elderly patients have to be evaluated in relation to potential presence of an asymptomatic peripheral arterial disease due to its high prevalence in the aged population.

Acknowledgments This study has been supported by the Swiss Heart Foundation.

References 1. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121(4):505–11. 2. Mitchell GF. Arterial Stiffness and Wave Reﬂection: Biomarkers of Cardiovascular Risk. Art Res. 2009;3(2):56–64. 3. Mitchell GF, Parise H, Benjamin EJ, Larson MG, Keyes MJ, Vita JA, et al. Changes in arterial stiffness and wave reﬂection with advancing age in healthy men and women: the Framingham Heart Study. Hypertension. 2004;43(6):1239–45. © 2017 Hogrefe

M. Frick et al., Markers of arterial organ damage

4. Deluca N, Mallion J, Orourke M, Obrien E, Rahn K, Trimarco B, et al. Regression of Left Ventricular Mass in Hypertensive Patients Treated With Perindopril/ Indapamide as a First-Line Combination. Am J Hypert. 2004;17(8):660–7. 5. Agabiti-Rosei E, Porteri E, Rizzoni D. Arterial stiffness, hypertension, and rational use of nebivolol. Vasc Health Risk Managem. 2009;5:353–60. 6. Ahimastos A, Dart A, Lawler A, Blombery P, Kingwell B. Reduced arterial stiffness may contribute to angiotensin- converting enzyme inhibitor induced improvements in walking time in peripheral arterial disease patients. J Hypertens. 2008;26(5): 1038–42. 7. Ben-Shlomo Y, Spears M, Boustred C, May M, Anderson SG, Benjamin EJ, et al. Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant metaanalysis of prospective observational data from 17,635 subjects. JACC. 2014;63(7):636–46. 8. Laurent S, Cockcroft J, Van Bortel L, Boutouyrie P, Giannattasio C, Hayoz D, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Europ Heart J. 2006;27(21):2588–605. 9. Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Europ Heart J. 2013;34(28):2159–219. 10. Benetos A, Safar M, Rudnichi A, Smulyan H, Richard JL, Ducimetiere P, et al. Pulse Pressure : A Predictor of Long-term Cardiovascular Mortality in a French Male Population. Hypertension. 1997;30(6):1410–5. 11. Mosimann K, Jacomella V, Thalhammer C, Meier TO, Kohler M, Amann-Vesti B, et al. Severity of peripheral arterial disease is associated with aortic pressure augmentation and subendocardial viability ratio. J Clin Hypertens. 2012;14(12):855–60. 12. International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human use. Guideline for Good Clinical Practice. J Postgrad Med.1996. 13. Wassertheurer S, Mayer C, Breitenecker F. Modeling arterial and left ventricular coupling for non-invasive measurements. Simul Model Pract Theory. 2008;16(8):988–97. 14. Hametner B, Weber T, Mayer C, Kropf J, Wassertheurer S. Effects of Different Blood Flow Models on the Determination of Arterial Characteristic Impedance. Math Comp Model Dyn. 2013;19(4):319–30. 15. Hametner B, Wassertheurer S, Kropf J, Mayer C, Eber B, Weber T. Oscillometric estimation of aortic pulse wave velocity: comparison with intra-aortic catheter measurements. Blood Press Monit. 2013;18(3):173–6. 16. Kazanavicius E, Gircys R, Vrubliauskas A. Mathematical methods for determining the foot point of the arterial pulse wave and evaluation of proposed methods. Inform Tech Control. 2005;34(1):29–36. 17. Hickson SS, Butlin M, Broad J, Avolio AP, Wilkinson IB, McEniery CM. Validity and repeatability of the Vicorder apparatus: a comparison with the SphygmoCor device. Hypertens Res. 2009;32(12):1079–85.

18. Muller J, Oberhoffer R, Barta C, Hulpke-Wette M, Hager A. Oscillometric carotid to femoral pulse wave velocity estimated with the Vicorder device. J Clin Hypertens. 2013;15(3):176–9. 19. Parragh S, Hametner B, Wassertheurer S. Influence of an Asymptotic Pressure Level on the Windkessel Models of the Arterial System. IFAC-PapersOnLine. 2015;48(1):17–22. 20. Grenon SM GJ, Hsiang Y. Ankle–brachial index for assessment of peripheral arterial disease. New Engl J Med. 2009;361(e40). 21. Luzardo L, Lujambio I, Sottolano M, da Rosa A, Thijs L, Noboa O, et al. 24-h ambulatory recording of aortic pulse wave velocity and central systolic augmentation: a feasibility study. Hypertens Res. 2012;35(10):980–7. 22. Kim S, Lee W. Does McNemar’s test compare the sensitivities and specificities of two diagnostic tests? Stat Meth Med Res. 2017;26(1):142–54. 23. Cochran WG. The Comparison of Percentages in Matched Samples. Oxford Journal Oxford University Press. 1950;Vol. 37, No. 3/4: 256–66. 24. Brand M, Woodiwiss AJ, Michel F, Booysen HL, Veller MG, Norton GR. A mismatch between aortic pulse pressure and pulse wave velocity predicts advanced peripheral arterial disease. Eur J Vasc Endovasc Surg 2013;46(3):338–46. 25. Wassertheurer S, Kropf J, Weber T, van der Giet M, Baulmann J, Ammer M, et al. A new oscillometric method for pulse wave analysis: comparison with a common tonometric method. J Hum Hypertens. 2010;24(8):498–504. 26. Fernández González R, Gómez Pajuelo C, Gabriel R, de La Figuera M, Moreno E, of The Verapamil-Frequency R. Effect of verapamil on home self-measurement of blood pressure and heart rate by hypertensive patients. Verapamil-Frequency Research Group. Blood Pres Monit. 2000;5(1):23–30. 27. Catalano M, Scandale G, Carzaniga G, Cinquini M, Minola M, Dimitrov G, et al. Increased aortic stiffness and related factors in patients with peripheral arterial disease. J Clin Hypertens. 2013;15(10):712–6. 28. Maksuti E, Westerhof N, Westerhof BE, Broome M, Stergiopulos N. Contribution of the Arterial System and the Heart to Blood Pressure during Normal Aging – A Simulation Study. PloS one. 2016;11(6):e0157493. 29. Lønnebakken M, Izzo R, Mancusi C, Losi M, Stabile E, Rozza F, et al. Aortic root dimension and arterial stiffness in arterial hypertension: the Campania Salute Network. J Hypertens (LWW Journals). 2016;34(6):1109–14. Submitted: 17.05.2017 Accepted after revision: 19.07.2017 There are no conflicts of interest existing. Published online: 22.09.2017 Correspondence address Martina Simone Frick University Hospital Basel Petersgraben 4 4031 Basel Switzerland martina.frick@gmx.ch

Vasa (2018), 47 (1), 30–35

Original communication

Gender differences in abdominal aortic aneurysms in Germany using health insurance claims data Konstanze Stoberocka, Henrik Christian Rießa, Eike Sebastian Debus, Thea Schwaneberg, Tilo Kölbel, and Christian-Alexander Behrendt Department of Vascular Medicine, University Heart Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany a These authors contributed equally to this work

Summary: Background: Endovascular aortic repair (EVAR) has emerged as standard of care for abdominal aortic aneurysm (AAA). Real-world evidence is limited to compare this technology to open repair (OAR). Major gaps exist related to short-term and long-term outcomes, particularly in respect of gender differences. Materials and methods: Health insurance claims data from Germany’s third largest insurance provider, DAK-Gesundheit, was used to investigate invasive in-hospital treatment of intact (iAAA) and ruptured AAA (rAAA). Patients operated between October 2008 and April 2015 were included in the study. Results: A total of 5,509 patients (4,966 iAAA and 543 rAAA) underwent EVAR or OAR with a median follow-up of 2.44 years. Baseline demographics, comorbidities, and clinical characteristics of DAK-G patients were assessed. In total, 84.6 % of the iAAA and 79.9 % of the rAAA were male. Concerning iAAA repair, the median age (74 vs. 73 years, p < .001) compared to men was higher in females, but their EVAR-rate (66.8 % vs. 71.1 %, p = .018) was lower. Besides higher age of female patients (80 vs. 75 years, p < .001), no further statistically significant differences were seen following rAAA repair. In-hospital mortality was slightly lower in males compared to females following iAAA (2.3 % vs. 3.1 %, p = .159) and rAAA (37.3 % vs. 43.1 %, p = .273) repair. Concerning iAAA repair, a higher rate of female patients was transferred to another hospital (3.7 % vs. 2.0 %, p = 0.008) or discharged to rehabilitation (6.0 % vs. 2.7 %, p < .001) compared to male patients. Conclusions: In this large German claims data cohort, women are generally older and more often transferred to another hospital or discharged to rehab following iAAA repair. Nonetheless, no significantly increased risk of in-hospital or late death appeared for women in multivariate analyses. Further studies are necessary to evaluate the impact of recent gender-specific treatment strategies on overall outcome under real-world settings. Keywords: Abdominal aortic aneurysm (AAA), endovascular aortic repair (EVAR), open aortic repair (OAR), administrative data, health insurance claims data, gender differences

Introduction Among the most common diseases of the aorta, aneurysms take the second place after atherosclerosis [1]. Numerous studies demonstrate significant gender differences in risk stratification and outcome following open surgical aortic repair (OAR) or endovascular aortic repair (EVAR) with respect to aortic diseases in general. The prevalence and incidence of abdominal aortic aneurysm (AAA) is two to six times higher in men than in women [2–5]. Higher risk of AAA rupture [6–10], higher perioperative and long-term mortality [11–17] as well as higher complication rates and longer hospitalization have been reported in women [18–21]. By contrast, other studies revealed no significant increase in mortality among women with AAA after EVAR [18, 19, 22] or OAR [6, 23]. The main reason for gender differences in outcome might be Vasa (2018), 47 (1), 36–42 https://doi.org/10.1024/0301-1526/a000665

a higher median age of women at diagnosis and therapy. However, genetic, hormonal, anatomical, and biological differences might also have an impact. Clinical guidelines [5] recommend a screening test with ultrasound for men at the age of 65 years, while only women with a positive family history are considered for screening [1, 24, 25]. In recently published data of 128,598 electively treated Medicare beneficiaries (OAR and EVAR), significant long-term differences in terms of reintervention and rupture have been elucidated, which was previously confirmed by large randomized controlled trials [26]. However, assessment of possible gender-specific differences in the Medicare cohort was not performed. This study aims to examine whether there are genderspecific differences in these AAA patients in regard of comorbidities, surgical treatment, mortality, and hospitalization, utilizing the DAK-G database of Germany’s third © 2017 Hogrefe

K. Stoberock et al., Gender differences in aneurysm repair

largest health insurance company. It further discusses possible reasons for these differences and touches on ways to optimize the treatment especially for female patients.

Materials and methods The health insurance claims data of Germany´s third largest insurance provider, DAK-Gesundheit (DAK-G), includes the outpatient and in-hospital medical care provided to approximately 6.5 million German citizens (8 %). In contrast to registry-based data from Germany, the DAK-G database is not restricted to vascular surgeons but includes all medical specialties treating the insured cohort for AAA (e. g. cardiac surgeons, cardiologists, angiologists, interventional radiologists, and general surgeons). The DAK-G cohort includes nationally generalizable data (40.4 % female and 29.1 % over 65 years old) and has been validated before [27]. For this study, the DAK-G database was used to determine in-hospital treatments for AAA using the International Classification of Diseases (ICD-10) coding I71.4 (iAAA) or I71.3 (rAAA) and Operations and Procedures Codes (OPS) coding for open (OAR; OPS code 5-384) or endovascular (EVAR; OPS code 5-38a) repair of infrarenal AAA. The cohort included procedures conducted between 21 October 2008 and 5 April 2015. The German OPS code is adapted to the International Classification of Procedures in Medicine (ICPM). For the identified cases that matched the basic search criteria, we collected data on demographics, procedures done while in-hospital (OPS codes), coded comorbidities (WHO ICD-10 codes at the time of discharge), and reason for discharge. For the long-term survival analyses, we censored patients whose insurance contract expired within the followup period. A similar percentage of censored cases was present in both groups. The dataset for this study was grouped into subgroups (male vs. female, intact vs. ruptured, open repair vs. endovascular repair) and baseline differences in demographics, comorbidities, and primary and secondary endpoints were assessed. The first submitted procedure was included as primary case. If two similar procedures were submitted on the same day, it was interpreted as a double coding error (n = 148). The coding of both EVAR and OAR within three days of surgery was interpreted as conversion. For a retrospective analysis of anonymized health insurance claims data, no local ethic committee approval was required and no patient informed consent was obtained for the study.

dence interval (CI) are presented for categorical variables. Tests of normality were conducted using Kolmogorov-Smirnov test. Student´s t-test was used for normally distributed data and Mann-Whitney U Test and KruskalWallis H test were used for non-normally distributed data. Rates and univariate differences were compared with Pearson´s chi-squared test and Fisher´s exact test. A multivariable Cox´s proportional hazard model was conducted to determine the effect of gender after adjusting for several covariates. A p-value of < .05 was considered statistically significant. Statistical analyses were performed with IBM SPSS Statistics software version 24.0 (IBM, Armonk, NY, U. S.).

Results A total of 5,509 patients underwent invasive treatment for abdominal aortic aneurysm during the study period. Of these patients, 4,966 were diagnosed with an iAAA and 543 patients with an rAAA. The median followup was 2.44 years (range 0 to 6.46) and loss of follow-up due to leaving the insurer (end of contract) was similar in male and female patients following both iAAA and rAAA repair. Baseline demographics, comorbidities, and clinical characteristics of male and female DAK-G patients are listed in Table I. Unadjusted in-hospital outcomes are listed in Table II. In total, 84.6 % (n = 4,202) of the intact and 79.9 % (n=434) of the ruptured AAA were male.

Intact AAA repair Although, median age (74 vs. 73 years, p < .001) and proportion of octogenarians (25.4 % vs. 19.6 %, p < .001) was higher in females, these patients showed a lower EVARrate (66.8 % vs. 71.1 %, p = .018) compared to male patients following intact AAA repair. Statistically significant differences were: a higher rate of delirium following intact AAA repair in male patients compared to female patients (2.2 % vs. 3.8 %, p = .033) and a higher rate of female patients transferred to another hospital (3.7 % vs. 2.0 %, p = 0.008) or discharged to rehabilitation (6.0 % vs. 2.7 %, p < .001) compared to male patients following intact AAA repair. A logistic regression was performed to ascertain the effect of several covariates on the likelihood that the patient deceased during the initial hospital stay. Regression coefficients and 95 % confidence intervals for iAAA can be found in Table III. Of the twelve predictor variables only five were statistically significant: age, EVAR, hypertension, COPD, and high grade renal insufficiency. Higher age, occurrence of COPD, and occurrence of high grade renal insufficiency were associated with higher odds to exhibit in-hospital death. EVAR and occurrence of hypertension was associated with lower odds of in-hospital death. Vasa (2018), 47 (1), 36–42

K. Stoberock et al., Gender differences in aneurysm repair

Table I. Baseline characteristics. Variable

Primary cases

iAAA n = 4,966

rAAA n = 543

Male n = 4,202 (84.6 %)

Female n = 764 (15.4 %)

p-value

Male n = 434 (79.9 %)

Female n = 109 (20.1 %)

p-value

71.1

66.8

.018

23.3

30.3

.137

73.0 (68–78)

74.0 (70–80)

< .001

75.0 (68–83)

80.0 (73–86)

< .001

Octogenarians

19.6

25.4

< .001

36.2

53.2

< .001

Hypertension

69.9

69.4

.764

53.5

48.6

.392

Coronary heart disease

36.6

21.9

< .001

25.1

22.9

.710

COPD

14.5

17.4

.028

10.1

15.6

.126

5.0

5.9

.328

6.0

8.3

.386

38.9

33.9

.010

20.5

12.8

.076

2.3

3.8

.023

6.0

6.4

.824

16.6

12.4

.004

14.3

18.3

.296

History of myocardial infarction

9.8

5.9

< .001

8.5

6.4

.560

History of stroke

1.8

1.0

.168

2.5

0.9

.475

EVAR-rate Patient age (years), median (IQR)

Atrial fibrillation or flutter Dyslipoproteinaemia Renal insufficiency (GFR < 30 ml/min) Diabetes type 2

iAAA: Intact abdominal aortic aneurysm; rAAA: ruptured abdominal aortic aneurysm; COPD: chronic obstructive pulmonary disease. GFR: Glomerular ﬁltration rate. IQR: Interquartile range. Values are reported in % unless otherwise indicated.

Table II. Unadjusted outcomes during the initial hospital stay. Variable

Primary cases

iAAA n = 4,966

rAAA n = 543

Male n = 4,202 (84.6 %)

Female n = 764 (15.4 %)

p-value

Male n = 434 (79.9 %)

Female n = 109 (20.1 %)

p-value

Acute bowel ischaemia

1.2

1.6

.370

13.1

6.4

.066

Delirium

3.8

2.2

.033

13.1

6.4

.066

Sepsis

1.5

0.9

.422

10.9

5.5

.226

Acute renal insufﬁciency

4.8

5.4

.466

34.6

28.4

.256

Acute respiratory insufﬁciency

6.2

6.7

.570

30.2

27.5

.640

Hypovolemic shock

1.8

1.0

33.2

31.2

.733

Cardiac arrest

1.1

0.9

.849

10.8

7.3

.374

Re-EVAR or Re-OAR

1.2

1.4

.600

0.9

1.8

.346

Mortality (in-hospital)

2.3

3.1

.159

37.3

43.1

.273

Transferred to another hospital

2.0

3.7

.008

10.1

7.3

.468

Discharged to rehab or nursery

2.7

6.0

< .001

8.3

13.8

.097

LOS, days, median (IQR)

10.0 (7–15)

11.0 (8–17)

< .001

13.0 (7–24)

13.0 (3–28)

.509

Postoperative LOS, days, median (IQR)

7.0 (5–11)

8.0 (6–12)

< .001

12.0 (6–24)

12.0 (2–25)

.558

LOS: Length of stay. EVAR: Endovascular aortic repair. OAR: Open aortic repair. IQR: Interquartile range. Values are reported in % unless otherwise indicated.

Vasa (2018), 47 (1), 36–42

K. Stoberock et al., Gender differences in aneurysm repair

Table III. Multiple regression. Odds ratio for in-hospital mortality following intact AAA repair (n = 4,966). Covariate

95 % CI

p-value

Age (increase by 1 year)

1.096

(1.067)–(1.126)

< .001

EVAR (versus OAR)

0.153

(0.102)–(0.229)

< .001

Hypertension

0.601

(0.409)–(0.883)

.009

COPD

1.649

(1.047)–(2.598)

.031

High grade renal insufﬁciency (GFR < 30 ml/min)

3.499

(1.765)–(6.935)

< .001

CI: Confidence interval; OR: odds ratio; COPD: chronic obstructive pulmonary disease; EVAR: endovascular aortic repair; OAR: open aortic repair; GFR: glomerular filtration rate; AAA: abdominal aortic aneurysm. Variables excluded from the final model: Male gender, coronary heart disease, atrial fibrillation, diabetes, dyslipoproteinaemia, history of myocardial infarction, and history of stroke.

Ruptured AAA repair Besides higher age of female patients (80 vs. 75 years, p < .001), no further statistically significant differences were observed following ruptured AAA repair. A logistic regression was performed to ascertain the effect of several covariates on the likelihood that the patient deceased during the initial hospital stay. Regression coefficients and 95 % confidence intervals for rAAA can be found in Table IV. Of the twelve predictor variables only four were statistically significant: age, EVAR, hypertension, and dyslipoproteinaemia. Higher age was associated with higher odds of in-hospital death. EVAR, hypertension, and dyslipoproteinaemia were associated with lower odds of in-hospital death.

Long-term survival following AAA repair In the adjusted analyses using Cox’s proportional hazard model, long-term survival was not different between male and female patients (HR for male gender 0.877, 95 % CI 0.753 to 1.021, p = .091) (Table V).

Discussion In this large German investigation using health insurance claims data, we found that female patients showed significantly higher age when treated for intact or ruptured AAA. While in-hospital mortality was comparable for both gender following iAAA (3.1 % vs. 2.3 %, p = .159) and rAAA (43.1 % vs. 37.3 %, p = .273) repair, a significantly higher proportion of female patients were transferred to another hospital (3.7 % vs. 2.0 %, p = .008) or discharged to rehabilitation (6.0 % vs. 2.7 %, p < .001) following iAAA repair compared to male patients. Both for in-hospital and long-term period, male gender had no statistically © 2017 Hogrefe

significant effect on the prediction of survival while patients age and EVAR were associated with higher and lower odds of death, respectively. These results are in accordance with current research. In a large prospective study by Brown et al., women were older than men when first diagnosed and treated for AAA [28]. In the current literature, controversy exists considering gender-specific mortality following iAAA and rAAA repair. There is evidence that women are subjected to higher overall rates of AAA rupture [6–10], higher rates of perioperative and long-term mortality, and complications following EVAR or OAR [11–21]. Others have found no increased risk for female gender [6, 18, 19, 22, 23]. Most recent prospectively collected data of the Vascular Quality Initiative (VQI) registry found female gender to be independently associated with short-term and long-

Table IV. Multiple regression. Odds ratio for in-hospital mortality following ruptured AAA repair (n = 543). Covariate

95 % CI

p-value

Age (increase by 1 year)

1.078

(1.054)–(1.103)

< .001

EVAR (versus OAR)

0.436

(0.272)–(0.699)

.001

Hypertension

0.515

(0.349)–(0.759)

.001

Dyslipoproteinaemia

0.342

(0.190)–(0.616)

< .001

CI: Confidence interval; OR: odds ratio; EVAR: endovascular aortic repair; OAR: open aortic repair; AAA: abdominal aortic aneurysm. Variables excluded from the final model: Male gender, coronary heart disease, chronic obstructive pulmonary disease, atrial fibrillation, high grade renal insufficiency, diabetes, history of myocardial infarction, and history of stroke.

Table V. Hazard ratio and proportional hazard model for AAA repair. AAA repair (n = 5,509, no conversions) Covariate

95 % CI

p-value

Ruptured AAA (vs. intact AAA)

3.572

3.088–4.131

< .001

Age (increase by 1 year)

1.060

1.052–1.068

< .001

EVAR (vs. OAR)

0.864

0.763–0.979

.021

Hypertension

0.718

0.640–0.807

< .001

Coronary heart disease

1.161

1.029–1.310

.016

COPD

1.535

1.332–1.769

< .001

Atrial ﬁbrillation or ﬂutter

1.692

1.308–2.190

< .001

Dyslipoproteinaemia

0.738

0.646–0.842

< .001

High grade renal insufﬁciency

1.852

1.446–2.374

< .001

History of stroke

1.781

1.288–2.461

< .001

CI: Conﬁdence interval; HR: hazard ratio; COPD: chronic obstructive pulmonary disease; EVAR: endovascular aortic repair; AAA: abdominal aortic aneurysm. Male gender, diabetes, and history of myocardial infarction have been excluded from the model after three steps (backward).

Vasa (2018), 47 (1), 36–42

term mortality following thoracic endovascular aortic repair (TEVAR) [29]. The short-term benefits of EVAR, as compared to OAR, with respect to mortality and morbidity have been well demonstrated in large randomized controlled trials [30]. In a large propensity score matched analysis of Medicare beneficiaries, the initial advantage of survival for patients treated with EVAR compared to OAR was evident up to three years after surgery [31]. Beyond that point, higher rates for aneurysm-related complications, including rupture, have been reported following EVAR [31]. In the present study, women were more often discharged to a rehabilitation facility following iAAA (p < .001) and rAAA (p = .097) repair. These results are confirmed by findings of Egorova et al. using the Medicare beneficiary database which revealed that women are significantly more often depending on postoperative rehabilitation following EVAR or OAR for either iAAA or rAAA [14]. Others have revealed similar results [15]. A higher dependency of postoperative care found in women is most likely attributable to a higher age when scheduled for surgery and a consecutive higher probability for a sicker or deceased spouse incapable of providing care. This may also explain the longer duration of hospital stay of women, despite higher rates of comorbidities found in men. Unfortunately, we cannot verify these hypothesis by data of the present study. However, recent population based data from the Federal Statistical Bureau from 2015 revealed that women are subjected to overall higher rates of longterm care compared to men [32]. In a randomly selected sample of people over 65 years, 43.9 % of women (22.3 % of men) were found to be subjected to some sort of dependency assed by the “Activities of Daily Living, ADL” and “Instrumental Activities of Daily Living, IADL”. Furthermore, an increase in age was found to be associated with an increased risk of frailty and subsequent dependency for women and men. However, in a multivariate analysis this risk was found to be twice as high for female gender (OR 2.48 vs. 1.10) [33]. Recently, Arya et al. were able to show an independent significant association of frailty and a higher in-hospital mortality as well as risk for perioperative complications when undergoing elective EVAR or OAR [34]. Unfortunately, data of the present study is lacking information on the functional status of the patients included in this study. Although subjected to a higher age when undergoing operation (EVAR or OAR), female gender was not found to be associated with a higher in-hospital and long-term mortality. In the present study, women were less likely to undergo EVAR for iAAA. Possible reasons for the higher rate of OAR and accordingly longer hospital stays of women might be a smaller vessel diameter, a more severe atherosclerosis of the iliac arteries, or the more complex anatomy of females. Several studies showed that women less frequently meet the anatomic criteria for EVAR [18, 35]. The diameter of the aorta in women is usually smaller than in men [37], which may lead to increased complication rates and earlier rupture risks. Sweet et al. showed Vasa (2018), 47 (1), 36–42

K. Stoberock et al., Gender differences in aneurysm repair

that after adjustment for age and aneurysm size, women have decreased neck length, increased neck angulation, and smaller iliac access. Women undergoing EVAR in the Vascular Study Group of New England (VSGNE) had significantly smaller graft limb diameters. Sweet et al. also found that these features resulted in a lower likelihood of women meeting device instructions for use (IFU) criteria. It is reported that lower-profile endografts, such as the Excluder, Cordis, and Zenith low profile, were more frequently used in women [35, 36]. Another postulated fact is that EVAR devices are primarily developed for males and not for females. In the present study, men more often suffered a postoperative delirium when undergoing elective repair for iAAA compared to women (p =. 033). Dasgupta et al. conducted a large systematic review about this complication following non-cardiac surgery [38]. Considering the assessed studies some reported an association of sex and postoperative delirium; however, the overall evidence was found to be rather insufficient (p < .06). In cardiac surgery, however, the risk for postoperative delirium was directly linked to the overall degree of atherosclerosis (coronary vessels, ascending aorta, carotid arteries), an observation supporting results of the present study noting that more men suffered a coronary heart disease (p < .001) and have a history of myocardial infarction (p < .001) prior to elective AAA repair [39]. Gender as a risk factor for delirium following AAA repair has not been extensively studied so far. In order to close this gap, further studies should be conducted to confirm our findings and help identifying individuals exposed to a higher risk of suffering this unfavourable complication after EVAR or OAR.

Limitations Due to the fact that health insurance claims data are not collected for scientific evaluation but rather for reimbursement purposes, meticulous validation is necessary before and during usage for research and quality improvement efforts [40]. While coding errors are possible, we believe that these errors would affect both groups and approaches equally, as data collection occurs independently from scientific enquiries such as our investigation. There is no selfselection of cases by researchers. Furthermore, there is a significant risk selection for the compared groups. This study aims to investigate real-world data that cannot replace randomized trials. However, it can examine if results of randomized controlled trials (RCTs) are similar to realworld experiences. This study is limited to patients with rAAA that reach the hospital, while prehospitally deceased patients are not covered at all. However, registry-based studies and RCT are facing this limited external validity as well. More importantly, WHO-ICD-coding does not allow to distinguish between symptomatic and asymptomatic iAAA. Moreover, no further anatomic specifications or data on pharmacotherapy are available for this study. © 2017 Hogrefe

K. Stoberock et al., Gender differences in aneurysm repair

Conclusions In this large German claims data cohort, women are generally at higher age and more often transferred to another hospital or discharged to rehab following intact AAA repair. Nonetheless, no significantly increased risk of in-hospital or late death appeared for women in multivariate analyses. Further studies are necessary to evaluate the impact of recent gender-specific treatment strategies on overall outcome under real-world settings.

References 1. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014; 35(41): 2873–926. 2. Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg. 2002; 89(3): 283–5. 3. Starr JE, Halpern V. Abdominal aortic aneurysms in women. J Vasc Surg. 2013; 57(4 Suppl): 3S–10S. 4. Bloomer LD, Bown MJ, Tomaszewski M. Sexual dimorphism of abdominal aortic aneurysms: a striking example of “male disadvantage” in cardiovascular disease. Atherosclerosis. 2012; 225(1): 22–8. 5. Moll FL, Powell JT, Fraedrich G, Verzini F, Haulon S, Waltham M, et al. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg. 2011; 41 Suppl 1: S1–S58. 6. Skibba AA, Evans JR, Hopkins SP, Yoon HR, Katras T, Kalbﬂeisch JH, et al. Reconsidering gender relative to risk of rupture in the contemporary management of abdominal aortic aneurysms. J Vasc Surg. 2015; 62(6): 1429–36. 7. Brown LC, Powell JT. Risk factors for aneurysm rupture in patients kept under ultrasound surveillance. UK Small Aneurysm Trial Participants. Ann Surg. 1999; 230(3):289–96; Discussion 296–7. 8. Collaborators R, Bown MJ, Sweeting MJ, Brown LC, Powell JT, Thompson SG. Surveillance intervals for small abdominal aortic aneurysms: a meta-analysis. JAMA. 2013; 309(8): 806–13. 9. Lo RC, Lu B, Fokkema MT, Conrad M, Patel VI, Fillinger M, et al. Relative importance of aneurysm diameter and body size for predicting abdominal aortic aneurysm rupture in men and women. J Vasc Surg. 2014; 59(5): 1209–16. 10. Brown PM, Zelt DT, Sobolev B. The risk of rupture in untreated aneurysms: the impact of size, gender, and expansion rate. J Vasc Surg. 2003; 37(2): 280–4. 11. Grootenboer N, van Sambeek MR, Arends LR, Hendriks JM, Hunink MG, Bosch JL. Systematic review and meta-analysis of sex differences in outcome after intervention for abdominal aortic aneurysm. Br J Surg. 2010; 97(8): 1169–79. 12. McPhee JT, Hill JS, Eslami MH. The impact of gender on presentation, therapy, and mortality of abdominal aortic aneurysm in the United States, 2001–2004. J Vasc Surg. 2007; 45(5): 891–9. 13. Mureebe L, Egorova N, McKinsey JF, Kent KC. Gender trends in the repair of ruptured abdominal aortic aneurysms and outcomes. J Vasc Surg. 2010; 51(4 Suppl): 9S–13S. 14. Egorova NN, Vouyouka AG, McKinsey JF, Faries PL, Kent KC, Moskowitz AJ, et al. Effect of gender on long-term survival after abdominal aortic aneurysm repair based on results from the Medicare national database. J Vasc Surg. 2011; 54(1): 1–12 e6; discussion 1–2. © 2017 Hogrefe

15. Dillavou ED, Muluk SC, Makaroun MS. A decade of change in abdominal aortic aneurysm repair in the United States: Have we improved outcomes equally between men and women? J Vasc Surg. 2006; 43(2): 230–8; discussion 8. 16. Hultgren R, Granath F, Swedenborg J. Different disease proﬁles for women and men with abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2007; 33(5): 556–60. 17. Ulug P, Sweeting MJ, von Allmen RS, Thompson SG, Powell JT, SWAN collaborators. Morphological suitability for endovascular repair, non-intervention rates, and operative mortality in women and men assessed for intact abdominal aortic aneurysm repair: systematic reviews with meta-analysis. Lancet. 2017; 389(10088):2482–91. 18. Abedi NN, Davenport DL, Xenos E, Sorial E, Minion DJ, Endean ED. Gender and 30-day outcome in patients undergoing endovascular aneurysm repair (EVAR): an analysis using the ACS NSQIP dataset. J Vasc Surg. 2009; 50(3): 486–91, e1–4. 19. Chung C, Tadros R, Torres M, Malik R, Ellozy S, Faries P, et al. Evolution of gender-related differences in outcomes from two decades of endovascular aneurysm repair. J Vasc Surg. 2015; 61(4): 843–52. 20. Flink BJ, Long CA, Duwayri Y, Brewster LP, Veeraswamy R, Gallagher K, et al. Women undergoing aortic surgery are at higher risk for unplanned readmissions compared with men especially when discharged home. J Vasc Surg. 2016; 63(6): 1496–504 e1. 21. Kauvar DS, Martin ED, Givens MD. Thirty-Day Outcomes after Elective Percutaneous or Open Endovascular Repair of Abdominal Aortic Aneurysms. Annals of vascular surgery. 2016; 31: 46–51. 22. De Rango P, Lenti M, Cieri E, Simonte G, Cao P, Richards T, et al. Association between sex and perioperative mortality following endovascular repair for ruptured abdominal aortic aneurysms. J Vasc Surg. 2013; 57(6): 1684–92. 23. Larsson E, Granath F, Swedenborg J, Hultgren R. More patients are treated for nonruptured abdominal aortic aneurysms, but the proportion of women remains unchanged. J Vasc Surg. 2008; 48(4): 802–7. 24. Eckstein HH, Böckler D, Flessenkämper I, Schmitz-Rixen T, Debus S, Lang W. Ultrasonographic screening for the detection of abdominal aortic aneurysms. Dtsch Arztebl Int. 2009; 106(41): 657–63. 25. Ferket BS, Grootenboer N, Colkesen EB, Visser JJ, van Sambeek MR, Spronk S, et al. Systematic review of guidelines on abdominal aortic aneurysm screening. J Vasc Surg. 2012; 55(5): 1296–304. 26. Schermerhorn ML, Buck DB, O’Malley AJ, Curran T, McCallum JC, Darling J, et al. Long-Term Outcomes of Abdominal Aortic Aneurysm in the Medicare Population. N Engl J Med. 2015; 373(4): 328–38. 27. Debus ES, Torsello G, Behrendt CA, Petersen J, Grundmann RT. [Perioperative mortality following repair for abdominal aortic aneurysm in Germany : Comparison of administrative data of the DAK health insurance and clinical registry data of the German Vascular Society]. Chirurg. 2015. 28. Brown PM, Sobolev B, Zelt DT. Selective management of abdominal aortic aneurysms smaller than 5.0 cm in a prospective sizing program with gender-speciﬁc analysis. J Vasc Surg. 2003; 38(4): 762–5. 29. Deery SE, Shean KE, Wang GJ, Black JH 3rd, Upchurch GR Jr., Giles KA, et al. Female sex independently predicts mortality after thoracic endovascular aortic repair for intact descending thoracic aortic aneurysms. J Vasc Surg. 2017; 66(1): 2–8. 30. Blankensteijn JD, de Jong SE, Prinssen M, van der Ham AC, Buth J, van Sterkenburg SM, et al. Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med. 2005; 352(23): 2398–405. 31. Schermerhorn ML, Buck DB, O’Malley AJ, Curran T, McCallum JC, Darling J, et al. Long-Term Outcomes of Abdominal Aortic Aneurysm in the Medicare Population. New England Journal of Medicine. 2015; 373(4): 328–38. 32. Krankenhausdiagnosestatistik [Internet]. Statistisches Bundesamt DeStatis. 2014. Vasa (2018), 47 (1), 36–42

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33. Millan-Calenti JC, Tubio J, Pita-Fernandez S, GonzalezAbraldes I, Lorenzo T, Fernandez-Arruty T, et al. Prevalence of functional disability in activities of daily living (ADL), instrumental activities of daily living (IADL) and associated factors, as predictors of morbidity and mortality. Arch Gerontol Geriatr. 2010; 50(3): 306–10. 34. Arya S, Kim SI, Duwayri Y, Brewster LP, Veeraswamy R, Salam A, et al. Frailty increases the risk of 30-day mortality, morbidity, and failure to rescue after elective abdominal aortic aneurysm repair independent of age and comorbidities. J Vasc Surg. 2015; 61(2): 324–31. 35. Lo RC, Bensley RP, Hamdan AD, Wyers M, Adams JE, Schermerhorn ML, et al. Gender differences in abdominal aortic aneurysm presentation, repair, and mortality in the Vascular Study Group of New England. J Vasc Surg. 2013; 57(5): 1261–8, e1–5. 36. Sweet MP, Fillinger MF, Morrison TM, Abel D. The inﬂuence of gender and aortic aneurysm size on eligibility for endovascular abdominal aortic aneurysm repair. J Vasc Surg. 2011; 54(4): 931–7. 37. Writing C, Riambau V, Bockler D, Brunkwall J, Cao P, Chiesa R, et al. Editor’s Choice – Management of Descending Thoracic Aorta Diseases: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 2017; 53(1): 4–52. 38. Dasgupta M, Dumbrell AC. Preoperative risk assessment for delirium after noncardiac surgery: a systematic review. Journal of the American Geriatrics Society. 2006; 54(10): 1578–89.

39. Rudolph JL, Babikian VL, Birjiniuk V, Crittenden MD, Treanor PR, Pochay VE, et al. Atherosclerosis is associated with delirium after coronary artery bypass graft surgery. Journal of the American Geriatrics Society. 2005; 53(3): 462–6. 40. Behrendt CA, Heidemann F, Riess HC, Stoberock K, Debus E. Registry and health insurance claims data in vascular research and quality improvement. VASA. 2017; 46(1):11–5.

Submitted: 31.05.2017 Accepted after revision: 19.07.2017 There are no conﬂicts of interest existing. Published online: 24.10.2017

Correspondence address Dr. Christian-Alexander Behrendt Department of Vascular Medicine University Heart Center Hamburg University Medical Center Hamburg-Eppendorf Martinistrasse 52 20246 Hamburg Germany ch.behrendt@uke.de

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Vasa (2018), 47 (1), 36–42

Original communication

Mortality in endovascular and open abdominal aneurysm repair – trends in Germany Olga von Beckerath1, Sebastian Schrader1, Marcus Katoh2, Bernd Luther1, Frans Santosa3, and Knut Kröger1 1 2 3

Department of Vascular Medicine, HELIOS Klinikum Krefeld, Krefeld, Germany Department of Radiology, HELIOS Klinikum Krefeld, Krefeld, Germany Medical Faculty Universitas Pembangunan Nasional Veteran Jakarta, Jakarta, Indonesia

Summary: Background: We analysed trends in mortality of endovascular (EVAR) and open aortic repair (OAR) in patients hospitalized for abdominal aortic aneurysms (AAA) in Germany from 2005 to 2015. Patients and methods: We used national statistics published by the Federal Statistical Ofﬁce in Germany to calculate mortality rate of patients hospitalized with ruptured (rAAA, n = 2,448 in 2005, n = 2,180 in 2015) and non-ruptured (iAAA, n = 11,626 in 2005, n = 14,205 in 2015) AAA. Results: Considering only those who were treated with EVAR or OAR, treatment rates of iAAA with EVAR increased to 78.2 % in males and 72.6 % in females in 2015 and treatment rates of rAAA to 36.9 % and 40.7 %, respectively. In cases with iAAA, death rates associated with EVAR decreased in males from 2.1 to 1.1 % (p = 0.0005) in the period from 2005 to 2015 but not in females (1.8 % in 2005 and 2.3 % in 2015, p = 0.8511). Similar trends are seen in cases with rAAA (males 30.1 % and 24 %, p = 0.1034, females 36.4 to 37.3 %, p = 0.8511). Death rates associated with OAR increased in males from 4.7 % in 2005 to 5.7 % in 2015 (p = 0.0103) and tended to increase in females from 6.8 to 8.2 % (p = 0.1476). In cases of rAAA, there were no changes. EVAR treatment rates increased in cases with iAAA in both genders with age, as well as in males with rAAA, but not in females. OAR associated death rates increased with age in rAAA (from around 30 % in the sixth/seventh decade of life to almost 80 % in cases with patients over the age of 90) and in iAAA (from 1.1 to 20 %). Conclusions: The general increase in EVAR procedures in males and females hospitalized for rAAA and iAAA went along with a decrease in in-hospital mortality in males treated with EVAR for iAAA only and an increasing mortality in males treated with OAR for iAAA. Keywords: Abdominal aortic aneurysm, endovascular aortic repair, open aortic repair, mortality, incidence

Introduction Most aortic aneurysms occur in the infrarenal part of the abdominal aorta (AAA). Ruptured abdominal aortic aneurysm (rAAA) is associated with a high mortality rate [1–3]. AAAs can be treated with open aortic repair (OAR) or endovascular repair (EVAR) to prevent rupture. As OAR carries a substantial risk of mortality and morbidity, in recent years, a trend towards endovascular aneurysm repair (EVAR) could be noted. As a minimally invasive technique, EVAR reduces the risk of mortality [4–8]. Potential advantages of EVAR over OAR include reduced time under general anaesthesia, elimination of the pain and trauma associated with major abdominal surgery, reduced length of stay in the hospital and intensive care unit, and reduced blood loss [9–12]. However, it must be emphasized that EVAR is not suitable for all morphologies [13]. © 2017 Hogrefe

Recently, an analysis of the prospective quality assurance registry of the German Vascular Society from 1999 to 2010 showed significantly improved post-procedural inhospital outcomes and decreased use of resources for intact AAA (iAAA) repair [14]. The use of EVAR increased from 16.7 % in 1999 to 62.7 % in 2010 (p < 0.001) and the overall in-hospital mortality decreased from 3.1 % in 1999 to 2.3 % in 2010 (p < 0.001). It has to be mentioned that only a very limited proportion of actually conducted procedures by vascular surgeons is submitted to this prospective quality assurance registry and that not all special disciplines are participating. Without validation, the value of this data source remains questionable. A second analysis based on hospital discharge data from 2005 to 2014 reported an additional increase in EVAR procedures to 75 % and an EVAR-related mortality of 1.7 % as well as an OAR related mortality of 5.3 % [15]. Studies from other countries confirmed this trend [16–18]. Vasa (2018), 47 (1), 43–48 https://doi.org/10.1024/0301-1526/a000667

Unfortunately all these reports failed to present continuous data regarding trends of mortality rates distinguishing between OAR and EVAR in patients with rAAA and iAAA. Thus, we analysed hospital discharge data from the last decade for all patients hospitalized with the principal diagnosis AAA.

Patients and methods Nationwide hospitalization data Hospitals in Germany annually transfer their individual hospitalization data, including one primary diagnosis, up to 89 secondary diagnoses coded by ICD-10 (International Classification of Diseases, 10th edition), and up to 100 medical procedures according to a national classification of operations and procedures to the Institute for the Hospital Renumeration System (InEK). After a plausibility control, the InEK forwards anonymized data to the Federal Bureau of Statistics. Principles of the analysis of this hospitalization file have been published several times in the past [19, 20]. In brief, we requested the Federal Bureau of Statistics to identify all hospitalizations in the years 2005 through 2015 that had a principal diagnosis for AAA (ICD-10: I713 ruptured, I714 non-ruptured), arranged by calendar year, sex, and five-year age group. In addition, for all these cases with these principal diagnoses, all cases with the OPS code covering an EVAR or OAR procedure were identified. The OPS codes 5-38a.1* cover all aorto-iliacal endoprotheses, including fenestration and branches. For OAR, all cases with AAA and the OPS codes 5-384.5*, 5-384.6*, and 5-384.7*, which include resection or replacement of the aorta with tube or bifurcation prosthesis, were identified. As all OPS subcodes for EVAR and OAR procedures were included, we did not check for changes in coding practice over the years. Mortality defined as in-hospital mortality was analysed for all cases with the principal diagnoses rAAA and iAAA treated with EVAR or OAR. According to the occupational regulations for the North Rhine-Westphalian physicians, retrospective epidemiological research and projects are specifically excluded from the necessity of an ethics vote. Specific linking of cases and procedures is possible but not allowed for legal reasons. Finally, we received a defined data set from the Federal Bureau of Statistics, including information exclusively from fully-reimbursed inpatient cases with the principal diagnosis of AAA, including the performed procedures and the documented in-hospital mortality, separated by year, age, and gender of the cases. As we did not analyse the impact of other covariables on mortality, only linear regression analysis was used for statistical evaluation of the trends over the 10-year study period. The analysis is solely descriptive. Calculations were done using Microsoft® Access 2003. Vasa (2018), 47 (1), 43–48

O. von Beckerath et al., Abdominal aneurysm repair in Germany

Results From 2005 to 2015 the total number of patients admitted with the principal diagnosis iAAA increased from 10,116 men and 1,510 women in 2005 to 12,141 (20.0 % increase) men and 2,064 (36.7 % increase) women in 2015 (ESM 1). The numbers of those treated with EVAR or OAR are lower but the rates increased over time; from 6,749 men (66.7 % of all admitted cases with the principal diagnosis) in 2005 to 8,842 (72.8 %) in 2015. For women, the corresponding data were 855 (56.6 %) to 1,330 (64.4 %), respectively. The total number of patients admitted with the principal diagnosis rAAA decreased from 1,942 men in 2005 to 1,723 (10.8 %) in 2015 and from 506 women in 2005 to 457 (9.7 %) in 2015. The numbers of those treated with EVAR or OAR remained unchanged in males (1,096 (56.4 %) in 2005 and 1,060 (61.5 %) in 2015) and in females (217 (42.9 %) in 2005 and 204 (44.6 %) in 2015). In general, treatment strategy steadily shifted from OAR to EVAR. Considering only those patients treated with EVAR or OAR, treatment rates with EVAR increased to 78.2 % for males and 72.6 % for females in 2015 in cases with iAAA and to 36.9 % for males and 40.7 % for females with rAAA (ESM 2) In cases with iAAA, death rates associated with EVAR decreased from 2.1 to 1.1 % from 2005 to 2015 for males. For females, an increase from 1.8 % in 2005 to 2.3 % in 2015 can be noted, however, this increase remains statistically insignificant (ESM 3). Although death rates are much higher, a similar trend emerges for cases with rAAA in males, even if it did not reach statistical significance. Death rates associated with OAR are on a higher level compared to death rates associated with EVAR and did not decrease over time. In contrast, they increased significantly in males. In 2015, 5.7 % of all male cases and 8.2 % of all female cases treated with OAR for iAAA died in the hospital. For rAAA, the figures were 40.4 % and 48.8 %, respectively. Figure 1 shows age-related procedure rates in 2015 for those 50-years and older. In iAAA, the rate of EVAR treatment increased in both genders from approximately 60 % in the age group 50–55-years to more than 80 % in the age group 85–90 years. Also, in males with rAAA, the rates increased from 23 to 58 %, whereas no age-dependent effect in females was evident. Figure 2 shows age-related death rates in 2015 for female and male cases 50-years and older. Death rates associated with OAR increased with age in rAAA (from approximately 30 % in sexagenarians and septuagenarians to almost 80 % in patients 90-years and older) and iAAA (from 1.1 to 20 %). Death rates associated with EVAR were age-related as well but with a much lower increase.

O. von Beckerath et al., Abdominal aneurysm repair in Germany

Figure 1. Rate of ruptured and non-ruptured AAA treated with EVAR in the year 2015. Data are separated for gender and age.

Figure 2. Rate of in-hospital mortality in ruptured and non-ruptured AAA treated with EVAR or OAR in the year 2015, separated for age. Included are p-values of linear regression analysis.

Discussion The general increase in EVAR procedures went along with a decreasing in-hospital mortality in males treated with EVAR for iAAA only. In females with iAAA and in males and females with rAAA, no reduction of mortality could be demonstrated. In contrast, the decreasing number of OAR for iAAA is associated with an increasing mortality in males. There is a general increase in the use of EVAR procedures in Germany and similar reports worldwide with large regional variations [14, 21, 22]. A retrospective analysis of the cross-sectional National Inpatient Sample of the US, including 101,978 patients treated from 2000 to 2010 showed that the overall use of EVAR has risen significantly in the past 10 years (5.2 to 74 % of the total number of AAA repairs), even though the total number of AAAs remains stable at 45,000 cases per year [23]. In the nationwide Swedish Vascular Registry (Swedvasc), the utilization of EVAR increased to 58 % © 2017 Hogrefe

of all iAAA and to 30 % of all rAAA repairs in the period from 2010 to 2014 [24]. The overall incidence of cases with iAAA slightly increased, while it decreased for rAAA in the last decade. A small increase in iAAA cases is reported in some countries [11, 16, 17], but not in all [18]. Changes might be caused by the ageing population but may also be the effect of a more consequent treatment strategy [25]. In Sweden, a decreasing incidence of ruptured AAA was already observed before the start of screening [26]. Thus, either a general increasing awareness was present before screening or a general improved control of cardiovascular risk factors and, in particular, decreasing smoking rates might have had some impact on the number of rAAA. The International Consortium of Vascular Registries, a collaboration of 11 vascular surgical quality registries, reported that during 2010 and 2013 among 51,153 patients, 86 % were treated for iAAA and 14 % for rAAA. In countries with a fee-for-service reimbursement system (Australia, Germany, Switzerland, and the United Vasa (2018), 47 (1), 43–48

States), the rate of small AAA (33 %) and octogenarians undergoing iAAA repair (25 %) were higher compared to countries with a population-based reimbursement model [1]. Not every case hospitalized with the principal diagnosis AAA is treated with EVAR or OAR during the in-hospital stay. In 2013, in France, 16.9 % of all cases hospitalized with iAAA and 33.7 % of rAAA did not receive such a procedure [18]. In our database, the portion of those finally not treated with EVAR or OAR is higher compared to France. Thus, we focused on those cases with a definitive treatment only and present two striking results: first, the decreasing mortality in those treated with EVAR for non-ruptured AAAs is limited to males. Second, there is a significant increase in mortality in males treated with OAR for non-ruptured AAA. The VASCUNET report published in 2011, based on 2005 to 2009 data, concluded that the overall perioperative mortality after iAAA repair was 2.8 % (2.6–3.0) and was stable over time [14]. The perioperative mortality rate varied from 1.6 % (1.3–1.8) in Italy to 4.1 % (2.4–7.0) in Finland. More recent data from France covering the period from 2002 and 2013 reported a decreasing standardized mortality rate for iAAA of 50.3 % in men and 32.3 % in women, and a decreased rate for rAAA of 45.8 % and 39.0 %, respectively [18]. A general decrease in mortality in men and women treated for iAAA and rAAA is reported in Germany as well [14, 15]. Such a decrease of standardized mortality rates per 100,000 inhabitants does not reflect procedure associated mortality, as they are influenced by the increasing number of older people in a population. A close look at the procedures shows that the general trend in reduction of mortality in Germany is driven by a small decrease of EVAR-associated mortality in males treated for iAAA only (from 2.1 % in 2005 to 1.1 % in 2015). Although this decrease by 1 % is rather small, it is the largest patient group, representing 89.2 % of all males treated for AAA or 77.3 % of female and male cases. It needs to be pointed out that there is no decrease in mortality associated with EVAR procedures in females presenting with iAAA, neither is it in males and females presenting with rAAA. Numbers of EVAR procedures for iAAA in females are much lower than in males. It is well known that mortality for females undergoing EVAR for iAAA is significantly higher than in males. A group from Albany Medical College reported a mortality rate in females of 3.2 % and in males of 0.96 % (p < 0.005) for all EVAR procedures performed between 2002 and 2009 [27]. Mortality in females undergoing elective EVAR is significantly higher than in males and also more hazardous. Colon ischaemia, native arterial rupture, and type 1 endoleaks are more frequent. The lack of a decreasing mortality rate with rAAA is in line with a recent Cochrane review including four randomised controlled trials with a total of 868 participants who receive either EVAR or OAR. The authors stated that there is no difference in the 30-day mortality between EVAR and OAR [28]. Thus, a change from OAR to EVAR does not necessarily decrease mortality. A retrospective, single-centre population-based study by Stavanger University Hospital between 2000 and 2012 reported a stable incidence and mortality rate during this decade [29]. Vasa (2018), 47 (1), 43–48

O. von Beckerath et al., Abdominal aneurysm repair in Germany

Similar to our result, mortality rates for OAR of iAAA in the National Inpatient Sample of the US, including 101,978 patients treated from 2000 to 2010, increased from 3.8 to 4.8 %; p > 0.05) [23]. One explanation might by a decreasing experience and lack of training in OAR by the vascular surgeons. An Australian study stated that reduced exposure to OAR by younger trainees did not significantly affect surgical outcome when compared with those surgeons trained in an earlier period [30]. However, it is not just the training but the whole logistic that improves treatment. Today in Germany, most patients with AAA are not treated in specialized vascular centres but in smaller hospitals that perform less than eight OARs a year. Another explanation might be the fact that cases with a more complex anatomy, not suitable for EVAR, are treated with OAR. Elderly patients have a significant but still acceptable perioperative mortality and morbidity after rAAA repair. The use of endovascular repair in the elderly population has increased and is associated with better perioperative survival and 30-day outcomes compared with traditional open repair in this study [31, 32]. The American College of Surgeons National Surgical Quality Improvement Program reported that among 1,048 elderly patients who underwent rAAA repair, 43 and 57 % were treated with EVAR and OAR between 2005 and 2015, respectively. The use of EVAR to treat rAAA has increased significantly in this population of patients (0 % in 2005 vs. 56 % in 2014; p < .001). The overall 30-day mortality rate among octogenarians was significantly higher among those treated with OAR compared to EVAR (47 % vs. 33 %; p < .001) [31]. In Swedvasc, the utilization of EVAR increased to 80 % of all octogenarians for iAAA repairs in the period from 2010 to 2014 and the 30-day mortality decreased from 9 % in the period from 1994 to 1999 to 2 % in the period from 2010 to 2014 (p < .001). For octogenarians, the overall 30-day mortality after rAAA repair was 28 % after EVAR vs. 42 % after open repair in the period from 2010 to 2014 [24]. Similar to these studies, the rate of EVAR procedures increased with age in Germany as well. In cases with iAAA in the ages of 80-years and above, more than 80 % received EVAR. In cases with rAAA, the rate of EVAR procedures increased in males only but not in females. Mortality associated with OAR is age-dependent and can reach over 60 % in rAAA cases and 10 % in iAAA cases with 90-year-olds, which is much higher than in the Swedvasc register. Moreover, mortality associated with EVAR is age-dependent, statistically the increase is much lower.

Strengths and limitations A major strength of this study is the large data set, which includes virtually all German hospitals, and the observation period of 10 years. This allows for a unique view at the current clinical practice. There are factors that limit our results. First, our ecologic study design did not allow to control confounding indications for treatment and quality of treatment. Second, the consequence of this approach is © 2017 Hogrefe

O. von Beckerath et al., Abdominal aneurysm repair in Germany

that we do not have information about the indications for treatment, quality of treatment or any outcomes. Moreover, our data do not allow for cross-linking of diagnosis and procedures. Third, it has to be pointed out that the analysis is based on cases and not on individual patients. As a consequence, a patient could be included several times in the statistics, if they were hospitalized for iAAA and rAAA at two separate times within one year. Fourth, although hospitalization rates are frequently used for secondary purposes, there is no systematic analysis of coding quality in Germany and the agreement of coding and “reality” has yet to be investigated in controlled trials. Therefore, we cannot assess if and how coding errors may have impacted our analysis. But a matching study between health insurance claims data of the third-largest German health insurance provider, DAK-Gesundheit, and a prospective primary registry of the German Society for Vascular Surgery demonstrated a good level of validity regarding the mortality of EVAR and OAR of AAA in German hospitals [33]. Fifth, it is possible that changes in coding of the EVAR and OAR procedures could have influenced our results; however, as we included all OPS sub-codes for EVAR and OAR procedures, this possibility was minimized. Sixth, study duration covers more than one generation of stent grafts and several training effects, but we cannot specifically address effects of different generations of stent grafts.

Conclusions There is a relevant increase in EVAR procedures to treat AAA in Germany in the recent decade which results in small decrease in EVAR-related mortality in males presenting with iAAA only. Future analyses have to focus on the question why women in general and cases with rAAA do not benefit from this development. They have to address the following questions: do women need specific devices? Does mortality depend much more on individual hospital logistic than on the kind of treatment? Does concentrating AAA treatment to a few specialized centres result in the reduction of mortality rates?

Acknowledgement We thank Referat VIII A 1 from the Federal Statistical Office for extracting and providing the data from the DRG-Statistik.

ESM 1. Table. Total number of cases admitted to hospital with the principal diagnosis ruptured and non-ruptured AAA. ESM 2. Table. Rate of cases treated with EVAR or OAR from those admitted to hospital with the principal diagnosis ruptured and non-ruptured AAA. ESM 3. Table. Rate of in-hospital deaths of cases admitted to hospital with the principal diagnosis ruptured and elective AAA treated with EVAR or OAR distinguishing between males and females.

References 1. Beck AW, Sedrakyan A, Mao J, et al. Variations in Abdominal Aortic Aneurysm Care: A Report From the International Consortium of Vascular Registries. Circulation. 2016;134: 1948–58. 2. Karthikesalingam A, Holt PJ, Vidal-Diez A, et al. Mortality from ruptured abdominal aortic aneurysms: clinical lessons from a comparison of outcomes in England and the USA. Lancet. 2014;383(9921):963–9. 3. Budtz-Lilly J, Venermo M, Debus S, et al. Assessment of International Outcomes of Intact Abdominal Aortic Aneurysm Repair over 9 Years. Eur J Vasc Endovasc Surg. 2017;54:13–20. 4. National Institute for Health and Clinical Excellence. Stentgraft placement in abdominal aorticaneurysm. Interventional Procedure Guidance 163. London: NICE; 2006. 5. Nordon IM, Hinchliffe RJ, Holt PJ, et al. Should the role of EVAR be re-evaluated in light of the 10 year results of EVAR-1? J Cardiovasc Surg (Torino). 2011;52:179–87. 6. Filipovic M, Goldacre MJ, Roberts SE, et al. Trends in mortality and hospital admission rates for abdominal aortic aneurysm in England and Wales, 1979–1999. Br J Surg. 2005;92:968–75. 7. McPhee J, Eslami MH, Arous J, et al. Endovascular treatment of ruptured abdominal aortic aneurysms in the United States (2001–2006): a signiﬁcant survival beneﬁt over open repair is independently associated with increased institutional volume. J Vasc Surg. 2009;49:817–26. 8. Lesperance K, Andersen C, Singh N, et al. Expanding use of emergency endovascular repair for ruptured abdominal aortic aneurysms: disparities in outcomes from a nationwide perspective. J Vasc Surg. 2008;47:1165–70. 9. Berardi G, Ferrero E, Fadde M, et al. Combined spinal and epidural anesthesia for open abdominal aortic aneurysm surgery in vigil patients with severe chronic obstructive pulmonary disease ineligible for endovascular aneurysm repair. Analysis of results and description of the technique. Int Angiol. 2010;29: 278–83. 10. Edwards MS, Andrews JS, Edwards AF, et al. Results of endovascular aortic aneurysm repair with general, regional, and local/monitored anesthesia care in the American College of Surgeons National Surgical Quality Improvement Program database. J Vasc Surg. 2011; 29:1097–104. 11. Chambers D, Epstein D, Walker S, et al. Endovascular stents for abdominal aortic aneurysms: a systematic review and economic model. Health Technol Assess. 2009;13:1–215. 12. Medicare Services Advisory Committee. Endoluminal grafting for abdominal aortic aneurysm. Canberra: Medicare Services Advisory Committee; 1999. 13. Woodburn KR, Chant H, Davies JN, et al. Suitability for endovascular aneurysm repair in an unselected population. Br J Surg 2001;88:77–81. Vasa (2018), 47 (1), 43–48

O. von Beckerath et al., Abdominal aneurysm repair in Germany

14. Trenner M, Haller B, Storck M, et al. Trends in Patient Safety of Intact Abdominal Aortic Aneurysm Repair: German Registry Data on 36,594 Procedures. Eur J Vasc Endovasc Surg 2017;53, 641–7. 15. Kühnl A, Erk A, Trenner M, et al. Incidence, treatment and mortality in patients with abdominal aortic aneurysms— an analysis of hospital discharge data from 2005–2014. Dtsch Arztebl Int 2017; 114: 391–8. 16. Schermerhorn ML, Bensley RP, Giles KA, et al. Changes in abdominal aortic aneurysm rupture and short-term mortality, 1995–2008: a retrospective observational study. Ann Surg. 2012;256:651–8. 17. Mani K, Lees T, Beiles B, et al. Treatment of Abdominal Aortic Aneurysm in Nine Countries 2005–2009: A Vascunet Report. Eur J Vasc Endovasc Surg. 2011;42:598–607. 18. Robert M, Juillière Y, Gabet A, et al. Time trends in hospital admissions and mortality due to abdominal aortic aneurysms in France, 2002–2013. Int J Cardiol. 2017;234:28–32. 19. Stang A, Merrill RM, Kuß O. Nationwide rates of conversion from laparoscopic or vaginal hysterectomy to open abdominal hysterectomy in Germany. Eur J Epidemiol. 2011;26:125–33. 20. Stang A, Kääb-Sanyal V, Hense HW, et al. Effect of mammography screening on surgical treatment for breast cancer: a nationwide analysis of hospitalization rates in Germany 2005– 2009. Eur J Epidemiol. 2013;28:689–96. 21. Joh JH, Park YY, Cho SS, et al. National trends for open and endovascular repair of aneurysms in Korea: 2004–2013. Exp Ther Med. 2016;12:3333–8. 22. Wendt K, Kristiansen R, Krohg-Sørensen K, et al. Trends in Abdominal Aortic and Iliac Aneurysm Repairs in Norway from 2001 to 2013. Eur J Vasc Endovasc Surg. 2016;51:194–201. 23. Dua A, Kuy S, Lee CJ, et al. Epidemiology of aortic aneurysm repair in the United States from 2000 to 2010. J Vasc Surg. 2014 ;59:1512–7. 24. Lilja F, Mani K, Wanhainen A. Trend-break in Abdominal Aortic Aneurysm Repair with Decreasing Surgical Workload. Eur J Vasc Endovasc Surg. 2017;53:811–9. 25. Overbey DM, Glebova NO, Chapman BC, et al. Morbidity of endovascular abdominal aortic aneurysm repair is directly related to diameter. J Vasc Surg. 2017; 17:30369–5. 26. Otterhag SN, Gottsäter A, Lindblad B, et al. Decreasing incidence of ruptured abdominal aortic aneurysm already before start of screening. BMC Cardiovasc Disord. 2016;16:44.

27. Mehta M, Byrne WJ, Robinson H, et al. Women derive less beneﬁt from elective endovascular aneurysm repair than men. J Vasc Surg. 2012;55:906–13. 28. Badger S, Forster R, Blair PH, et al. Endovascular treatment for ruptured abdominal aortic aneurysm. Cochrane Database Syst Rev. 2017;5:CD005261. 29. Reite A, Søreide K, Ellingsen CL, et al. Epidemiology of ruptured abdominal aortic aneurysms in a well-deﬁned Norwegian population with trends in incidence, intervention rate, and mortality. J Vasc Surg. 2015;61:1168–74. 30. Beiles CB, Walker S. Mortality after open aortic aneurysm surgery by Australasian surgeons trained in the endovascular era. ANZ J Surg. 2016;86:544–8. 31. Park BD, Azefor NM, Huang CC, et al. Elective endovascular aneurysm repair in the elderly: trends and outcomes from the Nationwide Inpatient Sample. Ann Vasc Surg. 2014;28:798–807. 32. Tan TW, Eslami M, Rybin D, et al. Outcomes of endovascular and open surgical repair of ruptured abdominal aortic aneurysms in elderly patients. J Vasc Surg. 2017;16:31780–3. 33. Behrendt CA, Heidemann F, Rieß HC, et al. Registry and health insurance claims data in vascular research and quality improvement. Vasa. 2017;46:11–5.

Submitted: 08.07.2017 Accepted after revision: 13.08.2017 There are no conﬂicts of interest existing. Published online: 16.10.2017

Correspondence address Knut Kröger, MD Klinik für Gefäßmedizin Helios Klinikum Krefeld Lutherplatz 40 47805 Krefeld Germany knut.kroeger@helios-kliniken.de

Mit dem Unbewussten das Rauchen vergessen Maja Storch

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Vasa (2018), 47 (1), 43–48

Original communication

Treatment of femoropopliteal lesions with the AngioSculpt scoring balloon – results from the Heidelberg PANTHER registry Ira Lugenbiel1, Michaela Grebner2, Qianxing Zhou3, Anna Strothmeyer4, Britta Vogel2, Rita Cebola2, Oliver Müller2, Bernadett Brado5, Marc Mittnacht6, Benedikt Kohler7, Hugo Katus2, and Erwin Blessing8 1 2 3 4 5 6 7 8

Augenklinik, Universitätsklinikum Heidelberg, Heidelberg, Germany Medizinische Klinik III, Universitätsklinikum Heidelberg, Heidelberg, Germany Department of Cardiology, Zhongda Hospital, Medical School of Southeast University, Guangdong, China Evangelisches Krankenhaus, Düsseldorf, Germany Praxis für Angiologie und Hämatologie, Heidelberg, Germany Gefäßpraxis Dr. Mittnacht, Heidelberg, Germany Praxis Dr. Kohler, Mannheim, Germany SRH Klinikum Karlsbad-Langensteinbach, Germany

Summary: Background: Treatment of calcified femoropopliteal lesions remains challenging, even in the era of drug-eluting balloon angioplasty. Lesion recoil and dissections after standard balloon angioplasty in calcific lesions often require subsequent stent implantation. Additionally, poor patency rates in calcified lesions despite the use of drug-eluting balloons may be due to the limited penetration depth of the antiproliferative drug in the presence of vascular calcium deposits. Therefore, preparation of calcified lesions with the AngioSculpt™ scoring balloon might be a valuable option either as a stand-alone treatment, followed by drug-eluting balloon angioplasty or prior to subsequent stent deployment. Patients and methods: In this retrospective, single centre registry, 124 calcified femoropopliteal lesions were treated in 101 subsequent patients. All patients were treated with scoring balloon angioplasty, either alone, in combination with drug-eluting balloons, or prior to stent deployment. The primary outcome was safety and technical success during the index procedure as well as patency at six and 12 months, as evaluated by duplex sonography. Results: Successful scoring was safely performed in all 124 lesions with the AngioSculpt™ balloon. Overall primary patency after 12 months was 81.2 %. Patency rates did not differ significantly between the three treatment strategies. Degree of calcification did not predict patency. Improved clinical outcomes (Rutherford-Becker class and ankle-brachial index) were also observed in the study cohort. Conclusions: Preparation with the AngioSculpt™ scoring balloon offers a safe and valuable treatment option for calcified femoropopliteal lesions. Keywords: Scoring balloon, calcification, lesion, AngioSculpt, stent, drug-eluting balloon

Introduction Established predictors of restenosis following endovascular treatment of femoropopliteal lesions include presence of diabetes [1, 2], impaired renal function [2], lesion length [3, 4], chronic total occlusions [2], and degree of calcification [5]. Heavily calcified lesions remain challenging for a variety of reasons. First, intraluminal recanalization of calcified occlusions can be difficult or sometimes even impossible. Attempting to pass the occlusion via the subintimal © 2017 Hogrefe

space is a reasonable option; however, this often requires advanced techniques, such as additional retrograde access or the use of dedicated re-entry devices, adding complexity and costs to the endovascular procedure. Second, after successful passage with a wire, elastic recoil or flow-limiting dissections after primary balloon dilatations often require a bail-out stent placement. Although stent fractures are observed less frequently with new generation nitinol stents, recent data indicate that post-procedure stent areas may be a predictor of restenosis [6], and thus, lesion prepVasa (2018), 47 (1), 49–55 https://doi.org/10.1024/0301-1526/a000671

aration prior to implantation may be important to ensure adequate stent expansion. Finally, the well-documented benefits of drug-eluting balloon (DEB) angioplasty [7–9] seem to be limited in heavily calcified lesions [5], potentially due to the reduced penetration depth of the antiproliferative agent. The latter could have potentially been overcome by advanced debulking techniques, such as directional atherectomy. However, this would add significant cost and complexity to the procedure. Lesion preparation with scoring balloons might offer a valuable treatment approach for heavily calcified lesions due to controlled dilatation leading to less balloon slippage, fewer dissections, and reduced need for bail-out stenting [10]. Additionally, lesion scoring might lead to less elastic recoil, reducing the need for stents to maintain luminal gain [10]. Initial experience with the AngioSculpt™ scoring balloon were encouraging, proving safety and efficacy of the device in a rather small patient cohort with infrapopliteal lesions [10]. In the PANTHER registry (Evaluation of treatment of femoroPopliteal lesions with ANgioSculpT scoring balloon – HeidElberg Registry), we evaluated safety, technical success, and clinical outcomes in mild to severe calcified femoropopliteal lesions.

Patients and methods Study population This is a retrospective, single centre, non-randomized registry of patients with arterial occlusive disease that underwent peripheral intervention using a scoring balloon. Between January 2011 and December 2011, a total number of 124 calcified de novo and restenotic lesions were treated in 101 subsequent patients at our institution with the AngioSculpt™ scoring balloon (Figure 1), (Spectranetics, USA).

Study procedure The criteria for interventional therapy were a reduced ankle-brachial index (ABI) at rest as well as clinical symptoms of claudication and/or insufficient wound healing. The use

E. Blessing et al., AngioSculpt in femoropopliteal lesions

of the scoring balloon was prompted by the appearance of a calcified lesion on the angiogram. Degree of calcification was defined as follows: mild calcification – calcium deposits unilateral and < 3 cm longitudinal extension; moderate calcification – calcium deposits unilateral and > 3 cm longitudinal extension; severe calcification – dense bilateral calcium deposits independent of length. The scoring balloon used for therapy was the AngioSculpt™ balloon, which consists of a nitinol-coated scoring element mounted on a semi-compliant balloon with a low profile. The use of DEBs or stent implantation after scoring balloon angioplasty was performed at the discretion of the interventionist. Technical success was verified with angiographic imaging and was defined as absence of balloon rupture and ≤ 30 % residual stenosis after the final dilatation. A total of 5000 IU heparin was administered after insertion of either a crossover or an antegrade introducer sheath according to our standard protocol. In the majority of cases, wire passage was achieved within the lumen. No predilatations were performed prior to use of the scoring balloon. The stenosis was dilated by manometrically controlled inflation of the scoring balloon with a contrast agent and saline mixture for 30 to 60 seconds. In cases with heavily calcified lesions with dense circumferential deposits of calcium, scoring balloons were specifically used to prepare the lesion for subsequent implantation of a Supera™ stent (Abbott), a stent with a unique interwoven design, characteristic for a fourfold increased radial strength as compared to standard nitinol stents. The AngioSculpt™ balloon, with its potential to reduce recoil in fibrotic or calcified lesions, might be of value in those challenging situations since adequate lesion preparation prior to stent deployment is crucial for appropriate expansion of the Supera™ stent. Provisional stenting was performed in cases where flow-limiting dissections persisted despite prolonged dilatations. The scoring balloon was also used to prepare the lesion for DEB use in calcified lesions. DEBs (In.PACT Admiral™, Medtronic, USA) were inflated for at least 60 seconds. In cases where the entire lesion could not be covered with one DEB, an overlap of at least 1 cm was provided with an additional DEB. After the sheath was withdrawn, a closure system (Starclose™, Abbott) was used, or, in rare cases, manual compression was performed and a pressure bandage was applied for four to six hours. Dual antiplatelet therapy with aspirin (100 mg/day) and clopidogrel (75 mg/day) was recommended for a minimum of four weeks following the procedure and aspirin (100 mg/day) alone thereafter.

Study endpoints

Figure 1. AngioSculpt™ scoring balloon 5 x 40 mm pre inflation (A), inflated to 8 bar (B), and after deflation (C). Vasa (2018), 47 (1), 49–55

Patient follow-up was scheduled six and 12 months after the index procedure. As part of our clinical routine, patients were asked to report their symptom-free walking distance, presence of rest pain or appearance or changes of wounds in the index limb, if applicable. Rutherford-Becker Classification (RBC) was obtained and compared with the © 2017 Hogrefe

E. Blessing et al., AngioSculpt in femoropopliteal lesions

pre-procedural score. Finally, ABI and pulse wave velocity were obtained by duplex ultrasound. A peak systolic velocity ratio of ≥ 2.4 was defined as a significant stenosis and considered a loss of patency. In cases in which a clinicallydriven angiography was performed, the index lesion was imaged and a binary stenosis of ≥ 50 % was defined as loss of patency. Secondary patency was defined as absence of significant stenosis after target lesion or target vessel revascularization at each defined time point. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee as well as with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Table I. Patient and baseline lesion characteristics. Relevant parameters at baseline of 101 patients (124 lesions). Patient characteristics Age (years) Gender (M/F)

71.9 ± 9.3 76/25

Arterial hypertension, n (%)

94 (93.1)

Diabetes, n (%)

45 (44.6)

Active smoking, n (%)

25 (24.7)

Hyperlipidemia, n (%)

74 (93.1)

BMI (kg/m ) Ankle brachial index

26.9 ± 4.5 0.63 ± 0.22

Claudicants, n (%)

66 (65.3)

Critical limb ischaemia, n (%)

35 (34.7)

Baseline lesion characteristics

Statistical analysis Continuous patient data are provided as mean ± standard deviation (SD) and categorical variables are given in frequency and percentage. Statistical differences of continuous variables were determined using paired and unpaired Student’s t-tests (two-sided tests), where appropriate. The change of Rutherford classification from baseline to sixmonth and 12-month follow-up was calculated for each patient individually using non-parametric Wilcoxon signed-rank test. P < 0.05 was considered statistically significant. Kaplan-Meier analyses were performed to estimate patency and target lesion revascularization. Statistical analyses were performed with GraphPad Prism 6.0 software (GraphPad Software, La Jolla, CA, USA).

Occlusions, n (%)

20 (16.1)

Lesion length (cm)

7.4 ± 5.9

Lesion length (cm)***

7.4 ± 59

Lesion length < 5 cm

3.1 ± 0.7

Lesion length 5–10 cm

6.8 ± 1.5

Lesion length > 10 cm

17.8 ± 5.5

Degree of stenosis (%)

85.5

Degree of calciﬁcation n (%) 1 (mild)

27 (21.8)

2 (moderate)

43 (34.7)

3 (severe)

54 (43.5)

Lesion localization – iliac (%)

Results Baseline characteristics of patients and lesions are listed in Tables I and II. Successful scoring (defined as crossing of the lesion and inflation to at least nominal pressure without balloon rupture) was performed in all 124 lesions with the AngioSculpt™ balloon; lesions were treated with either scoring balloon angioplasty alone (37.1 %; n = 46), scoring balloon followed by DEB inflation (32.3 %; n = 40) or scoring balloon followed by stent deployment (30.6 %; n = 38). Twenty occlusions (16.1 %) and 104 stenoses (83.9 %) were treated. The average degree of stenosis was 85 %. Lesions in a vessel with a vascular distance of more than 3 cm were counted as two separate lesions. According to the Trans-Atlantic Inter-Society Consensus (TASC) classifications, short stenoses and occlusions that are less than 5 cm long are currently seen as an indication for percutaneous transluminal angioplasty (PTA) of the thigh arteries. In our study, the average length of treated lesions was 7.4 cm (1.5–30 cm). Out of a total of 124 lesions, 52 short lesions (41.9 %) under 5 cm length and 48 lesions (38.7 %) with a length of five to 10 cm were treated. © 2017 Hogrefe

2.5

– femoral (%)

78.6

– popliteal (%)

18.9

Lower leg vascular outﬂow n (%) 3-vessel outﬂow (3)

28 (22.6 %)

2-vessel outﬂow (2)

49 (39.5 %)

1-vessel outﬂow (1)

40 (32.3 %)

no vascular outﬂow (0)

7 (5.6 %)

Intervention combinations AngioSculpt™

46 (37.1 %)

AngioSculpt™ + DEB

40 (32.3 %)

AngioSculpt™ + Stent

38 (30.6 %)

Utilized AngioSculpt™ sizes n (%) AngioSculpt™ 3.0

1 (0.8 %)

AngioSculpt™ 4.0

14 (11.3 %)

AngioSculpt™ 5.0

72 (58.1 %)

AngioSculpt™ 6.0

37 (29.8 %)

Vasa (2018), 47 (1), 49–55

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Table II. Baseline lesion characteristics* by Intervention. Baseline characteristics of lesions of the three treatment strategies AngioSculpt™ only, AngioSculpt™ followed by drug eluting balloon, and AngioSculpt™ followed by stent implantation. AngioSculpt™ 46/124 (37.1 %)

AngioSculpt™ + DEB 40/124 (32.3 %)

AngioSculpt™ + Stent 38/124 (30.6 %)

Calciﬁcation – minor (1)

10/46 (21.7 %)

11/40 (27.5 %)

6/38 (15.8 %)

– moderate (2)

17/46 (37.0 %)

11/40 (27.5 %)

15/38 (39.5 %)

– severe (3)

19/46 (41.3 %)

18/40 (45.0 %)

17/38 (44.7 %)

1/46 (2.2 %)

7/40 (17.5 %)

12/38 (31.6 %)

45/46 (97.8 %)

33/40 (82.5 %)

26/38 (68.4 %)

6.1 ± 4.6 (2.0–25.0 %)

5.9 ± 5.2 (1.5–30.0 %)

10.1 ± 7.1 (2.0–30.0 %)

A. femoralis superﬁcialis

32/46 (69.6 %)

32/40 (80.0 %)

26/38 (68.4 %)

A. poplitea artery

12/46 (26.1 %)

6/40 (15.0 %)

11/38 (28.9 %)

2/46 (4.3 %)

2/40 (5.0 %)

1/38 (2.6 %)

Occlusions Stenoses Lesion length (cm)

Other *displayed average ± SD or n/N (%).

Twenty-four lesions (19.4 %) measured over 10 cm. Compared to the scoring balloon only treatment, lesions treated with the combination of scoring balloon and stent were longer (average length: 10.1 cm vs. 6.1 cm) and were more often occluded (31.6 % vs. 2.2 %). Various diameters of the AngioSculpt™ balloons were used in the treated patient collective. Seventy-two lesions (58.1 %) were treated with a balloon diameter of 5.0 mm, and 37 lesions (29.8 %) with a balloon diameter of 6.0 mm. The degree of calcification was determined by the examiner before the intervention. Out of 124 lesions, 54 lesions (43.5 %) showed a particularly severe degree of calcifications, 43 lesions (34.7 %) a moderate degree, and 27 lesions (21.8 %) a mild degree of calcification. The initial angiography only detected 3-vessel and 2-vessel outflows in the lower leg in 77 lesions (62.1 %). Forty lesions (32.3 %) initially showed 1-vessel outflow. In seven treated lesions (5.6 %), no vascular outflow could be imaged in the patient’s lower leg. At six-month follow-up, 60 lesions in 48 patients (out of an initially treated 124 lesions in 101 patients) were checked with duplex sonography. The primary patency rate in this group was 91.7 %; out of 60 lesions, 55 lesions were patent, i. e. < 50 % stenosed without an interim intervention. Two lesions had been successfully re-treated, i. e. a total of 57 lesions were patent at six months, with a secondary patency rate equalling 95 %. At 12-month follow-up, 69 patients (85 lesions) out of 101 patients (124 lesions) at baseline were assessed with duplex sonography. Overall, the primary patency rate was 81.2 %; meaning out of 85 lesions, 69 lesions were patent, i. e. < 50 % stenosed without an interim intervention. Nine lesions had been successfully re-treated during follow-up and were patent at the 12 month time-point, while seven lesions were occluded, accumulating in a secondary patency rate of 91.8 %. Vasa (2018), 47 (1), 49–55

Patency rates did not differ significantly between the three treatment strategies (scoring only: 81.5 % [22 out of 27]; scoring plus DEB: 83.9 % [26 out of 31]; scoring plus stent: 77.8 % [21 out of 27] [Figure 2]). Degree of lesion calcification did not predict patency after six and 12 months (Figure 3). The strongest predictor of primary patency was lesion length (< 5 cm: 85.7 %, 5–10 cm: 86.5 %, > 10 cm: 53.8 %). In patients who were treated due to claudication (66 lesions in 53 patients), the overall primary patency rate was 83.3 %, and the secondary patency rate equalled 93.9 %. Patients with critical limb ischaemia (CLI) at baseline showed an overall primary patency rate of 73.7 % and a secondary patency rate of 84.2 %. Figure 4 shows angiographic images of a severe stenosis before and after intervention and at the 12-month follow-up. In addition, 16 patients with 18 lesions had to be excluded from the analyses due to failure to attend the 12-month follow-up examinations. In seven patients, this was due to a subjective state of well-being. These were classified as lost to follow-up. For nine initially treated patients, a lack of contact data made scheduling a visit or enquiring about the current state of health and complaints impossible. These nine patients were classified as dropouts and taken into account in all analyses. RBC and ABI improved significantly after six and 12 months. The baseline showed an initial ABI of 0.63 ± 0.22 (n = 70) and > 1.3 in 20 patients, considered not evaluable due to medial sclerosis. In the six-month follow-up, the ABI was 0.79 ± 0.29 (n = 34 >; p < 0.01) and at the 12-month follow-up, the ABI improved to 0.85 ± 0.17 (n = 54; p < 0.0001). The average Rutherford class at baseline was 3.35 ± 1.12 and improved to 1.71 ± 1.80 at six months (n = 53; p < 0.0001) and 1.22 ± 1.36 at 12 months (n = 69; p < 0.0001). © 2017 Hogrefe

AngioSculpt

Mild (1)

AngioSculpt + DEB

Moderat (2)

AngioSculpt + Stent

Severe (3)

100

Months AngioSculpt

83.9 81.5 77.8

primary patency (%)

E. Blessing et al., AngioSculpt in femoropopliteal lesions

0 0

6 1

9 10 11 12

Months

81.8 81.3 78.9

12 7

100

0 0

6 1

12 7

9 10 11 12

46 46 46 46 46 46 46 46 46 46 40 40 39

Mild

17 17 17 17 17 17 16 16 16 16 15 15 14

AngioSculpt + DEB

40 40 40 40 40 40 40 40 40 39 39 39 38

Moderat

28 28 28 28 28 28 28 25 25 24 23 22 21

AngioSculpt + Stent

38 38 38 38 35 35 35 35 35 35 34 33 32

Severe

29 29 29 29 29 29 29 29 29 29 29 29 28

Figure 2. Patency rates per treatment strategy – Kaplan-Meier survival curve up to one year is shown for primary patency per treatment strategy.

Figure 3. Patency rates per lesion calciﬁcation – Kaplan-Meier survival curve up to one year is shown for primary patency per lesion calciﬁcation.

Figure 4. Angiographic images of a calciﬁed stenosis of the proximal superﬁcial femoral artery at baseline (A), after scoring angioplasty with a 5 x 40 mm AngioSculpt™ and 6 x 60 mm In.PACT AdmiralÔ (B), and at 12-month follow-up (C).

Discussion In the current study, a scoring balloon was used to treat mild to severely calcified lesions, either alone or in combination with a stent or DEB, and resulted in high patency rates and improved clinical outcomes at 12-month follow-up. Standard balloon angioplasty has clear limitations, particularly in heavily calcified lesions. Additionally, traditional cutting balloon angioplasty has failed to prove superiority over standard balloon angioplasty in the treatment of primary [11] and in-stent restenotic peripheral lesions [11]. Therefore, the use of scoring balloon angioplasty might be more suitable in the presence of significant vascular calcification. Indeed, 12-month patency rates were encouraging after AngioSculpt™ scoring balloon angioplasty in a small cohort of patients with calcified infrapopliteal lesions [12]. Primary and secondary patency was exceptionally high after 12 months in our present registry (81.2 % and 91.8 %, respectively) and correlated also with favourable clinical outcomes, such as improvement in © 2017 Hogrefe

RBC and ABI. Conflicting data between standard cutting balloons and the AngioSculpt™ scoring balloon might also be explained by a somewhat different mode of action between the two approaches: in a cutting balloon, longitudinal oriented razor blades provide a rather “static” cutting of the plaque, whereas the nitinol wires, wrapped around the semi-compliant AngioSculpt™ balloon, might offer a more dynamic, and potentially more effective, lesion incision during inflation. The strongest predictor for primary patency in our registry after 12 months was lesion length. Primary patency after one year was outstanding in short lesions, but somewhat disappointing in lesions that extended a total length of 10 cm (53.8 %). Use of the AngioSculpt™ balloon might therefore be a valuable treatment option for rather short, heavily calcified femoropopliteal lesions. Calcification per se was not an exclusion criterion in the landmark DEB trials that convincingly proved the concept of local release of paclitaxel to inhibit restenosis in femoropopliteal lesions [7–9]. However, there is no well-established classification to assess severity and extension of Vasa (2018), 47 (1), 49–55

vascular calcium deposits. Fanelli et al. used CT scans to assess longitudinal as well as circumferential extensions of vascular calcium deposits [5]. Circumferential calcium distribution was a better predictor for loss of patency than longitudinal extension of vascular calcification. Since there was no control group treated with standard angioplasty, it remains speculation, whether calcification really limits the benefits of antiproliferative therapy or if it generally results in poorer long-term patency. There are different concepts of lesion preparation prior to the use of DEBs. One option is to remove the plaque and thereby reduce the perfusion barrier to improve penetration of the antiproliferative agent into the vessel wall. Scoring of severely calcified lesions obviously does not remove plaque, but might help to enhance penetration depth of paclitaxel by breaking up the relevant perfusion barrier, in particular, in cases of full circumferential coverage of the vessel by calcium deposits. In our retrospective registry, primary patency was 83.9 % after 12 months in the patient cohort that underwent combination therapy of scoring balloon angioplasty followed by DEB treatment and is therefore comparable with the outcome in patients that underwent AngioSculpt™ PTA only. Of note, lesion characteristics differed substantially between those two cohorts. Rate of occlusions were significantly higher in the combination group (17.5 % vs. 2.2 %) and more likely prompted the interventionist to use an antiproliferative treatment strategy. Whether lesion preparation prior to treatment with a DEB improves outcome clearly needs to be evaluated in a randomized controlled trial. The rate of bail-out stenting was relatively high in our registry. Flow limiting dissections or significant residual stenosis due to recoil prompted the interventionist to use stents in the present cohort. Reported 12-month primary patency rates of several Supera™ registries vary widely between 68.4 and 87.7 % [13–15], with a substantial heterogeneity of lesion and patient characteristics. In our study, patency rates were 77.8 % after 12 months in the patient cohort that underwent stent placement after the use of the AngioSculpt™ balloon angioplasty. Lesion characteristics in the stent group differed significantly from those of the other cohorts with the highest rate of occlusions (31.6 %) and lesion length (10.1 cm). Therefore, lesions that underwent subsequent stent placement were the most challenging of the present registry.

Limitations The main limitation of this retrospective registry is that the use of adjunctive therapies post scoring balloon angioplasty (drug eluting-balloons, stenting etc.) was based on the judgement of the interventionist and did not occur in a prospective randomized fashion. Another limitation is the lack of generally accepted calcification scores, which makes it difficult to compare our results with other published data. Finally, relevant variables were unevenly disVasa (2018), 47 (1), 49–55

E. Blessing et al., AngioSculpt in femoropopliteal lesions

tributed and interdependent and can therefore only be determined by multivariable regression models in adequately powered prospective studies.

Conclusions In summary, AngioSculpt™ treatment in severely calcified lesions was able to produce an acceptable high patency rate after six and 12 months. The therapy of calcified lesions using AngioSculpt™ represents a safe and effective method, which also offers a promising treatment option, potentially in combination with DEB or stents. The present registry generates the hypothesis that calcification might no longer translate into poorer patency as long as proper lesion preparation is performed with scoring balloon angioplasty. This idea warrants further evaluation in the setting of a prospective randomized clinical trial.

References 1. DeRubertis BG, Pierce M, Ryer EJ, et al. Reduced primary patency rate in diabetic patients after percutaneous intervention results from more frequent presentation with limb-threatening ischemia. J Vasc Surg. 2008;47(1):101–8. 2. Iida O, Takahara M, Soga Y, et al. Shared and differential factors influencing restenosis following endovascular therapy between TASC (Trans-Atlantic Inter-Society Consensus) II class A to C and D lesions in the femoropopliteal artery. JACC Cardiovasc Interv. 2014;7(7):792–8. 3. Baril DT, Marone LK, Kim J, et al. Outcomes of endovascular interventions for TASC II B and C femoropopliteal lesions. J Vasc Surg. 2008;48(3):627–33. 4. 4. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33 Suppl 1:S1–75. 5. Fanelli F, Cannavale A, Gazzetti M, et al. Calcium burden assessment and impact on drug-eluting balloons in peripheral arterial disease. Cardiovasc Intervent Radiol. 2014;37(4):898–907. 6. Miki K, Fujii K, Kawasaki D, et al. Intravascular Ultrasound-Derived Stent Dimensions as Predictors of Angiographic Restenosis Following Nitinol Stent Implantation in the Superficial Femoral Artery. J Endovasc Ther. 2016. 7. Scheinert D, Werner M, Scheinert S, et al. Treatment of complex atherosclerotic popliteal artery disease with a new self-expanding interwoven nitinol stent: 12-month results of the Leipzig SUPERA popliteal artery stent registry. JACC Cardiovasc Interv. 2013;6(1):65–71. doi:10.1016/j.jcin.2012.09.011. 8. Tepe G, Zeller T, Albrecht T, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med. 2008;358(7):689–99. 9. Werk M, Albrecht T, Meyer DR, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv. 2012;5(6):831–40. 10. Scheinert D, Peeters P, Bosiers M, et al. Results of the multicenter first-in-man study of a novel scoring balloon catheter for the treatment of infra-popliteal peripheral arterial disease. Catheter Cardiovasc Interv. 2007;70(7):1034–9. 11. Dick P, Sabeti S, Mlekusch W, et al. Conventional balloon angioplasty versus peripheral cutting balloon angioplasty for treatment of femoropopliteal artery in-stent restenosis: initial experience. Radiology. 2008;248(1):297–302. © 2017 Hogrefe

E. Blessing et al., AngioSculpt in femoropopliteal lesions

12. Bosiers M, Deloose K, Cagiannos C, et al. Use of the AngioSculpt scoring balloon for infrapopliteal lesions in patients with critical limb ischemia: 1-year outcome. Vascular. 2009;17(1):29–35. 13. George JC, Rosen ES, Nachtigall J, et al. SUPERA interwoven nitinol Stent Outcomes in Above-Knee IntErventions (SAKE) study. J Vasc Interv Radiol. 2014;25(6):954–61. doi:10.1016/j. jvir.2014.03.004. 14. Goltz JP, Ritter CO, Kellersmann R, et al. Endovascular treatment of popliteal artery segments P1 and P2 in patients with critical limb ischemia: initial experience using a helical nitinol stent with increased radial force. J Endovasc Ther. 2012;19(3):450–6. doi:10.1583/11-3591MR.1. 15. Werner M, Paetzold A, Banning-Eichenseer U, et al. Treatment of complex atherosclerotic femoropopliteal artery disease with a self-expanding interwoven nitinol stent: midterm results from the Leipzig SUPERA 500 registry. EuroIntervention. 2014;10(7):861–8. doi:10.4244/EIJV10I7A147.

Submitted: 24.05.2017 Accepted after revision: 05.09.2017 Conﬂicts of interest: Erwin Blessing received research funding support and speakers honoraria from Spectranetics. All of the other authors have nothing to disclose. Published online: 08.11.2017

Correspondence address Prof. Dr. med. Erwin Blessing SRH Klinikum Karlsbad-Langensteinbach Guttmannstraße 1 76307 Karlsbad erwin.blessing@kkl.srh.de

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Vasa (2018), 47 (1), 49–55

Original communication

Early clinical outcomes of a novel rheolytic directional thrombectomy technique for patients with iliofemoral deep vein thrombosis Jörn F. Dopheide1, Tim Sebastian1, Rolf P. Engelberger2, Axel Haine1, and Nils Kucher3 1 2 3

Clinic for Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland Division of Angiology, Cantonal Hospital Fribourg, Fribourg, Switzerland UniversitätsSpital Zürich, Zürich, Switzerland

Summary: Background: Rheolytic thrombectomy (RT) for acute iliofemoral deep vein thrombosis (DVT) with ﬁrst-generation techniques is often incomplete and adjunctive conventional catheter-directed thrombolysis (CDT) is required in more than half of patients to achieve venous patency. Patients and methods: From the prospective Bern Venous Stent Registry, we investigated rates of primary treatment success, primary patency, and post-thrombotic syndrome (PTS) from 40 consecutive patients (mean age 51 ± 19 years, 45 % women) with acute iliofemoral DVT, treated with a novel directional RT technology and stent placement. Overall, 24 patients were treated for native-vessel iliofemoral DVT (11 with single-session RT, 13 with bailout RT after failed CDT) and 16 for iliofemoral stent thrombosis. Pulse-spray thrombolysis (r-tPA 10 mg) was performed in 29 (73 %) patients. The mean follow-up duration was 193 ± 132 days (minimum 90 days). Results: Overall, primary treatment success of RT was 95 %; only two patients required adjunctive CDT to restore patency. In 24 patients with native-vessel DVT, six-month primary patency was 92 % (95 %CI 75–99 %), and 23 patients (96 %) were free from the PTS according to the Villalta score. In 16 patients with stent thrombosis, six-month primary patency was 63 % (95 %CI 35–85 %) and 50 % were free from PTS. Except for transient macroscopic haemoglobinuria in all patients, no other side effects were recorded. Conclusions: In patients with iliofemoral DVT of native or stented vessels, RT followed by stent placement appears to be effective and safe. The novel technique enables single-session DVT treatment in the majority of patients without the need for prolonged CDT. Keywords: Iliofemoral deep vein thrombosis, post-thrombotic syndrome, rheolytic thrombectomy, catheter-directed thrombolysis, AngioJet ZelanteDVT

Introduction Acute iliofemoral deep vein thrombosis (DVT) is a major cause for morbidity, as approximately half of the patients managed conservatively with anticoagulation therapy and compression stockings develop the post-thrombotic syndrome (PTS) [1–4]. The residual thrombus load correlates with the probability of a future PTS [5, 6]. The degree of the PTS correlates with impairment of quality of life [7, 8]. As compared to conservative therapy, catheter-directed thrombolysis (CDT) is associated with greater venous patency and reduced risk of PTS at two years [9]. International consensus guidelines recommend CDT with provisional stent placement of the underlying venous outflow obstruction for selected patients with acute iliofemoral DVT [10, 11]. However, CDT with provisional stent placement is complex because it involves catheter placement Vasa (2018), 47 (1), 56–62 https://doi.org/10.1024/0301-1526/a000666

in a first session, prolonged monitoring in the intermediate care unit during the administration of local thrombolysis, and venography with provisional stent placement in a second session. In recent years, a trend emerged to complete the DVT revascularization and stent placement procedure in a single session. Rheolytic thrombectomy (RT) uses the Venturi-Bernoulli effect (negative pressure induced by fast flowing saline jets) and enables single-session DVT therapy [12]. Rheolytic thrombectomy can be combined with adjunctive local administration of a high-pressure thrombolysis spray (PowerPuls®) to facilitate thrombus removal. In the Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths (PEARL) study of 329 DVT patients, RT with a first-generation system (AngioJet® 6F, Boston Scientific, Maple Grove, MN, USA) was effective and safe [13]. However, 61 % of the PEARL © 2017 Hogrefe

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

patients required adjunctive CDT to restore venous patency. The Angiojet ZelanteDVT® catheter (Boston Scientific, Maple Grove, MN, USA) is a novel 8-French RT system specifically designed for single-session treatment of acute iliofemoral DVT. The aim of the present study was to investigate patency rates and early clinical outcomes of patients with acute iliofemoral DVT treated with the Angiojet ZelanteDVT® system.

Patients and methods Study design The current analysis was derived from the Bern Venous Stent Registry, an ongoing study that consecutively enrols patients who received venous stents at the University Clinic of Angiology in Bern, Switzerland, since 1 January 2008. From this registry we included all patients with least 90 days of follow-up, who underwent AngioJet ZelanteDVT® for acute iliofemoral DVT or iliofemoral venous stent thrombosis since market introduction in December 2015. Exclusion criteria for registry enrolment are the inability to provide informed consent, age below 18 years, or estimated life expectancy < 3 months. The registry and participant consent form were approved by the Swiss Ethics Committee on research involving humans. The study is registered on the National Institutes of Health website (ClinicalTrials.gov; identifier NCT02433054). For all enrolled patients, baseline demographic information (age, gender, weight, height, indication), comorbid conditions (concomitant pulmonary embolism, active cancer or treatment, thrombophilia, hypertension), risk factors (smoking, hormonal therapy, previous DVT, immobility, recent surgery/trauma, May-Thurner compression, obesity), and anticoagulant/antiplatelet therapy were recorded. Procedural data included type, diameter, length, and site of implanted stents. Venograms were used to analyse thrombus extension and primary treatment success. For this analysis we predefined three patient groups: 1. primary single-session RT for iliofemoral DVT of native vessels, 2. bail-out RT after incomplete or failed CDT for iliofemoral DVT of native vessels, 3. primary single-session RT of DVT caused by iliofemoral venous stent thrombosis.

Study device The Angiojet ZelanteDVT ® (Boston Scientific, Marlborough, MA, USA) catheter is a novel RT device which has been specially designed for single-session treatment of iliofemoral DVT (Figure 1). © 2017 Hogrefe

Figure 1. AngioJet ZelanteDVT® catheter. Schematic drawing of the tip of the 8-French AngioJet ZelanteDVT® catheter (Boston Scientific, Maple Grove, MN, USA). It is an isovolumetric, directional, hydrodynamic thrombectomy device using accelerated reversed fluid, which runs through the inside of the catheter and provides a strong –600 mmHg suction (Venturi) effect at the catheter tip. The treatment segment with one larger proximal suction window and one smaller distal outflow window (arrows) can be identified under fluoroscopy through two marker bands. Between the marker bands is an eccentric middle marker, indicating the (opposite) direction of the inflow and outflow windows.

Procedures Iliofemoral DVT was objectively confirmed by duplex ultrasound or contrast-enhanced computed tomography. All patients were initially treated with intravenous unfractionated heparin, adjusted to target and partial thromboplastin time corresponding to therapeutic heparin levels was activated (equivalent to 0.3 to 0.7 U/mL by factor Xa inhibition). In patients with thrombus extension into the popliteal veins, initial CDT was mainly performed as a first thrombus removal strategy. Following popliteal access with a 10-French sheath, RT (AngioJet ZelanteDVT ®) was performed using two thrombectomy passes of the thrombotic occlusion by advancing the device by 2–3 millimetre per second. Each device activation run lasted no longer than 30 seconds with breaks of 30 seconds in between the runs to avoid arrhythmia. During the thrombectomy procedure, the rotation hub at the catheter shaft was rotated by 270 degrees back and forth to accomplish circumferential thrombus removal. If RT was incomplete, defined as absence of flow or residual thrombus with near complete vessel occlusion, an intraclot injection of 10 mg of r-tPA (total injected volume 30 millilitres) using the PowerPulse® technique was performed. After 20 Minutes dwell time, another two thrombectomy passes were performed as described above, not exceeding a total device activation time of 300 seconds. Diagnosis of an iliac vein compression syndrome or of residual post-thrombotic obstruction was established after successful thrombus removal by digital subtraction venography in two orthogonal views or by intravascular ultrasound if venography was equivocal. Stenting was performed in the presence of a venous stenosis > 50 % by intravascular ultrasound or venography or in the presence of collateral flow, or in the absence of flow [14]. Depending on the affected venous segment and the presence or absence of a compression syndrome, the following stents were used: for the inferior vena cava SinusXL® stent, for compressed iliac veins Sinus-Obliquus® May Thurner stent, for post-thrombotic iliac or common femoVasa (2018), 47 (1), 56–62

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

ral veins Sinus-XL Flex® stent, and for the deep femoral vein Sinus-SuperFlex® stent (Optimed, Ettlingen, Germany). Stent diameters were 20–24 mm for the inferior vena cava, 14–16 mm for the iliac veins, 14 mm for the common femoral vein, and 12 mm for the deep femoral vein. Following endovascular therapy, oral anticoagulation therapy was initiated. Patients received either vitamin K antagonists or direct oral anticoagulants (rivaroxaban, apixaban, or dabigatran).

used to estimate patency rates, which were reported with the 95 % confidence interval. A log rank test was used to compare primary patency rates between patients with iliofemoral DVT and patients with iliofemoral venous stent thrombosis. A p < 0.05 indicated statistical significance. For data management and statistical analysis, we used the Prism® V5.0f statistical software package (GraphPad®, San Diego, CA, USA).

Clinical follow-up

Results

Clinical follow-up assessments with duplex sonography were performed in all patients at the vascular outpatient clinic by vascular specialists at the first postinterventional day, at three, six, and 12 months. At each visit, signs and symptoms of post-thrombotic syndrome, including all points of the Villalta score [15] and the revised venous clinical severity score [16] were systematically examined by vascular specialists. Each stented venous segment was examined by ultrasound for (1) the presence or absence of thrombotic changes (thickening of the venous wall, intraluminal webs, intraluminal material) and (2) flow patterns in treated segments to determine if they were modulated by the cardiac cycle, spontaneously modulated with respiration, or modulated with deep inspiration. Peak flow velocities [cm/sec] were recorded from the common femoral vein.

Baseline characteristics Overall, 40 patients (mean age 51 ± 19 years; 18 women) were treated with directional RT between December 2015 and March 2017. During the observation period, five patients with iliofemoral DVT were treated conservatively. Baseline characteristics were similar in the groups except for a history of previous DVT and hormonal therapy (Table I). Overall, 24 patients (60 %) had acute iliofemoral DVT of native veins of which 11 were treated in a single session and 13 in a bail-out session after incomplete CDT with r-tPA 20 mg over 15 hours. Sixteen patients (40 %) presented with iliofemoral venous stent thrombosis; the index diagnosis and reason for stent implantation was PTS in 11 cases (69 %) and acute iliofemoral DVT in five cases (31 %).

Deﬁnition of outcomes Procedural data Primary treatment success was defined as antegrade flow and maximal luminal stenosis of 30 % assessed on the final procedural venography and evidence of a spontaneous Doppler signal in the treated vein segment [17]. Primary patency rate was defined as the percentage of patients with primary treatment success and without the occurrence of either thrombosis of the treated segment or a reintervention to maintain patency of the treated segment. Restenosis in the treated venous segment was defined by ultrasound as a luminal obstruction of > 50 % of the venous cross-sectional area in B-mode or deterioration of the Doppler flow pattern from the first postinterventional day to the follow-up ultrasound study. This included an increase of the peak flow velocity to > 1 m/s or a loss of respiratory modulation of flow.

Statistical analyses Continuous baseline and outcome data were presented as mean ± standard deviations and were compared between the three groups, using one-way analysis of variance and Dunn’s multiple comparison tests. Categorical baseline and outcome data were analysed between the groups using the chi-square test. Kaplan-Meier survival analysis was Vasa (2018), 47 (1), 56–62

Figure 2 shows an example of venograms at baseline, after RT, and at completion of the procedure for the three groups. Primary treatment success after RT was achieved in 38 patients (95 %). In two patients, adjunctive CDT was necessary to achieve venous patency. None of the 40 patients received an IVC filter. Balloon angioplasty and stent placement was performed in all patients (mean 3.5 ± 3.2 stents) (Table II). Among the 16 patients with stent thrombosis, 15 (94 %) patients had post-thrombotic venographic changes of the leg inflow veins (femoral and deep femoral veins) at the time of the index procedure. There were no periprocedural adverse events, such as arrhythmia, bleeding complications or symptomatic pulmonary embolism. Transient macroscopic haemoglobinuria during the first 24 hours after intervention was recorded in all patients. The majority of patients received oral anticoagulation therapy with either direct oral anticoagulants [n = 31 (78 %)] or vitamin K antagonists [n = 8 (20 %)]. One patient with active cancer received low molecular weight heparin. Duration of oral anticoagulation therapy was distributed as following: for a limited period of three months [n = 11 (28 %)], six months [n = 3 (7 %)], and 12 months [n = 1 (2 %)]; and for an indefinite period [n = 25 (63 %)]. © 2017 Hogrefe

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

Table I. Baseline characteristicsa. Overall (n = 40)

Iliofemoral DVT (n = 24) Single session (n = 11)

Stent thrombosis (n = 16)

Bail out (n = 13)

Demographics Age, y

50.5 ± 19.5

58.8 ± 19.0

47.9 ± 18.9

46.8 ± 19.7

18 (45)

5 (45)

7 (54)

6 (38)

26.2 ± 6.0

26.9 ± 5.2

27.0 ± 3.5

25.0 ± 8.0

DVT symptoms < 14 days

28 (70)

8 (73)

11 (85)

9 (56)

May-Thurner compression

12 (30)

5 (45)

3 (23)

4 (25)

7 (18)

2 (18)

4 (31)

1 (6)

Previous DVT

19 (48)

3 (27)

2 (15)

14 (88)

Hypertension

10 (25)

4 (36)

4 (31)

2 (13)

8 (20)

3 (27)

3 (23)

2 (13)

10 (25)

2 (18)

4 (31)

4 (25)

7 (18)

2 (18)

3 (23)

2 (13)

Hormonal therapy

7 (18)

5 (38)

2 (13)

Surgery and/or traumae

6 (15)

2 (18)

2 (15)

2 (13)

Smoking

8 (20)

1 (9)

1(8)

6 (38)

Active cancer or treatmentf

6 (15)

3 (27)

2 (15)

1 (6)

3 (8)

3 (19)

Inferior vena cava

10 (25)

2 (18)

2 (15)

6 (38)

Common iliac vein

38 (95)

11 (100)

13 (100)

14 (88)

External iliac vein

40 (100)

11 (100)

13 (100)

16 (100)

Common femoral vein

40 (100)

11 (100)

13 (100)

16 (100)

Femoral vein

30 (75)

6 (55)

11 (85)

13 (81)

Popliteal vein

12 (30)

1 (9)

7 (54)

4 (25)

Women 2

Body mass index (kg/m ) Venous pathology

Atypical iliofemoral compression Risk factors and comorbidities

Immobilizationb c

Obesity

Concomitant pulmonary embolism d

Known thrombophilia Thrombus extension

a: Continuous data are presented as the mean ± standard deviation, categorical data are given as numbers with percentages; b: within the previous three months; c: deﬁned as body mass index > 30 kg/m2; d: oestrogens, tamoxifen or substitute; e: within the previous four weeks; f: within the previous six months.

Clinical outcome during follow-up The mean follow-up duration was 193 ± 132 days (Table II). For the 24 patients with iliofemoral DVT of native vessels, the primary patency rate was 92 % [95 % CI 75–99 %] at 180 days (Figure 3). There was one female patient with metastatic bladder cancer who had right-sided iliac stent thrombosis at day 165, due to tumour progression with compression of the inferior vena cava and iliac veins. She underwent successful stent reconstruction of the inferior vena cava and iliac veins. © 2017 Hogrefe

For the 16 patients with stent thrombosis, the primary patency rate was 63 % [95 % CI 35–85 %] at 180 days (Figure 3). Six patients with an index diagnosis of PTS had symptomatic complete stent rethrombosis, of whom two had early rethrombosis within 30 days. Among the six patients, reintervention was attempted in three, but not successfully. Among the seven patients who developed symptomatic stent thrombosis at follow up, six (86 %) had post-thrombotic venographic changes of the femoral leg inflow veins at the index procedure. Among the 33 patients with patent stents at the latest follow-up, only nine (27 %) had post-thrombotic Vasa (2018), 47 (1), 56–62

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

Figure 2. Digital subtraction venograms. A1: Baseline venogram from a patient with acute descending iliofemoral thrombosis and typical compression of the left common iliac vein; A2: near complete thrombus removal after single session rheolytic thrombectomy and PowerPuls® thrombolysis (r-tPA 10 mg); A3: final venographic result after stent placement in common iliac vein (Sinus Obliquus®, Optimed, Germany); B1: venogram after failed catheter-directed thrombolysis (20 mg r-tPA over 15 hours) of a patient with acute descending iliofemoral thrombosis and May-Thurner compression; B2: near complete thrombus removal after bailout rheolytic thrombectomy and PowerPuls® thrombolysis (r-tPA 10 mg); B3: final venographic result after stent placement in common iliac vein (Sinus Obliquus®, Optimed, Germany); C1: baseline venogram from a patient with acute thrombosis of an iliac vein stent; C2: near complete thrombus removal after rheolytic thrombectomy and PowerPuls® thrombolysis (r-tPA 10 mg); C3: final venographic result after high-pressure balloon angioplasty of the stent.

venographic changes of the femoral leg inflow veins at the index procedure (p = < 0.001). Among the 40 patients, there were no cases of asymptomatic venous restenosis. Overall, the Villalta score at six months was 3.87 ± 5.04; 30 patients (75 %) were free from PTS with a Villalta score of < 5 points (Table II). Among the 24 patients with iliofemoral DVT, 23 (96 %) remained free from the PTS at six months with a Villalta score of < 5 points. Among the 16 patients with venous stent thrombosis, seven (44 %) were free from PTS at six months.

Discussion We report the first early clinical results of a novel directional RT technique for the treatment of iliofemoral DVT. Directional RT using the AngioJet ZelanteDVT® system Vasa (2018), 47 (1), 56–62

was effective to restore patency in combination with balloon angioplasty and venous stent placement in patients with iliofemoral DVT of native or stented vessels. PowerPuls® thrombolysis was performed in 73 % patients and only 5 % required adjunctive CDT to achieve venous patency. Except for transient haemoglobinuria, no periprocedural complications occurred. In the 24 patients with acute iliofemoral DVT of native vessels, six-month primary patency was 92 % and only one patient developed PTS. In patients with iliofemoral venous stent thrombosis, six-month primary patency was 63 %, and 56 % of the patients remained free from PTS. The main reason for the less favourable patency rate in patients with iliofemoral venous stent thrombosis was likely an impaired venous stent inflow because almost all patients had post-thrombotic femoral veins at the index procedure. Despite lower patency rates, interventions for venous stent thrombosis should be considered because a permanently obstructed deep venous system may be associated with impaired quality of life and invalidity, leading to substantial disease-related costs [18, 19]. The novel directional RT technique was specifically designed for thrombus removal in large veins. In contrast to first-generation RT systems, features of the novel technique include (1) a larger catheter lumen (8F instead of 6F), (2) modifications at the treatment segment with one larger proximal suction window and one smaller distal outflow window, and (3) a rotational hub to accomplish directional thrombus removal (see Figure 1). The novel RT technique provides a strong –600 mmHg suction (Venturi-) effect at the catheter tip which is likely the reason for the observed primary treatment success without the need for adjunctive prolonged CDT in all but two patients. This clearly is an improvement when comparing our results to the results of the PEARL study, in which 61 % of the patients treated by the first-generation RT technique required adjunctive CDT to restore venous patency [13]. There is an ongoing debate whether an early revascularization strategy is superior to anticoagulation therapy exclusively for the reduction of PTS in patients with acute iliofemoral DVT [20]. First results from the Acute venous Thrombosis: Thrombus Removal with Adjunctive Catheter-directed Thrombolysis randomized (ATTRACT) trial [21], which compared an early revascularization strategy to just anticoagulation therapy in 692 patients with proximal DVT, were presented at the congress of the Society of Interventional Radiology (SIR) in March 2017 [22]. Unfortunately, almost half of the ATTRACT patients had femoropopliteal DVT without involvement of the iliac veins; several thrombus removal strategies were allowed and only 30 % of the patients had stent placement. The ATTRACT study failed to show that an early revascularization strategy was superior to just anticoagulation with similar overall PTS rates at two years of follow-up. Currently, there is no evidence from randomized trials that RT is more effective than conventional CDT. It re© 2017 Hogrefe

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

Table II. Procedural and clinical outcome dataa. Overall (n = 40)

Iliofemoral DVT (n = 24) Single session (n = 11)

Stent thrombosis (n = 16)

Bail out (n = 13)

Follow-up Mean follow-up, days

193 ±132

184 ± 93

220 ± 129

179 ± 160

0.65

3.9 ± 5.0

2.3 ± 2.4

1.1 ± 1.2

6.1 ± 6.2

0.01

31 (78)

10 (91)

13 (100)

8 (50)

< 0.01

4.2 ± 5.2

3.6 ± 4.8

1.5 ± 1.4

6.1 ± 6.2

0.04

30 (75)

9 (82)

12 (92)

9 (56)

0.07

9 (23)

2 (18)

1 (8)

6 (38)

0.15

10 (25)

2 (18)

2 (15)

6 (38)

0.57

3.5 ± 3.2

2.1 ± 2.2

2.0 ± 2.3

5.7 ± 3.2

< 0.001

241 ± 192

236 ± 227

185 ± 138

290 ± 202

0.18

29 (73)

7 (64)

7 (54)

15 (94)

0.04

27.7 ± 15.6

31.6 ± 20.5

30.7 ± 14.4

22.5 ± 11.9

0.28

Inferior vena cava

9 (18)

2 (18)

2 (15)

5 (31)

0.55

Common iliac vein

38 (95)

11 (100)

13 (100)

14 (88)

0.21

External iliac vein

36 (90)

11 (100)

11 (92)

14 (88)

0.42

Common femoral vein

25 (63)

5 (45)

5 (22)

15 (94)

< 0.01

4 (10)

4 (25)

0.04

Villalta scoreb No PTS (< 5 points) rVCSS pointsc Direct oral anticoagulants Vitamin K antagonists Clopidogreld Procedural Implanted stents Stent length [mm] PowerPuls® Peak ﬂow velocitye (cm/sec) Stent localization

Deep Femoral vein

a: Continuous data are presented as the mean ± standard deviation, categorical data are given as numbers with percentages; b: at last follow-up; c: revised venous clinical severity score at last follow-up; d: for the initial three months after intervention; e: by Doppler ultrasound in the common femoral vein after completion of the procedure; PTS: post-thrombotic syndrome.

Vasa (2018), 47 (1), 56–62

J. Dopheide, T. Sebastian et al., Rheolytic thrombectomy for deep vein thrombosis

mains unclear whether a single-session strategy of this novel thrombectomy technique is effective and safe in patients with extensive DVT involving the popliteal and lower leg veins. Advantages of the novel RT technique include thrombus removal and provisional stent placement in a single session, without the need for prolonged CDT, admission to the intermediate care unit or second look venography. In contrast, CDT always requires a staged intervention with catheter placement, prolonged CDT in a monitor unit, and second or third look venography with provisional stent placement.

Limitations and conclusions Our study is limited by the relatively low number of study participants and short follow-ups. Nevertheless, our first clinical results suggest that primary treatment success and early clinical outcomes with this novel RT technique are favourable for patients with iliofemoral DVT. Overall, RT was effective to restore patency in combination with provisional PowerPuls® thrombolysis, balloon angioplasty, and venous stent placement. The novel technique enables single-session DVT treatment in the majority of patients without the need for prolonged catheter-directed thrombolysis. Future studies should investigate the long-term efficacy and safety of this promising technique in large cohorts of patients with acute iliofemoral DVT.

References 1. Stain M, Schonauer V, Minar E, et al. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost. 2005;3: 2671–6. 2. Day ISCfWT. Thrombosis: a major contributor to the global disease burden. J Thromb Haemost. 2014;12:1580–90. 3. Roumen-Klappe EM, den Heijer M, Janssen MC, van der Vleuten C, Thien T and Wollersheim H. The post-thrombotic syndrome: incidence and prognostic value of non-invasive venous examinations in a six-year follow-up study. Thromb. Haemost. 2005;94:825–30. 4. Kahn SR, Shrier I, Julian JA, et al. Determinants and time course of the postthrombotic syndrome after acute deep venous thrombosis. Ann Intern Med. 2008;149:698–707. 5. Comerota AJ, Grewal N, Martinez JT, et al. Postthrombotic morbidity correlates with residual thrombus following catheterdirected thrombolysis for iliofemoral deep vein thrombosis. J Vasc Surg. 2012;55:768–73. 6. Grewal NK, Martinez JT, Andrews L, Comerota AJ. Quantity of clot lysed after catheter-directed thrombolysis for iliofemoral deep venous thrombosis correlates with postthrombotic morbidity. J Vasc Surg. 2010;51:1209–14. 7. Kahn SR, Hirsch A and Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med. 2002;162:1144–8. 8. Kahn SR, Shbaklo H, Lamping DL, et al. Determinants of health-related quality of life during the 2 years following deep vein thrombosis. J Thromb Haemost. 2008;6:1105–12. 9. Enden T, Haig Y, Klow NE, et al. Long-term outcome after additional catheter-directed thrombolysis versus standard Vasa (2018), 47 (1), 56–62

treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial. Lancet. 2012; 379:31–8. 10. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest. 2016;149:315–52. 11. Kahn SR, Comerota AJ, Cushman M, et al. The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2014;130:1636–61. 12. A. L. Baert MK, K. Sartor. Vascular Interventional Radiology: Angioplasty, Stenting, Thrombolysis and Thrombectomy. In: Cowling MG, (ed.). 2006, 66. 13. Garcia MJ, Lookstein R, Malhotra R, et al. Endovascular Management of Deep Vein Thrombosis with Rheolytic Thrombectomy: Final Report of the Prospective Multicenter PEARL (Peripheral Use of AngioJet Rheolytic Thrombectomy with a Variety of Catheter Lengths) Registry. J Vasc Interv Radiol. 2015;26:777–85. 14. Engelberger RP, Fahrni J, Willenberg T, et al. Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis. Thromb. Haemost. 2014;111:1153–60. 15. Villalta S, Bagatella P, Piccioli A, Lensing A, Prins M and Prandoni P. Assessment of validity and reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis. 1994; 24:158a. 16. Vasquez MA, Rabe E, McLafferty RB, et al. Revision of the venous clinical severity score: venous outcomes consensus statement: special communication of the American Venous Forum Ad Hoc Outcomes Working Group. J Vasc Surg. 2010; 52:1387–96. 17. Vedantham S, Grassi CJ, Ferral H, et al. Reporting standards for endovascular treatment of lower extremity deep vein thrombosis. J Vasc Interv Radiol. 2006;17:417–34. 18. MacDougall DA, Feliu AL, Boccuzzi SJ, Lin J. Economic burden of deep-vein thrombosis, pulmonary embolism, and postthrombotic syndrome. Am J Health Syst Pharm. 2006;63:5–15. 19. Guanella R, Ducruet T, Johri M, et al. Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation. J Thromb Haemost. 2011; 9:2397–405. 20. Sharifi M, Mehdipour M, Bay C, Smith G, Sharifi J. Endovenous therapy for deep venous thrombosis: the TORPEDO trial. Catheter Cardiovasc Interv. 2010;76:316–25. 21. Vedantham S, Goldhaber SZ, Kahn SR, et al. Rationale and design of the ATTRACT Study: A multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis. Am Heart J. 2013;165:523–30.e3. 22. Vedantham S. ATTRACT Trial Results Society of Interventional Radiology (SIR). Washington, D. C.2017.

Submitted: 13.08.2017 Accepted after revision: 07.09.2017 Conﬂicts of interests: Nils Kucher has received speaker and consulting honoraria from Boston Scientiﬁc and Optimed. Published online: 05.10.2017

Case report

Laser-assisted transprosthesial coil embolization combined with thrombin injection for treatment of an endoleak type II after endovascular aneurysm repair Tanja Boehme, Aljoscha Rastan, Elias Noory, Peter-Christian Fluegel, and Thomas Zeller Department of Angiology, University Heart Center Freiburg-Bad Krozingen, Bad Krozingen, Germany

Summary: The treatment of endoleaks type II had to be adapted to the anatomy of each individual patient. The laser-assisted perforation of the prosthesis can be an easier method to reach the aneurysm sac directly than using transarterial or translumbar approaches. Keywords: Abdominal aortic aneurysm, endovascular aneurysm repair, endoleak, embolization

Introduction Endovascular aneurysm repair (EVAR) is performed increasingly often. In the United States, the proportion of elective endovascular treated abdominal aortic aneurysms increased from 6.3 % in 2000 to 43.0 % in 2003 [1]. In 2008, the percentage had already risen to 77 % in all age groups and to 83 % in the patient group older than 80 years [2]. Blood flow outside the graft into the aneurysm sac with consecutive sac growth, the so called endoleak, is a complication after endovascular procedures. In a retrospective study, a sac enlargement of 5 mm or more was found in 41 % after five years [3]. Endoleaks are classified in five different types [4] (Table I). After EVAR an endoleak was detected in 31 % within 6.2 ± 2.4 year follow-ups. The most common endoleak was type II (76 %) followed by type I (12 %) [5]. Due to technical graft improvements, the endovascular aneurysm repair will continue to grow in significance and therefore, it is important that endoleaks can be treated successfully with interventional methods.

Case report A 75-year-old male patient underwent regular check-ups because of an abdominal aortic aneurysm. In November 2015, a progression was documented. The computed tomography angiography (CTA) showed an infra-renal abdominal aortic aneurysm with thrombotic deposits and a diameter of 63 x 66 mm. The patient was free of symptoms in daily life. After an interdisciplinary discussion, the patient was scheduled for an EVAR procedure in December 2015. The procedure was done percutaneously using a pre-closing technique (two Perclose Proglide™ (Abbott Vascular, CA, USA)) suture-based closure device for each common femoral artery. An Endurant 2 S 36/14/103 mm main body endoprosthesis was implanted via the right and was extended to the left and right common iliac arteries with 16/24/124 mm iliac endoprosthesis legs. Because of an endoleak type III on the left side, an additional 16/24/156 mm endoprosthesis was implanted. The prosthesis was subsequently dilated. After that, the aneurysm sac was still minimally perfused; however, an endoleak could not be verified. The day after

Table I. Classiﬁcation of endoleaks [4]. Type of endoleak Deﬁnition Type I A B

Insufficient sealing at the edges of the prosthesis Proximal insufficiency Distal insufficiency

Type II

Retrogradely perfusion of aneurysm sac via branch vessels

Type III

Structural failure of the endoprosthesis

Type IV

Porosity of the endoprosthesis

Type V (endotension)

Continued aneurysm sac growing without evidence of an endoleak

Vasa (2018), 46 (6), 63–67 https://doi.org/10.1024/0301-1526/a000648

the implantation in duplex sonography, the endoleak was no longer detectable and the prosthesis was adequately perfused. The patient was subsequently discharged under antiplatelet mono-therapy with aspirin 100 mg/day. Three months later, CTA showed an endoleak type II with retrograde perfusion originating at least from one lumbar artery (Figure 1). The size of the aneurysm sac remained unchanged. Therefore, it was recommended that a control examination should take place six months thereafter. After another six months, the CTA showed an increase in the size of the aneurysm, hence the endoleak required treatment. In a first intervention, a coil embolization attempt was unsuccessful due to vessel tortuosity. Bilateral femoral access was used, but both approaches failed to reach the aneurysm sac. A few days later, this was attempted again. For this attempt only the left common femoral artery access was used. The preinterventional angiography showed the an-

Figure 1. Computed tomography angiography showed the aneurysm excluded. An endoleak type II was discoverable.

T. Boehme et al., Transprosthesial endoleak embolization

eurysm sac to be retrogradely perfused via both lumbar arteries at the level of the fourth lumbar vertebral body and in addition, via the right lumbar artery at the level of the third lumbar vertebral body (Figure 3). Due to known tortuosity, the intended strategy was to use a direct access to the aneurysm sac via the left iliac endoprosthesis leg. For this purpose, a deflectable 6.5F sheath (Oscor, FL, USA) and a 5F diagnostic catheter with in LIMA configuration (Cordis, a Cardinal Health Company, CA, USA) was used to orientate a 0.9 mm excimer laser (Spectranetics, CO, USA) towards the aneurysm sac and create an access via the endoprosthesis (Figure 2). A 0.014’’ guidewire was inserted and the passage to the endoleak was progressively dilated with low profile coronary balloons up to 3 mm in diameter. Using a Progreat-microcatheter (Terumo, NJ, USA), the fourth left lumbar artery was embolized with four Azur coils 4/60 mm in size (Terumo, NJ, USA) (Figure 4). In addition, the third right lumbar artery was embolized with one coil via a 4F vertebral catheter (Cordis, a Cardinal Health Company, CA, USA). Despite several attempts, a selective insertion into the right fourth lumbar artery failed. Because of that, three 4/10 mm Tornado-coils (Cook Medical, IN, USA) were placed in front of the origin of the branch. Finally, the intervention was completed with a fractionated thrombin injection into the remaining perfused aneurysm sac. At the end of the procedure, after selective contrast medium application into both internal iliac arteries, no retrograde perfusion of the aneurysm sac was visible any more. The endoleak was no longer detectable and 2500 IU of heparin was given periprocedurally. The catheter materials were removed from the aneurysm sac. The control angiography showed adequate perfusion of the left iliac prosthesis leg and no type III en-

Figure 2. A) The limbs of the endoprosthesis are crossed. The prosthesis is in ballerina position and the sheath is positioned in the left prosthesis limb. B) The sheath (continuous arrow) has been introduced into the prosthesis and the IMA-catheter (large dotted arrow) and the Progreat-microcatheter (small dotted arrow) is situated in the aneurysm sac. The angiogram shows the endoleak (*1) and the lumbar artery (*2). Vasa (2018), 46 (6), 63–67

T. Boehme et al., Transprosthesial endoleak embolization

Figure 3. A) Via a left femoral crossover sheath, a vertebralis catheter (short arrow) was introduced into the internal iliac artery. The angiogram shows the endoleak retrograde perfused via the lumbar artery. B) Enlarged view of the endoleak (continuous arrow) and lumbar artery (dotted arrow).

After three months, the CTA control showed good results. The diameter of the aneurysm sac had not increased. Typical clinical signs of intermittent claudication and abdominal discomfort were still negated by the patient.

Discussion

Figure 4. The Progreat-microcatheter has been introduced to periscope technique to reach the lumbar artery. Azur coils 4/60 mm in size are already decoiled.

doleak via the access site, potentially due to the two overlapping endoprosthesis legs, which had been placed during the index procedure (Figure 5). Therefore, additional prosthesis implantation was not required. A contrast enhanced duplex sonography the day after the procedure showed a low flow in the orifice of one lumbar artery but no perfusion of the aneurysm sac. © 2017 Hogrefe

For a long time abdominal aortic aneurysms were treated surgically. It is now 25 years ago that EVAR as a less invasive method has been introduced [6]. If the anatomic conditions are met, EVAR is a gentle method because there is no need to disconnect the aorta as opposed to surgical therapy. This so-called cross-clamping increases the afterload and is therefore responsible for myocardial ischaemia and decompensation during or shortly after surgery [7]. Perhaps cross-clamping is one reason for the inferior short-term outcome of the surgical therapy. Three randomized studies showed a significant better 30-day survival rate after EVAR in comparison to surgical therapy [8–10]. After approximately two years the survival benefit is no longer verifiable. One possible explanation for this is the rupture of the aneurysm sac after primarily successful EVAR. A risk factor for rupture is the persisting perfusion of the aneurysm sac after EVAR. These endoleaks are common complications after EVAR with a reported incidence of up to 30 percent [11]. The type of endoleak is of great importance in therapeutic considerations because the risk of rupture is depending on the endoleak type. Endoleaks type I and III have to be promptly treated. An endoleak type II can be observed. This endoleak can spontaneously clot but even without Vasa (2018), 46 (6), 63–67

Figure 5. The control examination using computed tomography angiography three months after the endoleak treatment shows that the endoleak is no longer detectable.

clotting, if the aneurysm sac is constant in size, it can be controlled in regular intervals. Endoleaks type IV require no specific treatment. They are self-limiting. In cases of endotension (endoleak type V), an open repair or further intervention is indicated [4]. If the abdominal aortic aneurysm was treated by endovascular means, the goal is certainly to treat endoleaks type II also endovascularly and not laparoscopically or by open surgical repair. Therefore, many different endovascular therapy options have been described. The goal is to directly embolize the aneurysm sac or to embolize branch vessels inducing the endoleak. Embolization can be achieved directly translumbarly/transabdominally or transarterially [12]. In a small study the outcome after transarterial or translumbar embolization was compared. The outcome was poor. Just four out of ten transarterial embolizations were technically successful and only in two cases resolution of the endoleak was achieved. Three patients were treated with translumbar embolizations and one with transabdominal embolization. All interventions were technically successful. A clinical success, defined as resolution of the endoleak without enlargement of the aneurysm sac on follow-up CTA, was achieved in three out of four patients [13]. Another study suggested that the direct translumbar embolization of the endoleak is more effective in the elimination of type II endoleaks than the transarterial embolization of inferior mesenteric arteries. After transarterial inferior mesenteric artery embolization 80 % of the endoleaks were re-perfused over time, whereas 92 % of the Vasa (2018), 46 (6), 63–67

T. Boehme et al., Transprosthesial endoleak embolization

endoleaks were successfully treated with translumbar embolization during the follow-up period [12]. A review included 23 studies which evaluated inter alia outcome of translumbar and transarterial embolizations for treatment of type II endoleaks after EVAR. Even in this review, the number of patients is low. Fifty-seven translumbar interventions were performed and 81 % of the endoleaks were not perfused after embolization during follow-up. No complications had occurred. After transarterial embolization, 62.5 % of the endoleaks were not perfused after intervention. Furthermore, the number of complications was higher [14]. Often an endoleak is compared with an AV-malformation and so, a single feeding vessel embolization cannot be successful because the endoleak is then perfused by nearby vessels. When the central nidus requires treatment, this can be achieved by translumbar embolization because the endoleak itself is treated. The communication between the aortic branches is interrupted by the embolization of the aneurysm sac. This may explain why the results of the translumbar embolization are better than those of the transarterial embolization [12]. This assumption is confirmed by Kasirajan et al. One reason for treatment failure is the isolated coiling of feeding vessels. A further reason for therapy failure is that the aneurysm sac is out of reach and a direct coiling is not possible. The direct access to the aneurysm sac was of such importance to the authors that they changed treatment procedure. If the aneurysm sac could not be reached transarterially, they performed a CTguided puncture of the aneurysm sac [15]. Another approach for treatment of endoleaks was described by Mansueto et al. The embolization was performed transcavally by thrombin injection and partly by coiling. Technically, 92 % of the interventions were successful. Within a year just one endoleak was reperfused and so clinical success was achieved in 10 out of 12 patients (83 %) [16]. In another study, a transcaval approach was technically successful in 90 % of the interventions. Because of sac expansion, five patients had a reintervention. After 16.5 months in average, in 70 % of the cases, there was no longer a perfusion in the aneurysm sac and the sac diameter was stable or had decreased [17]. Torres-Blanco et al. describe a direct access to the aneurysm sac via puncture between the iliac limb of the prosthesis and the arterial wall. Through a femoral retrograde approach the attachment site of the endograft was found and locating a cranny between the iliac prosthesis and the arterial wall was attempted. Via this cranny, it was possible to access the aneurysm sac with a wire and a catheter and a coil embolization and thrombin injection was performed [18]. In our case, using the method of perforation of the iliac endoprosthesis leg with a laser appears to be technically easier than the method used by Torres-Blanco. To find a cranny between the endograft and the arterial wall seems to be difficult and time-consuming. Our first attempt of © 2017 Hogrefe

T. Boehme et al., Transprosthesial endoleak embolization

embolization was not successful because the endoleak was not retrogradely reachable via the lumbar arteries using the available catheters. The transprosthesial laser-assisted direct access to the aneurysm sac was easily possible via transfemoral puncture. This made a transprosthesial coil embolization combined with thrombin injection into the aneurysm sac possible. Perforation of the iliac endoprosthesis leg with a laser is a feasible method to reach the aneurysm sac directly.

Conclusions Due to the demographic trend, EVAR will be increasingly often performed in the future. Hence, it is important to reduce the frequency of endoleaks and if they occur, they should be resolved endovascularly. Whether it is possible to find the gold standard treatment of endoleaks type II is not certain, as the treatment has to be adapted to the anatomy of each individual patient. However, perforation of the iliac endoprosthesis leg with a laser appears to be a good method to reach the aneurysm sac directly. Nevertheless, more studies will be necessary to compare different techniques and embolic agents for treatment of endoleaks type II.

References 1. Nowygrod R, Egorova N, Greco G, Anderson P, Gelijns A, Moskowitz A, et al. Trends, complications, and mortality in peripheral vascular surgery. J Vasc Surg 2006;43(2):205–16. 2. Schermerhorn M, Bensley R, Giles K, Hurks R, O’Malley A, Cotterill P, et al. Changes in Abdominal Aortic Aneurysm Rupture and Short-Term Mortality, 1995–2008. Ann Surg 2012;256(4):651–8. 3. Schanzer A, Greenberg R, Hevelone N, Robinson W, Eslami M, Goldberg R, et al. Predictors of Abdominal Aortic Aneurysm Sac Enlargement After Endovascular Repair. Circulation 2011;123 (24):2848–55. 4. Heye S. Diagnosis and treatment of endoleaks after endovascular repair of thoracic and abdominal aortic aneurysms. JBRBTR 2013;96(4):189. 5. Lal B, Zhou W, Li Z, Kyriakides T, Matsumura J, Lederle F, et al. Predictors and outcomes of endoleaks in the Veterans Affairs Open Versus Endovascular Repair (OVER) Trial of Abdominal Aortic Aneurysms. J Vasc Surg 2015;62(6):1394–404. 6. Parodi J, Palmaz J, Barone H. Transfemoral Intraluminal Graft Implantation for Abdominal Aortic Aneurysms. Ann Vasc Surg 1991;5(6):491–9.

7. Zammert M, Gelman S. The pathophysiology of aortic crossclamping. Best Pract Res Clin Anaesthesiol 2016;30(3):257–69. 8. Endovascular versus Open Repair of Abdominal Aortic Aneurysm. N Engl J Med 2010;362(20):1863–71. 9. de Bruin J, Baas A, Buth J, Prinssen M, Verhoeven E, Cuypers P, et al. Long-Term Outcome of Open or Endovascular Repair of Abdominal Aortic Aneurysm. N Engl J Med 2010;362(20):1881–9. 10. Lederle FA, Freischlag JA, Kyriakides TC, Padberg FT, Matsumura JS, Kohler TR, et al. Outcomes Following Endovascular vs Open Repair of Abdominal Aortic Aneurysm: A Randomized Trial. JAMA. 2009;302(14):1535–42. 11. Veith F, Baum R, Ohki T, Amor M, Adiseshiah M, Blankensteijn J, et al. Nature and signiﬁcance of endoleaks and endotension: Summary of opinions expressed at an international conference. J Vasc Surg 2002;35(5):1029–35. 12. Baum R, Carpenter J, Golden M, Velazquez O, Clark T, Stavropoulous S, et al. Treatment of type 2 endoleaks after endovascular repair of abdominal aortic aneurysms: Comparison of transarterial and translumbar techniques. J Vasc Surg 2002; 35(1):23–9. 13. Nevala T, Biancari F, Manninen H, Aho P, Matsi P, Mäkinen K, et al. Type II Endoleak After Endovascular Repair of Abdominal Aortic Aneurysm: Effectiveness of Embolization. Cardiovasc Intervent Radiol 2010;33(2):278–84. 14. Sidloff D, Stather P, Choke E, Bown M, Sayers R. Type II endoleak after endovascular aneurysm repair. Br J Surg 2013;100(10): 1262–70. 15. Kasirajan K, Matteson B, Marek J, Langsfeld M. Technique and results of transfemoral superselective coil embolization of type II lumbar endoleak. J Vasc Surg 2003;38(1):61–6. 16. Mansueto G, Cenzi D, Scuro A, Gottin L, Griso A, Gumbs A, et al. Treatment of type II endoleak with a transcatheter transcaval approach: Results at 1-year follow-up. J Vasc Surg 2007;45(6): 1120–7. 17. Giles K, Fillinger M, De Martino R, Hoel A, Powell R, Walsh D. Results of transcaval embolization for sac expansion from type II endoleaks after endovascular aneurysm repair. J Vasc Surg 2015;61(5):1129–36. 18. Torres-Blanco Á, Schmidt A, Gómez-Palonés F, Ortiz-Monzón E. The Roadside Technique for Type II Endoleak Embolization 4 Years after Endovascular Aortic Aneurysm Repair. Ann Vasc Surg 2015;29(4):837.e13–837.e16.

Submitted: 26.02.2017 Accepted after revision: 08.05.2017 There are no conﬂicts of interest existing. Published online: 08.08.2017

Correspondence address Tanja Boehme, M.D. Angiology Universitaets-Herzzentrum Bad Krozingen Suedring 15 79189 Bad Krozingen Germany tanja.boehme@universitaets-herzzentrum.de

Vasa (2018), 46 (6), 63–67

Journal club

Drug coated ballons for femoro-popliteal interventions Interventional treatment of femoropopliteal arteries is challenging, as the superficial femoral artery is at high risk of restenosis. In previous publications, drug-coated balloons showed significant reduction of late-lumen loss, for example in the THUNDER-Study in 2008 [1]. The ILLUMENATE Study, a multi-centre, single-blind, randomized controlled study investigated 12-month outcomes of the Stellarex low-dose paclitaxel drug-coated balloon in comparison with conventional PTA (uncoated balloon angioplasty) between 2013 and 2015 [2]. In this study, 300 symptomatic patients with peripheral artery disease were randomized, either assigned to drug-coated balloon (DCB) treatment or PTA. The study population had presented with leg claudication, i. e. a Rutherford class 2–4, an angiographic evidence of 70–99 % stenosis or a chronic total occlusions between 30 and 180 mm length, within the superficial femoral or popliteal artery. Mean lesion length was 7.2 and 7.1 cm, with 19.2 and 19 % total occlusions. An angiography with pre-dilatation and a standard PTA balloon was performed, thereafter patients were randomized in a 3:1 ratio; 200 patients were treated with the DCB, 100 patients had a second PTA. The balloon inflation times per lesion were 3.9 ± 2.0 Minutes in the DCB group and 3.7 ± 2.3 Minutes in the PTA group. The primary safety endpoint was a composite of freedom from device- and procedure-related death through 30 days and freedom from target limb major amputation and clinically driven target lesion revascularization within the 12-month follow-up. The primary effectiveness endpoint was primary patency at 12 months. Looking at safety outcomes, the DCB was non-inferior to PTA. Primary effectiveness endpoint was met as well. DCB was superior to PTA. DCB showed a significantly higher primary patency rate with 82.3 and 70.9 % in the PTA group (p = 0.002), estimated per Kaplan-Meier method through the full 12 months of follow-up. Freedom from CD-TLR per Kaplan-Meier estimates was significantly higher in the DCB group with 93.6 vs. 87.3 % in the PTA group (p = 0.025). In the discussion, the ILLUMENATE study suggests superiority in safety and effectiveness of the Stellarex drugeluting balloon in comparison with conventional PTA. The authors admit that the higher number, almost double amount, of restenosis lesions in the PTA group may have had an impact on the results (9.5 % in the DCB and 18.0 % in the PTA group). Furthermore, the spread of the dilatation times as well as the exact modalities during pre-dilatation may have afVasa (2018), 47 (1), 68–69 https://doi.org/10.1024/0301-1526/a000674

fected the measured endpoints. Concerning the necessity of pre-dilatation in revascularization with drug-eluting balloons, Schroeder et al. published a pilot study regarding this question [3]. The study had the objective to compare two-year outcomes of patients who underwent predilatation prior to DCB angioplasty with those who were treated directly with a DCB balloon. The summarized results showed lumen loss at six months to be lower in the predilatation group (0.03 ± 0.68 mm vs. 0.54 ± 0,97 mm) at similar rates of major adverse effects (15 % in predilatation vs. 19 % in the direct DCB group) and primary patency over two years (80.3 vs. 78.2 %). In the case in Schroeder’s study, dilatation times were specified to a minimum of one minute, whereas the ILLUMINATE study did not specify a minimum dilatation time. Another drug-coated balloon was already presented in the LEVANT 2 trial in 2015 [4], in which patients with comparable baseline characteristics where included and after predilatation were randomized to either treatment with the Lutonix drug-coated balloon or conventional PTA. In the results, the Lutonix group showed a primary patency rate, estimated with Kaplan-Meier survival analysis, of 73.5 and 56.8 % in the conventional PTA group at 12 months. Also, the composite safety endpoint, consisting of freedom from perioperative death and from limp-amputation, index-limb reintervention, and index-limb related death, showed a non-inferiority of the drug-coated balloon (83.9 % in the Lutonix vs. 79.0 % in the conventional PTA group). When comparing the results of the ILLUMINATE with the LEVANT 2 trial, a 12 months primary patency of 82.3 % in the Stellarex group and 83.9 % in the Lutonix group is observable. Although both studies showed superiority of drug-coated balloons in terms of technical endpoints, it is striking that one of the most important goals of interventions, for example improvement in quality of life, showed no difference in drug-coated balloons compared to conventional PTA in both the ILLUMENATE and the LEVANT study. One study that showed inferior results, when compared to the previously described drug-coated balloons, was the BIOLUX P-II trial [8], a prospective, multicentre, randomized first-in-man study with a total of 72 patients, who were randomized 1:1, assigned to either a Passeo-18 LUX drug-coated balloon or conventional PTA. The primary performance endpoint was six-month target lesion primary patency. At 12 months, a patency loss occurred in 50.8 % in the drug-coated balloon group; 41.1 % of the patients © 2018 Hogrefe

Journal club

experienced a major adverse event with a major amputation rate of 3.3 %, which is high compared with the safety endpoints of the mentioned studies. In total, the authors concluded that there was no superiority in either safety- or performance-endpoints of the drug-coated balloon compared to conventional PTA. The authors justify the results with the smallest vessel diameter compared to similar studies (2.3 mm vs. 2.5 to 2.9 mm), which evokes the question, whether the use of drug-coated balloons has limitations in safety and efficacy when performed on small vessels, for example in below-the-knee lesions. In the recently issued guidelines of the European Society of Cardiology (ESC-Guidelines [5]), drug-coated balloons are mentioned for the first time as a recommendation for revascularization of femoropopliteal occlusive lesions with a class of recommendation of IIB and an A level of evidence in short (< 2 5 mm) lesions, and with a B level of evidence in the treatment of in-stent restenosis, as they proved to meet the requirements for long-term patency improvements in the very mobile femoropopliteal region. Regarding the improvement of the long-term patency, the recommendations are also supported by the results of the IN.PACT SFA study [6], a prospective, multicentre, multinational, randomized trial with the goal of investigating the longer term outcomes of drug-coated balloons compared to conventional PTA. Like the previously mentioned studies, superiority in primary patency rates was shown for the drug-coated balloon group (78.9 vs. 50.1 % in the conventional PTA group), but no change was found with regard to quality of life. Nonetheless, it should be acknowledged that, when comparing the twoyear results of the IN.PACT study with the 12-month patency rates of the ILLUMENATE and LEVANT 2 trial, although there was one year of difference between the final follow-ups, the patency rates do not seem to decrease significantly. The data are also supported by the results of the two-year results of a real-world registry, published in 2016 [9]. In the study, 288 limbs treated either with the IN.PACT Pacific or Admiral DCB were retrospectively analysed with up to two years of follow-up. Kaplan-Meier estimates of primary patency were 79.2 ± 2.6 % at one year and 53.7 ± 3.4 % at two years for the entire cohort. It should be acknowledged that the mean lesion length was 24.0 ± 10.2 cm and 65.3 % were total occlusions. Furthermore, two-thirds of the treated lesions were classified as TASC D (Trans-Atlantic Intersociety Consensus), which surely had an impact on the primary patency rate for the two-year follow-up. So the results suggest that drug-coated balloons are effective in delaying rather than preventing restenosis in long, complex lesions and restenosis of the femoropopliteal vessels. Although the described trials suggest good patency rates for up to two years, there are still questions that

need to be answered in regard to drug-eluting balloons. Besides one of the most important questions, whether an improvement in quality of life and walking impairment can truly be achieved, long-term patency rates above the two-year mark must still be attended. Another important question is, whether the use of drug-coated balloons can improve the outcome of below-the-knee revascularization, which imposes another difficult task in endovascular treatment of PAD, especially in patients with diabetes and/or chronic kidney disease as well as with a high level of lesion calcification. Regarding the last question, the actual guidelines of the German Society of Angiology [7] recommend primarily an endovascular approach in general for critical limb ischaemia in the infrapopliteal region, without primary stent implantation. On top of that, the advantage of drug-coated balloons has yet to be evaluated in its entirety.

References 1. Tepe G et al. Local Delivery of Paclitaxel to Inhibit Restenosis during Angioplasty of the Leg. N Engl J Med. 2008;358: 689–99. 2. Krishnan P et al. Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies. Circulation. 2017;136:1102–13. 3. Schroeder H et al. A Pilot Study of Femoropopliteal Artery Revascularisation with a Low Dose Paclitaxel Coated Balloon: Is Predilatation Necessary? Eur J Vasc Endovasc Surg. 2017;54: 348–55. 4. Rosenﬁeld K et al. Trial of a Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease. N Engl J Med. 2015;373:145–53. 5. Aboyans V et al. 2017 ESC Guidelines on the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). Eur Heart J. 2017:doi: 10.1093/eurheartj/ehx095. 6. Laird J et al. Durability of Treatment Effect Using a Drug-Coated Balloon for Femoropopliteal Lesions 24-Month Results of IN.PACT SFA. J Am Coll Cardiol 2015; 66 (21): 2329–38. 7. Lawall et al. German guideline on the diagnosis and treatment of peripheral artery disease – a comprehensive update 2016. Vasa. 2017;46(2):78–86. 8. Zeller T, et al. Paclitaxel-Coated Balloon in Infrapopliteal Arteries: 12-Month Results From the BIOLUX P-II Randomized Trial. JACC Cardiovasc Interv. 2015;8(12):1614–22. 9. Schmidt A et al. J Drug-Coated Balloons for Complex Femoropopliteal Lesions, 2-year results of a Real-world Registry. JACC: Cardiovsc Interv. 2016;9(7):715–24.

Correspondence address Luca Tamburrini, Markus Vosseler, and Christine Espinola-Klein Section of Angiology, Center of Cardiology – Cardiology I University Medical Center of the Johannes Gutenberg University Mainz, Germany luca.tamburrini@unimedizin-mainz.de

Vasa (2018), 47 (1), 68–69

DGA vergibt wissenschaftliche Preise Im Rahmen der 46. Jahrestagung der Deutschen Gesellschaft für Angiologie ehrte die DGA Wissenschaftler für ihre herausragenden Arbeiten auf dem Gebiet der Angiologie. Am 13. September 2017 überreichte in Berlin Prof. Dr. Ulrich Hoffmann, Präsident der DGA, den Promotionspreis, den CLI-Preis und den Young Investigator Award (YIA) und würdigte so die Leistungen der Wissenschaftler auf dem Gebiet der Gefäßmedizin. Mit dem Promotionspreis und dem YIA wird der angiologische Nachwuchs unterstützt und gefördert, was der Fachgesellschaft ein besonders wichtiges Anliegen ist.

CLI-Preis für Dr. Eva Freisinger Dr. Eva Freisinger, tätig im Department für Kardiologie und Angiologie des Universitätsklinikums Münster, erhielt den mit 5.000 Euro dotierten CLI-Preis. Mit diesem von der Fa. medac GmbH unterstützten Preis wird eine Persönlichkeit geehrt, die herausragende Forschungsarbeit zu Diagnostik und Therapie der kritischen Extremitätenischämie und/ oder dem angio(neuro)pathischen diabetischen Fußsyndrom geleistet hat:

From the societies

“Impact of diabetes on outcome in critical limb Ischemia with tissue loss – a large scaled routine data analysis” Patients with diabetes concomitant to critical limb ischemia (CLI) represent a sub-group at particular risk. Objective of this analysis is to evaluate the actual impact of diabetes on treatment, outcome, and costs in a real-world scenario in Germany. We obtained routine-data on 15,332 patients with CLI with tissue loss from the largest German health insurance, BARMER GEK from 2009 to 2011, including a follow-up until 2013. Patient data were analyzed regarding codiagnosis with diabetes with respect to risk profiles, treatment strategy, in-hospital and longterm outcome including costs. Diabetic patients received less overall revascularizations in Rutherford grades 5 and 6 (Rutherford grade 5: 45.0 vs. 55.5 %; Rutherford grade 6: 46.5 vs. 51.8; p < 0.001) and less vascular surgery (Rutherford grade 5: 13.4 vs. 23.4; Rutherford grade 6: 19.7 vs. 29.6; p < 0.001), however more often endovascular revascularization in Rutherford grade 6 (31.0 vs. Diabetes was associated with a higher observed ratio of infections (35.3 vs. 23.5 % Rutherford grade 5; 44.3 vs. 27.4 % Rutherford grade 6; p < 0.001) and in-hospital amputations (13.0 vs. 7.3 % Rutherford grade 5; 47.5 vs. 36.7 % Ruth6; p < 0.001). Diabetes further increased the risk for amputation during follow-up [Rutherford grade 5: HR 1.51 (1.38–1.67); Rutherford grade 6: HR 1.33 (1.25– 1.41); p < 0.001], but not for death. Diabetes increases markedly the risk of amputation attended by higher costs in CLI patients with tissue loss (OR 1.67 at Rutherford 5, OR 1.53 at Rutherford 6; p < 0.001), but is associated with lower revascularizations. However, in Rutherford grades 5 and 6, concomitant diabetes does not further worsen the overall poor survival.

Promotionspreis geht an Dr. Dr. Christoph Leib Dr. Dr. Christoph Leib aus dem St. Claraspital in Basel gewann den DGA-Promotionspreis. Der Preis ist mit 2.500 Euro dotiert und würdigt die wissenschaftliche Arbeit:

Elke Patelschick, Eva Freisinger, Ulrich Hoffmann.

Vasa (2018), 47 (1), 70–72

“Protective role of regulatory B-cells in atherosclerosis” B-cells are part of the adaptive immune system. Their regulatory functions in many immune diseases are poorly understood. The existence of regulatory B-cells (Bregs) as an anti-inflammatory component of the immune system has recently emerged. Autoimmune mechanisms play a major role in the pathophysiology of atherosclerosis. Knowledge on Bregs’ potential atheroprotective effects in atherosclerosis is very rare. In this project, we could show that a distinct subset of Bregs exerts atheroprotection in an experimental setting of atherosclerosis. In a first step, marginal zone B2-B cells have been isolated from recipients using FACS technique and have been subsequently stimulated with an agonistic αCD40-antibody in vitro. αCD40 stimu© 2018 Hogrefe

From the societies

Christoph Leib, Ulrich Hoffmann.

lation expanded Bregs with phenotype CD21(hi)CD23(hi) CD24(hi) and significantly increased the production of the anti-inflammatory cytokine Interleukin-10 (IL-10) in this Breg subset. In a second step, a potential atheroprotective effect of regulatory marginal zone B2-B-cells has been studied. For this purpose, total αCD40 stimulated B2-Bcells have been adoptively transferred into recipients, which had undergone carotid collar surgery in order to induce experimental atherosclerosis. Adoptive transfer significantly reduced neointima formation in recipients. Furthermore, adoptive transfer significantly increased numbers of anti-inflammatory T1-regulatory (Tr1) cells in the suprailiacal lymph nodes in recipients. The results in this project show for the first time that IL10 producing regulatory B-cells with phenotype CD21(hi) CD23(hi)CD24(hi) expand upon αCD40 stimulation in vitro. Those Bregs were shown to be atheroprotective in experimental atherosclerosis in vivo. Targeted cellular immune therapy might be a promising therapeutic tool for the treatment of atherosclerosis in the future.

angiotensin II – induced renal interstitial fibrosis and vascular oxidative stress. The current study was designed to test the hypothesis that transgenic overexpression of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Methods and results: DDAH1 transgenic (TG) mice grew and bred normally, did not manifest any obvious physical abnormalities and had decreased plasma ADMA levels. Angiotensin II was infused for four weeks in the dose of 0.75 mg/kg/day in DDAH1 transgenic mice and wild type littermates via osmotic minipumps. Echocardiography was performed in the first and fourth week after start of the infusion on anaesthetized mice. After 4 weeks of angiotensin II infusion wild type mice developed cardiac hypertrophy. The DDAH1 transgenic mice had significantly greater left ventricular lumen to wall ratio and significantly smaller collagen area in the aorta and aorta’s wall thickness compared to the wild type mice. They also had lower left ventricular posterior wall thickness in systole and diastole as compared to the wild type controls (1.18 ± 0.03 mm vs 1.95 ± 0.16 mm, P < 0.001 and 0.81 ± 0.03 mm vs 1.62 ± 0.25 mm, P < 0.001, respectively). Systolic blood pressure was lower in the transgenic mice and vasomotor function of aortic rings in response to acetylcholine was improved as compared to the wild type littermates.

Natalia Jarzębska.

Conclusions: We demonstrated that upregulation of DDAH1 protects from angiotensin II-induced cardiac hypertrophy. Our findings suggest that ADMA plays a role in angiotensin II – induced myocardial remodeling. Upregulation of DDAH1 might be a potential approach for protection from angiotensin II – induced end organ damage.

Young Investigator Award (YIA) geht an Natalia Jarzębska Mit dem YIA wird die beste Abstracteinreichung eines jungen Wissenschaftlers unter 35 Jahren ausgezeichnet. Bei der Preisträgersitzung zeichnete die Jury die Arbeit von Natalia Jarzębska aus dem Universitätsklinikum Dresden aus: Transgenic overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II – induced cardiac hypertrophy Background: ADMA (asymmetric dimethylarginine) is an endogenous inhibitor of nitric oxide synthase. One of degradation pathways of ADMA is metabolism to citrulline by dimethylarginine dimethylaminohydrolase (DDAH). DDAH1 overexpression lowers ADMA and protects from © 2018 Hogrefe

Deutsche Gesellschaft für Angiologie vergibt erneut den DGA-Journalistenpreis Die Deutsche Gesellschaft für Angiologie – Gesellschaft für Gefäßmedizin e. V. hat bei ihrer 46. Jahrestagung in Berlin zum dritten Mal den DGA-Journalistenpreis verliehen. Ausgezeichnet wurden Beiträge, die anschaulich und kompetent formuliert über Gefäßerkrankungen, deren Prävention, Verbreitung, Behandlung, Nachsorge und Folgen berichten. Der Preis wurde in den Kategorien Print/ Online sowie Hörfunk/TV vergeben und ist mit jeweils 2.000 Euro dotiert. Vasa (2018), 47 (1), 70–72

Der Preis in der Kategorie Hörfunk/TV wurde geteilt: Mit dem Beitrag „Thrombektomie – Die ‚Revolution‘ in der Schlaganfall-Therapie“ gehen Gabi Delingat und Claudia Bohm von service: gesundheit des Hessischen Rundfunks einer neuartigen und effektiven Therapie für Gefäßpatienten nach. Die Redaktion hat ein innovatives Thema aufgegriffen, dieses sehr gut recherchiert und damit ein beeindruckendes, umfassendes und verständliches Portrait der Therapiebandbreite von Gefäßverschlüssen gezeichnet. Jutta Rosbach, Redaktion „Visite“ vom Norddeutschen Rundfunk, hat in ihrem Beitrag ein Nischenthema, die chronischen und genetisch bedingten Thrombosen, aufgegriffen und beleuchtet eine Langzeittherapie durch direkt orale Anikoagulatien. Der Beitrag besticht durch die aufwendige Recherchearbeit und eine starke Wort-BildSprache. Dr. Nicola von Lutterotti erhielt in Abwesenheit den Preis in der Kategorie Print für den in der Frankfurter Allgemeinen Zeitung erschienenen Artikel „Wenn es den Beinen an Sauerstoff mangelt“. In dem hervorragend recherchierten Beitrag wirft die Autorin die Frage auf, wie viele der Ampu-

Vasa (2018), 47 (1), 70–72

From the societies

Claudia Bohm, Ulrich Hoffmann, Jutta Rosbach.

tationen dank einer adäquaten Diagnostik und Therapie zu verhindern wären und beschreibt altbewährte sowie innovative nicht invasive Therapieverfahren.

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