Vas 2016 45 issue 1 by Hogrefe

Volume 45 / Number 1 / 2016

Internationale Zusammenarbeit für die Gesundheit

Volume 45 / Number 1 / 2016

Vasa European Journal of Vascular Medicine

Oliver Razum et al. (Hrsg.)

Global Health Gesundheit und Gerechtigkeit 2014. 288 S., 22 Abb., 12 Tab., Kt € 39.95 / CHF 53.90 ISBN 978-3-456-85434-2 AUCH ALS E-BOOK

Dazu gehören

auf die wirtschaftliche, politische und

• die Identiﬁzierung prioritärer Gesund-

soziale Situation der Menschen werden breit diskutiert. Die Globalisierung birgt

• Hintergründe, Inhalt und Relevanz glo-

große Risiken, aber auch Chancen für

baler Vereinbarungen wie der Millenni-

die Gesundheit und die gesundheitliche

um-Entwicklungsziele

Versorgung. Betroffen sind alle Menschen, sowohl in den ärmeren Ländern des Südens als auch in den reichen Industrienationen wie Deutschland. Eine internationale Perspektive wird daher immer wichtiger. Ausgehend von Fragen der Verteilungsgerechtigkeit und anderer «klassischer» Herausforderungen an Public Health behandelt dieser Band eine Vielzahl von Themen.

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heitsprobleme

• die Ausbreitung alter und neuer Infektionskrankheiten • die Diskussion von Lösungsstrategien für globale Gesundheitsprobleme • die Bedeutung von weltweiten Katastrophen und Terrorismus.

Vasa

Die Auswirkungen der Globalisierung

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

Thrombosemanagement, das den Unterschied macht !

Einfach im Alltag Effektiv* in der Wirkung Sicher* in der Anwendung

Herausforderungen des Alterns meistern Einfach. Effektiv. Sicher. * Turpie AGG, Bauer KA, Eriksson BI et al. Arch Intern Med 2002; 162: 1833–1840 ARIXTRA® 1,5 mg/0,3 ml Injektionslösung, Fertigspritze. ARIXTRA® 2,5 mg/0,5 ml Injektionslösung, Fertigspritze. ARIXTRA® 5 mg/0,4 ml Injektionslösung, Fertigspritze. ARIXTRA® 7,5 mg/0,6 ml Injektionslösung, Fertigspritze. ARIXTRA® 10 mg/0,8 ml Injektionslösung, Fertigspritze. Wirkstoff: Fondaparinux-Natrium. Zusammensetzung: Fertigspritzen enthalten Fondaparinux-Natrium 1,5 mg/0,3 ml, 2,5 mg/0,5 ml, 5 mg/0,4 ml, 7,5 mg/0,6 ml und 10 mg/0,8 ml. Sonstige Bestandteile: Natriumchlorid, Wasser für Injektionszwecke, Salzsäure, Natriumhydroxid. Anwendungsgebiete 1,5 und 2,5 mg: Zur Prophylaxe venöser thromboembolischer Ereignisse (VTE) bei Erwachsenen, die sich größeren orthopädischen Eingriffen an den unteren Extremitäten unterziehen müssen, wie beispielsweise Hüftfrakturen, größere Knie- oder Hüftersatzoperationen, sowie bei Erwachsenen, die sich abdominalen Eingriffen unterziehen müssen und voraussichtlich einem hohen Risiko thromboembolischer Komplikationen ausgesetzt sind, wie beispielsweise bei einer abdominalen Krebsoperation, sowie bei erwachsenen internistischen Patienten mit einem erhöhten Risiko für VTE und bei Immobilisation wegen einer akuten Erkrankung wie beispielsweise Herzinsuffizienz und/oder akuter Atemwegserkrankung und/oder akuter infektiöser oder entzündlicher Erkrankung. Therapie akuter, symptomatischer, spontaner, oberflächlicher Venenthrombosen (OVT) der unteren Extremitäten ohne begleitende tiefe Venenthrombose bei Erwachsenen. Anwendungsgebiete 2,5 mg: Behandlung der instabilen Angina pectoris oder des Myokardinfarkts ohne ST-Strecken-Hebung (IA/NSTEMI) bei Erwachsenen, bei denen ein dringender (<120 min) invasiver Eingriff (PCI) nicht angezeigt ist sowie Behandlung des Myokardinfarkts mit ST-Strecken-Hebung (STEMI) bei Erwachsenen, die mit Thrombolytika behandelt werden oder die initial keine andere Form einer Reperfusionstherapie erhalten. Anwendungsgebiete 5 mg, 7,5 mg, 10 mg: Therapie von Erwachsenen mit tiefen Venenthrombosen (TVT). Therapie von Lungenembolien (LE), außer bei hämodynamisch instabilen Patienten oder Patienten, die einer Thrombolyse oder einer pulmonalen Embolektomie bedürfen. Gegenanzeigen: Bekannte Überempfindlichkeit gegenüber Fondaparinux oder einem der sonstigen Bestandteile, aktive klinisch relevante Blutungen; akute bakterielle Endokarditis; schwere Nierenfunktionsstörungen (VTE-Prophylaxe, Therapie von OVT, IA/NSTEMI und STEMI: Kreatinin-Clearance < 20 ml/min; Therapie von TVT und LE: Kreatinin-Clearance < 30 ml/min). Nebenwirkungen operativer Bereich: Häufig (≥ 1% < 10 %): postoperative Blutungen, Anämie. Gelegentlich (≥ 0,1 % < 1 %): Blutungen (Epistaxis, gastrointestinale Blutungen, Hämoptysen, Hämaturie, Hämatome), Thrombozytopenie, Purpura, Thrombozythämie, veränderte Blutplättchen, Gerinnungsstörungen, Übelkeit, Erbrechen, erhöhte Leberenzyme, Leberfunktionsstörung, Rash, Pruritus, Ödeme, periphere Ödeme, Fieber, Wundsekretion. Selten (≥ 0,01 % < 0,1 %): postoperative Wundinfektionen, allergische Reaktionen, Hypokaliämie, Ängstlichkeit, Somnolenz, Schwindel, Benommenheit, Kopfschmerz, Verwirrung, Blutdruckabfall, Dyspnoe, Husten, Bauchschmerzen, Dyspepsie, Gastritis, Verstopfung, Diarrhö, Hyperbilirubinämie, Brustschmerzen, Müdigkeit, Hitzewallungen, Beinschmerzen, Genitalödeme, Erröten, Synkope. Nebenwirkungen internistische Patienten: Häufig (≥ 1% < 10 %): Blutungen (Hämatome, Hämaturie, Hämoptysis, Zahnfleischblutungen). Gelegentlich (≥ 0,1 % < 1 %): Anämie, Dyspnoe, Rash, Pruritus, Brustschmerzen. Seit Markteinführung bzw. in anderen Studien seltene Fälle von intrakraniellen/intrazerebralen und retroperitonealen Blutungen berichtet. Nebenwirkungen in der Therapie akuter Koronarsyndrome (ACS): konsistent mit Nebenwirkungen in der VTE-Prophylaxe; Nebenwirkungen VTE-Therapie: Häufig (≥ 1% < 10 %): Blutungen (gastrointestinal, Hämaturie, Hämatome, Nasenbluten, Hämoptyse, utero-vaginale Blutungen, Hämarthrose, okular, Purpura, Hautunterblutung). Gelegentlich (≥ 0,1 % < 1 %): Anämie, Thrombozytopenie, Kopfschmerz, Übelkeit, Erbrechen, Leberfunktionsstörung, Schmerzen, Ödeme. Selten (≥ 0,01 % < 0,1 %): andere Blutungen (hepatisch, retroperitoneal, intrakraniell/intracerebral), Thrombozythämie, Allergische Reaktion, Erhöhung der nicht-eiweißgebundenen Stickstoffanteile (Npn)2, Benommenheit, erythematöser Hautausschlag, Reaktionen an der Injektionsstelle. Verschreibungspflichtig. Stand: Dezember 2011. Aspen Germany GmbH, Montgelasstraße 14, 81679 München. www.aspenpharma.com

Klaus Müller

Alternde Bevölkerung und gesundheitliche Versorgung Zehn Herausforderungen und ihre Konsequenzen für Prävention, Rehabilitation und das Versorgungsmanagement in Deutschland und der Schweiz

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Vasa

European Journal of Vascular Medicine

Volume 45 / Issue 1/2016

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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Contents Editorial

Ankle-brachial index measurement: Skill cannot be taken for granted

Ludwig Caspary 7

Endovascular-first strategy for acute and subacute limb ischaemia: Potential benefits of a pure mechanical thrombectomy approach Michael K.W. Lichtenberg, Wilhelm Friedrich Stahlhoff Reviews

Gender differences in patients with carotid stenosis Konstanze Stoberock, Eike Sebastian Debus, Atlihan Gülsen, Daum Günther, Axel Larena-Avellaneda, Sandra Eifert, Sabine Wipper

Inflammatory diseases of the aorta Ludwig Caspary Original communications

Predicting the prevalence of peripheral arterial diseases: modelling and validation in different cohorts

Yiqiang Zhan, Jie Zhuang, Ying Dong, Hong Xu, Dayi Hu, Jinming Yu 37

Knowledge about ankle brachial index procedure among residents: being experienced is beneficial but is not enough Ségolène Chaudru, Pierre-Yves de Müllenheim, Alexis Le Faucheur, Vincent Jaquinandi, Adrien Kaladji, Guillaume Mahe Accuracy of in-patients ankle-brachial index measurement by medical students

Matteo Monti, Luca Calanca, Adriano Alatri, Lucia Mazzolai Percutaneous mechanical thrombectomy in the treatment of acute and subacute occlusions of the peripheral arteries and bypasses

Frantisek Stanek, Radoslava Ouhrabkova, David Prochazka Paroxysmal finger haematoma – a benign acrosyndrome occurring in middle-aged women

Patrick H. Carpentier, Hildegard R. Maricq, Christine Biro, Myriam Jiguet, Christophe Seinturier Risk factors for superficial vein thrombosis in patients with primary chronic venous disease

Dalibor Musil, Marketa Kaletova, Jiri Herman Case report

Coil embolization of a posterior circumflex humeral aneurysm in a volleyball player

Mary Tao, Naomi Eisenberg, Jeff Jaskolka, Graham Roche-Nagle Journal club

From the societies

Vasa (2016), 45(1), 3

Aktuelle Übersicht zum Schweizer Gesundheitswesen Willy Oggier (Hrsg.)

Gesundheitswesen Schweiz 2015–2017 Eine aktuelle Übersicht

in Auch cher i ös s : franz erhältlich e h 6 c 5 a 4 Spr 978-3 ISBN 5552-3 8

5., vollst. überarb. Auﬂ. 2015. 488 S., 85 Abb., 129 Tab., Gb € 29.95 / CHF 39.90 ISBN 978-3-456-85441-0 AUCH ALS E-BOOK

Das Schweizer Gesundheitswesen ist komplex und im Umbruch. Reformversuche und Sparmassnahmen jagen sich, oft ohne klare Ziele und ohne Koordination. Gesundheitspolitik ist seit Jahren ein heissumstrittener und komplexer Politikbereich – mit ideologischen Polemiken und starken Interessengruppen. In einer solchen Lage ist Transparenz wichtig. Dieses Buch ist das Standardwerk über das schweizerische Gesundheitswesen. Es gibt eine aktuelle und sachliche Gesamtübersicht in 39 Kapiteln von 61 Autorinnen und Autoren, wobei besonderer Wert gelegt wurde auf möglichst hohe Objektivität, aussagekräftige Daten und

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auf gute Lesbarkeit. Gegenüber der 4. Auﬂage 2010 wurde es vollständig überarbeitet, erweitert und aktualisiert. Das Buch ist ein Nachschlagewerk für alle, die sich für das Gesundheitssystem und die Gesundheitspolitik interessieren: Fachleute aus dem Gesundheitswesen und den Sozialversicherungen, für Politik, Medien und Wissenschaft und selbstverständlich auch für interessierte Versicherte und Patientinnen/Patienten. Besonders geeignet ist es auch als Lehrmittel in den verschiedenen Aus-, Weiter- und Fortbildungsgängen im Gesundheits-, Sozial- und Versicherungswesen.

Editorial

Ankle-brachial index measurement: Skill cannot be taken for granted Comment on Chaudru et al, p. 37 – 41 and Monti et al, p. 43 – 48 Ludwig Caspary Angiologische Praxis Luisenstraße, Gefäßzentrum Klinikum Hannover, Germany

Doppler measurement of ankle artery pressures and the respective calculation of the ankle-brachial index (ABI) is a principal element of vascular diagnostic. Knowledge about its performance and interpretation is obvious for the vascular specialist but likewise important for the general practitioner, even if not performing it. The paper of Chaudru et al. [1] evaluates the theoretical knowledge about this technique among residents of 6 French medical schools, based on a questionnaire. The somewhat disconcerting message of the paper is that, with the current academic training method, none of the postgraduates in the departments of cardiology and vascular medicine answered correctly to all of the five questions. If residents who already had performed more than 20 measurements were compared to those with less ore none experience, they achieved a higher score but nevertheless were not correct in all points. Some wrong answers are explainable by features of the national health system. The questions were based on the recommendations of the American Heart Association [2]. While these are referring to the pressure determination just in the anterior and posterior tibial artery, the French reimbursement system requires pressure measurement in the fibular artery, too. The use of automatic devices, though not approved in the recommendations mentioned above, might be acceptable at least for the part of pressure determination in the arm; this procedure obviously is common in French teaching hospitals being time-saving. But even if these inaccuracies and the misclassification of an ABI of 0.6 to represent severe ischemia were disregarded, only a quarter of residents proved complete theoretical knowledge concerning the ABI. The paper of Monti et al. [3] deals with the practical knowledge of ABI measurement, acquired by twelve 6th year medical students during a nine-day training unit. The form of training corresponded to the proposals of the American Heart Association [2]. Subsequently, in 116 legs of 59 patients ABI was determined independently by stuVasa (2016), 45 (1), 5 – 6 DOI 10.1024/0301-1526/a000488

dents and an experienced angiologist whose measurements were taken as reference. According to the latter, 72 measurements resulted in a normal ABI between 0.9 and 1.4. The number of normal measurements obtained by the students was nearly identical (n = 74), but this was due to an underestimation of normal conditions in 7 and of abnormally high pressures in 8 patients and an overestimation of reduced pressures in 3 and of normal pressures in 2 patients. Over all measurements, the concordance correlation coefficient was only ρ = 0,62. Factors disturbing the accuracy of ABI measurements are numerous. Short time at rest, oedema or mediasclerosis are some of the factors on the patient side, while the measuring process itself may be affected by wrong choice or attachment of the cuff, or wrong position, angulation and insufficient contact via transmission gel for the Doppler probe, which furthermore may dislocate during the measurement or squeeze the underlying artery if the investigator exerts pressure. Being mindful to all pitfalls may be trivial to the experienced but not to the apprentice. Monti et al. demonstrate that, even with diligent teaching, measuring errors are common. ABI measurements are the main source of epidemiological studies reporting the prevalence of peripheral occlusive disease (PAD)[4]. An underestimation of ABI as shown in the study of Monti et al. would yield an increased prevalence of PAD. Underestimation of ABI in unaffected subjects is common in less experienced medical stuff. Nicolai et al. [5] found that in 19 out of 66 patients diagnosed with an ABI < 0.9 in primary care practice, the ABI actually was ≥ 0.9 in the vascular laboratory. The study of Davies et al. [6] – a questioning of general practitioners in Wales – confirmed that ABI measurement is mainly performed by nurses instead of doctors. A considerable number of both doctors and nurses admitted difficulties in locating ankle/foot pulses and in keeping the Doppler probe in place during the recording. Only 20 % of practices reported to the questioning, a quarter of whom revealed that © 2016 Hogrefe

L. Caspary: Ankle-brachial index measurement: Skill cannot be taken for granted

they did not perform ABI measurements at all. It is improbable that the expertise in the remaining 80 % would be superior. Wyatt et al. [7] showed that training of students considerably improved the ability of technical performance, calculation and interpretation of the ABI. However, even after education, only half of the participants accurately recorded the Doppler signal from brachial or pedal artery. One study, which asserted that a two-week training of 5th year students yielded in good accordance of ABI results compared to those obtained by a vascular specialist, was small and still implicated that ABI within the normal range was measured lower by the students [8]. Purposes of ABI measurements are numerous. They may prove or rule out underlying PAD in patients with claudication. Success of vascular interventions is assessed by ABI, and its deterioration signals increasing arterial obstruction in PAD. Other applications are to check if PAD contributes to peripheral ulcers or to rule out PAD before the placement of compression therapy. Most practitioners would restrict ABI measurements to these indications [5]. A more extensive application for ABI determination is the risk assessment in patients with classical cardiovascular risk factors (or in the older general population), since a subclinical PAD is a predictor of future cardio-cvascular events. Modification of the standard calculation procedure by taking the lower instead of the higher of the two ankle artery pressures (ABImod) would even identify an additional group of patients bearing almost the same risk of future cardiovascular events than those with reduced ABI levels according to the classical application of the method [9]. Recently the U.S. Preventive Services Task Force voted against a recommendation for such a widespread use because there was only limited advantage for risk prediction if added to the Framingham Risk Score, and there was no benefit of medical interventions in asymptomatic patients with reduced ABI [10]. This valuation was mainly based on the Scottish AAA trial which showed no cardiovascular event reduction by aspirin in such patients [11]. As stated in the discussion of this trial, interventions to other factors such as cholesterol should be evaluated given the increased vascular risk in those patients. Evidently, a physician’s instruction of necessary life style changes receives higher acceptance if it is substantiated by a measurable deficiency the patient had no notice of before. This discussion is pointless if the knowledge of ABI measurement remains restricted to physicians working in the vascular field. Both papers in this volume demonstrate that current medical education is not sufficiently enabling future physicians to apply the ABI measurement. Reim-

bursement policies, but also deficiencies of education may have lead to the placement of the ABI among the “Top 10 Forgotten Diagnostic Procedures” [12]. Efforts must be taken to extend and improve teaching programs. An essential condition for this task is a better representation of vascular medicine in academic institutions.

References 1. Chaudru S, de Müllenheim PY, Le Faucheur A, et al. Knowledge about ankle brachial index procedure among residents: be experienced is beneficial but is not enough. Vasa 2016; 45: 37 – 41 2. Aboyans V, Criqui MH, Abraham P, et al. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation 2012; 126: 2890-909. 3. Monti M, Calanca L, Alatri A, et al. Accuracy of in-patients ankle-brachial index measurement by medical students. Vasa 2016; 45: 43 – 48 4. Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res 2015; 116: 1509-26. 5. Nicolai SP, Kruidenier LM, Rouwet EV, et al. Ankle brachial index measurement in primary care: are we doing it right? Br J Gen Pract 2009; 59: 422-7. 6. Davies JH, Kenkre J, Williams EM. Current utility of the anklebrachial index (ABI) in general practice: implications for its use in cardiovascular disease screening. BMC Fam Pract 2014; 15: 69. 7. Wyatt MF, Stickrath C, Shah A, et al. Ankle-brachial index performance among internal medicine residents. Vasc Med 2010; 15: 99-105. 8. Georgakarakos E, Papadaki E, Vamvakerou V, et al. Training to measure ankle-brachial index at the undergraduate level: can it be successful? Int J Low Extrem Wounds 2013; 12: 167-71. 9. Espinola-Klein C, Rupprecht HJ, Bickel C, et al. Different calculations of ankle-brachial index and their impact on cardiovascular risk prediction. Circulation 2008; 118: 961-7. 10. Lin JS, Olson CM, Johnson ES, et al. The ankle-brachial index for peripheral artery disease screening and cardiovascular disease prediction among asymptomatic adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med 2013; 159: 333-41. 11. Fowkes FG, Price JF, Stewart MC, et al. Aspirin for prevention of cardiovascular events in a general population screened for a low ankle brachial index: a randomized controlled trial. JAMA 2010; 303: 841-8. 12. Ponka D, Baddar F. Ankle-brachial index. Can Fam Physician 2013; 59: 270. Correspondence address PD Dr. med. Ludwig Caspary Angiologische Praxis Luisenstr. 10/11 30159 Hannover Germany lcaspary@t-online.de

Vasa (2016), 45 (1), 5 – 6

Editorial

Endovascular-first strategy for acute and subacute limb ischaemia: Potential benefits of a pure mechanical thrombectomy approach Comment on Stanek et al, p. 49 – 56 Michael K.W. Lichtenberg and Wilhelm Friedrich Stahlhoff Klinikum Arnsberg, Arnsberg, Germany

Acute limb ischaemia is a challenging situation for every specialist in the vascular field since, depending on its severity, it may pose a threat for the affected limb or even the entire organism. Acute limb ischaemia is associated with high rates of amputation (10 – 30 %) and mortality (15 – 30 %), depending on concomitant risk factors and treatment options [1 – 3]. Ischaemia of the limb is initially reversible, but if left untreated, results in irreversible tissue death. The extent of organ damage depends on the ischaemic tolerance of the affected tissue. Exceedance of the tolerance limit results in lasting tissue injury, involving potential amputation and mortality. The prevalence of critical limb ischaemia is 1 – 3 %; its incidence is approximately 1.5 cases per 10,000 of the population per year, and rises with age [1]. In view of demographic developments and the rising prevalence of cardiovascular risk factors, approximately 2.8 million cases are anticipated by 2020 in the USA [4]. These facts constitute a major challenge for the healthcare system. Acute limb ischaemia has been associated with high rates of morbidity and mortality. The same is true of ampu-

tation rates, because of inadequate treatment options. In the 1970s, local thrombolytic therapy was used alongside the established vascular surgery technique of direct thrombectomy. New thrombolytic agents and modified forms of administration, such as pulse-spray thrombolysis, have markedly enhanced the speed of thrombolysis and its effectiveness. Over the years, various techniques of local thrombolysis have been developed. A mechanical component (pharmacomechanical thrombectomy) was introduced in the form of infiltration techniques, which reduced the time until recanalisation (Tab. I) and enhanced the efficacy of the treatment. However, infiltration techniques are associated with the well-known complication of bleeding and consequent costs of monitoring patients at the intensive care unit. The prognosis of clinically severe forms of ischaemia depends on the timely initiation of appropriate treatment and earliest possible revascularisation. Since this is not ensured by local thrombolysis, additional or alternative procedures such as pure mechanical thrombectomy must be

Table I. Actual thrombectomy devices Aspiration thrombectomy

Pharmacomechanical thrombectomy

Rotational thrombectomy

Ultrasound-enhanced lysis

A variety of catheters are available

Angiojet® (Boston Scientific)

Rotarex® (Straub Medical)

EKOS® (BTG Group)

Design

OTW/RX 0.035”/0.018” 0.014”

OTW/RX 0.035” / 0.018” 0.014”

OTW 0.018”

Sheath size

4 – 8 F

5 – 7 F

6 – 10 F

Treatable vessel diameter

2 – 6 mm

2 – 12 mm

3 – 12 mm

2 – 6 mm

Vasa (2016), 45 (1), 7 – 9 DOI 10.1024/0301-1526/a000489

M. Lichtenberg & W. Stahlhoff: Editorial

Table II. Technical and clinical outcomes after treatment with thrombolysis, surgical thrombectomy, and mechanical thrombectomy (rotational thrombectomy) Publication

Clinical success

Amputation-free survival after 12 months

Zeller et al. 2002 [8] Rotarex

97.0 % (patency of target vessel)

95 %

Wissgott et al. 2008 [14] Rotarex

265

94.7 % (patency of target vessel)

100 %

Bérczi et al. 2002 [5], Rotarex

94 % (patency of target vessel)

89 %

Duc et al. 2005 [6] Rotarex

100 % (patency of target vessel)

100 %

Stanek et al. 2015 [13], Rotarex

113

93.8 % (patency of target vessel)

90 %

TOPAS 1998 [15] Thrombolysis1 vs. vascular surgery thrombectomy

544

Thrombolysis: 67.9 % Surgery: N/A (dissolution of clot on the final angiogram)

65 % (thrombolysis therapy)

Thrombolysis: 46 % Surgery: 74.3 % (freedom from ongoing ischaemia at 1 month)

87 % (thrombolysis therapy)

STILE 1994 [16] Thrombolysis1 vs. vascular surgery thrombectomy

393

69.9 % (surgery)

89.6 % (surgery) (outcome at 6 months)

1 Catheter directed thrombolysis (TOPAS: Urokinase; STILE: rt-PA or urokinase)

used (Tab. I). One of the most extensively analysed devices for mechanical treatment is rotational thrombectomy with the Rotarex® catheter system [5 – 12]. Rotational thrombectomy is based on the principle of Archimedes’ screw for transporting water. Extrapolated to endovascular therapy, a rotating helix inside the catheter produces suction and removes the thrombotic material. Depending of the lumen size of the catheter, vessels of various diameters can be treated with various rates of suction. The advantage of a pure mechanical thrombectomy procedure is that it avoids additional thrombolysis therapy and thus reduces bleeding complications as well as prolonged intensive care surveillance. This issue of Vasa – European Journal of Vascular Medicine contains a prospective analysis by Stanek et al. [13], who provide further evidence of the benefits of a pure mechanical thrombectomy approach in an indifferent patient cohort with acute and subacute limb ischemia due to a variety of causes. A commendable feature is their inclusion of patients with a wide range of clinical symptoms (categories I – III of acute occlusions) and angiographic findings (native infra-inguinal arteries, bypasses), both of which are encountered frequently in daily routine. The authors conclude that, even in patients with limb-threatening acute ischaemia, mechanical percutaneous thrombectomy is superior to surgery in that it can be performed rapidly and easily without extensive preparation, and thus achieves rapid reperfusion. The economy of this approach for healthcare systems is also worthy of mention. Direct comparisons of the existing mechanical or pharmacomechanical thrombectomy devices do not exist. Prospective randomised controlled studies would be needed to demonstrate the superiority of one thrombectomy system over another, but studies of this nature seem to be unlikely for several reasons. Apart from the complexity of such trials, each system has its limitations. The Rotarex® catheter cannot be used for thrombectomy © 2016 Hogrefe

in crural arteries because of the small vessel size in this location; the Rotarex® system can only be used for vessels larger than 3 mm. Moreover, a 10-French system is now available for arteries or grafts with a large lumen. Promising high-level prospective investigations have been performed on pharmacomechanical thrombectomy systems like the Angiojet® system. The latter employs thrombolysis medication in conjunction with a mechanical approach, which signifies potentially higher bleeding rates. As far as the EKOS® system is concerned, the superior efficacy of ultrasound-enhanced local thrombolysis has not yet been proven; further prospective studies will be needed for this purpose. Comparisons of thromboembolectomy by the vascular surgery approach with percutaneous thrombectomy systems have also not been published. Indirect comparisons of the relevant endpoint – amputation-free survival after 12 months – revealed better results with the mechanical treatment procedure than with local thrombolysis or surgical intervention (Tab. II). An indirect comparison (Tab. II) of relevant endpoint data clearly shows the effectiveness and superiority of the pure mechanical thrombectomy approach. This, in addition to the availability of more effective and safer endovascular thrombectomy procedures for acute and subacute limb ischemia, will help to incorporate these endovascular technologies in future guidelines. Vascular surgery-based thromboembolectomy, which provides no additional benefits in terms of efficacy, safety or hospital stay, as well as catheter-directed thrombolysis with potential life-threatening complications, should only be considered in cases of failed or incomplete mechanical thrombectomy.

Vasa (2016), 45 (1), 7 – 9

M. Lichtenberg & W. Stahlhoff: Editorial

References 1. Creager MA, Kaufman JA, Conte MS. Acute limb ischemia. N Engl J Med 2012; 366: 2198 – 2206. 2. Faglia E, Clerici G, Clerissi J, et al. Early and five-year amputation and survival rate of diabetic patients with critical limb ischemia: Data of a cohort study of 564 Patients. Eur J Vasc Endovasc Surg 2006; 32: 484 – 490. 3. Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease morbidity and mortality implications. Circulation 2006; 114 (7): 688 – 99. 4. Baser O, Verpillat P, Gabriel S, et al. Prevalence, incidence and outcomes of critical limb ischemia in the US Medicare population. Vasc Dis Managem 2013; 10: 26 – 36. 5. Bérczi V, Deutschmann HA, Schedlbauer P, et al. Early experience and midterm follow-up results with a new, rotational thrombectomy catheter. Cardiovasc Intervent Radiol 2002; 25 (4): 275 – 81. 6. Duc SR, Schoch E, Pfyffer M, et al. Recanalisation of acute and subacute femoropopliteal artery occlusions with the Rotarex catheter: one year follow-up, single centre experience. Cardiovasc Intervent Radiol 2005; 28: 603 – 610. 7. Zeller T, C Mueller, Frank U, et al. The Straub-Rotarex thrombectomy system: initial experiences. Rofo 2001; 173 (7): 626 – 31. 8. Zeller T, Frank U, Bürgelin K, et al. Langzeitergebnisse nach Rekanalisation akuter und subakuter thrombotischer arterieller Verschlüsse der unteren Extremitäten mit einem Rotations-Thrombektomiekatheter. Fortschr Röntgenstr 2002; 174:1559 – 1565. 9. Wissgott C, Kamusella P, Andresen R. Recanalisation of acute and subacute venous and synthetic Bypass-graft occlusions with a mechanical rotational catheter. Cardiovasc Intervent Radiol 2013; 36: 936 – 942. 10. Lichtenberg M, Kaeunicke M, Hailer B, et al. Retrograde rotational thrombectomy with the Rotarex catheter system: treatment option for an acute thrombotic occlusion of a subclavian artery. Vasc Health Risk Manag 2011; 7: 623 – 7.

Vasa (2016), 45 (1), 7 – 9

11. Lichtenberg M, Kaeunicke M, Hailer B, et al. Percutaneous mechanical thrombectomy for treatment of acute femoropopliteal bypass occlusion. Vasc Health RiskManag 2012; 8: 283 – 9. 12. Lichtenberg M, Stahlhoff W, Böse D: Endovaskuläre Therapie der akuten Extremitätenischämie unter Verwendung der Rotationsthrombektomie: Aktuelle Studienlage. Zeitschrift für Gefäßmedizin 2013; 10 (3): 14 – 19. 13. Stanek F, Ouhrabkova R, Prochazka D: Percutaneous mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of the peripheral arteries and bypasses – Analysis of failures, complications, and long-term outcomes. VASA 2016; 45 14. Wissgott C, Kamusella P, Richter A, et al. Mechanical rotational thrombectomy for treatment thrombolysis in acute and subacute occlusion of femoropopliteal arteries: retrospective analysis of the results from 1999 to 2005. Rofo 2008; 180 (4): 325 – 31. 15. Ouriel K, Veith F, Sasahara A. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the legs. N Engl J Med 1998; 338: 1105 – 11. 16. STILE Investigators. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial. Ann Surg 1994; 220: 251 – 66. There are no conflicts of interest existing. Correspondence address Dr. Michael Lichtenberg, MD, FESC Vascular Center, Klinikum Arnsberg Stolte Ley 5 59759 Arnsberg Germany m.lichtenberg@klinikum-arnsberg.de

Fundierte Wissensgrundlage für Health Professionals

Volker B. Schulte / Arie Hans Verkuil (Hrsg.)

Management für Health Professionals 2016. 202 S., 32 Abb., 30 Tab., Gb € 49.95 / CHF 65.00 ISBN 978-3-456-85526-4 AUCH ALS E-BOOK

Das Lehrbuch zum «Management für Health Professionals» bietet Studierenden der neuen modularisierten MAS-Weiterbildungsstudiengänge eine fundierte Wissensgrundlage. Inhaltlich unterscheiden die Autoren zwischen Makro-, Meso- und Mikroebene. Auf der Makroebene werden die Trends der Gesundheitsversorgung und des Gesundheitsmarktes analysiert. Die Schwerpunkte liegen auf Gesundheitsökonomie und -politik, Integrierte Versorgung, Qualitätsmanagement, der Hybridisierung des Versorgungs- und Tourismusmarkts sowie dem Case Management und Managed Care Modellen.

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Die Mesoebene nimmt das Gesundheitsmanagement in Gesundheitsorganisationen und -unternehmen unter die Lupe. Im Einzelnen werden die Differenzierung von Proﬁt- und Non-Proﬁt-Organisationen im Gesundheitsbereich beschrieben sowie die Themen Unternehmensverantwortung und Gesundheitsmanagement dargestellt. Auf der individuellen Ebene stellt das Lehrbuch die Themen genetische Beratung, gesundheitspsychologische Beratung, Health Literacy/Patientenkompetenz und Lebensstile vor.

Review

Gender differences in patients with carotid stenosis Konstanze Stoberock1, Eike Sebastian Debus1, Atlihan Gülsen1, Daum Günther1, Axel Larena-Avellaneda1, Sandra Eifert2, and Sabine Wipper1 1 2

University Heart Center, Hamburg, Germany University Heart Center, Leipzig, Germany

Summary: This overview analyses gender differences in prevalence, epidemiology, risk factors and therapy in patients with carotid stenosis in a systematic review. Ischemic stroke is a leading cause of death in Western society, where about 20% of cases are triggered by a carotid stenosis or occlusion, which occurs more frequently in men than in women. The stroke-protective effect of carotid endarterectomy is greater in men. Men have lower peri-procedural stroke and death rates. Particularly men with carotid stenosis and a life expectancy of at least 5 years benefit from surgical treatment. Also, the recurrence rate of ipsilateral stroke 5 years after initial surgery is lower in men than in women. It is not yet fully clarified whether there are significant gender differences regarding the outcome after endovascular versus surgical treatment. Gender differences in the outcome of carotid artery repair may be caused by biological, anatomical (smaller vessel diameter in women) or hormonal differences as well as a protracted development of atherosclerotic changes in women and different plaque morphology. Moreover, women are on average older at the time of surgery and their surgical treatment is often delayed. To reduce the risk of stroke and to improve treatment outcome especially for women, further research on gender differences and their causes is mandatory and promising. Key words: Carotid stenosis, sex, gender, prevalence, carotid artery stenting, carotid endarterectomy

Introduction

Prevalence

In Western societies, stroke is a leading cause of death and hospitalisation. The average age-adjusted incidence per 100,000 is 200 and 170 for women. In advanced age, however, the risk of stroke adjusts for both sexes [1, 2]. Approximately 20 % of ischemic strokes in both sexes are caused by macroangiopathic stenoses or occlusions of extracranial vessels supplying the brain. In general, the extracranial carotid artery is concerned [3]. As most studies on carotid stenoses have been conducted with men, little is known about gender specifics regarding this disease. Here, we have examined publication records from 1987 until December 2014 to outline gender-specific differences in carotid artery stenosis.

According to the “North American Symptomatic Carotid Artery Trial” (NASCET) a significant stenosis of the internal carotid artery is defined as a loss of lumen of at least 50 %. A distinction is made between moderate (50 – 70 %) and high-grade stenosis (≥ 70 %). In a meta-analysis of 29 studies involving 22,636 patients, the pooled prevalence of moderate stenosis was 4.2 % (95 % CI 3.1 – 5.7 %). In a meta-analysis of 4 studies with 6518 patients, the prevalence of high-grade stenosis was 1.7 % (95 % CI 0.7 – 3.9 %) [4]. Carotid stenosis is more common in men than in women: 7 – 9 % of men > 65 years-old have at least a 50 % stenosis compared to 5 – 7 % of age-matched women [4,5]. In a meta-analysis of 8 studies, the prevalence in patients < 70 years-old was 4.8 % (95 % CI 3.1 – 7.3 %) for men and 2.2 % (95 % CI 0.9 – 4.9 %) for women [3,4]. In patients > 70 years-old, it was 12.5 % (95 % CI 7.4 – 20.3 %) for men, and 6.9 % (95 % CI 4.0 – 11.5 %) for women [3,4].

Methods The article reviews relevant studies, reviews, meta-analyses and consensus papers on carotid stenoses whether they deal with gender differences. For this purpose, Medline (PubMed) was searched for such studies etc. from January 1987 until December 2014. Keywords used were “carotid stenosis”, “sex”, “gender”, “prevalence”, “carotid artery stenting” and “carotid endarterectomy.” It was expected that these keywords cover all relevant articles on the subject. Vasa (2016), 45 (1), 11 – 16 DOI 10.1024/0301-1526/a000490

Epidemiology and risk factors for stroke Although the prevalence for carotid stenosis is higher in men, the risk of stroke is higher in women. In Western societies, one out of every 5 women and one out of every 6 men will suffer from a stroke during their lifetime [5]. Mul© 2016 Hogrefe

tiple factors may contribute to the higher risk of stroke in women. The Reynold’s Risk Score, which is based on data from the Women’s Health Study, is well suited to predict the risk of stroke within the next 10 years. The analysed criteria include gender, age, smoking, systolic blood pressure, total cholesterol, high density lipoprotein, high sensitivity C-reactive protein and positive family history of stroke before the age of 60 years [6 – 8]. In addition to the classical risk factors concerning both genders such as arterial hypertension, diabetes mellitus type II, obesity, smoking, lack of exercise, hyperlipidaemia, positive family history and age, women face specific risks such as pregnancy complications (pre-eclampsia, gestational diabetes or pregnancy-induced hypertension), as well as autoimmune diseases and rheumatoid arthritis [5]. In particular, both polycystic ovary syndrome and preeclampsia are associated with an increased risk for hypertension, coronary heart disease, diabetes mellitus and stroke [5]. Moreover, age may be an influencing factor, as age is a risk factor for atherosclerosis and in average, women become older than men. The incidence of stroke in menopausal women increases significantly [2], possibly due to decreasing oestrogen levels, as oestrogen protects from cardiovascular disease. Women also have smaller arteries than men which may predispose them to stroke. Women > 7 5 years show a greater prevalence of hypertension than men, which is a strong risk factor for stroke [5]. In contrast, men generally have more comorbidities compared to women, including cigarette smoking, diabetes mellitus, myocardial infarction with or without coronary bypass surgery, and peripheral arterial disease. Women are at higher risk for atrial fibrillation which is responsible for approximately 15 % to 20 % of all ischemic strokes [5]. The rate of “under-treatment” with anticoagulants doubles the risk for repeated stroke. Therefore, the American Heart Association (AHA) expert group has published separate guidelines about stroke in women with atrial fibrillation.

Plaque morphology by analysis of endarterectomy specimen The reasons for gender differences in the incidence rates of stroke and outcome after carotid endarterectomy (CEA) are poorly understood and certainly multifactorial. One contributing factor may be differences in carotid plaque morphology.

Analysis of plaque morphology The Doppler and color-coded duplex ultrasound is the method of choice for screening of carotid stenosis (Level of Evidence 1) [9]. A duplex ultrasound study of 1686 patients with vascular disease, stroke, transitoric ischemic attack or asymptomatic carotid stenosis with a 5-year follow-up showed that plaque area is a stronger predictor for © 2016 Hogrefe

K. Stoberock et al.: Gender differences with carotid stenosis

stroke than the degree of stenosis. In general, the incidence of carotid stenosis in men is more often and the plaque area is larger than in women [10]. Assessment of carotid plaques by duplex ultrasound revealed that a high ratio of fat to necrotic core, a thin or ruptured fibrinous cap, plaque haemorrhage and a larger wall thickness all are associated with a higher risk for an ischemic cerebrovascular event. MRI diagnostics of carotid arteries in patients with carotid artery stenosis resolves detailed plaque morphology as has been demonstrated by subsequent ex-vivo histological analysis of plaques following CEA. Vulnerable plaques with thin fibrous caps and large overlying necrotic lipid cores can be identified by MRI and high resolution MRI even allows quantification of the relative intima/media thickness of plaques [11]. MRI studies also reveal the association between stroke risk and plaques that are lipid-rich and centrally necrotic, have a thin or ruptured fibrous cap, show haemorrhage or exhibit a large wall thickness [11 – 14]. Multiple studies have addressed the issue of gender differences in plaque morphology using imaging methods on patients (duplex ultrasound, magnetic resonance imaging or computer tomography angiography) or histological examinations of excised plaque material. The studies show that carotid plaques in men have a greater intima-media thickness than in women [5]. Hellings et al. carefully analysed histomorphological and inflammatory parameters from intraoperatively removed plaques regarding gender differences. This study reports that plaques in women show higher smooth muscle cell content, contain less fat and are less inflamed, as concluded from lower IL-8 concentration, lower MMP8 activity and lower macrophage content [15]. Clearly, plaques in women are generally more stable than in men. The gender-associated differences in plaque morphology are most evident in women with asymptomatic carotid artery stenosis, which may explain why they in particular have lower long-term stroke reduction after CEA [11-15].

Gender-specific therapy of carotid artery stenosis and stroke Sex-related differences in pharmacokinetics and pharmacodynamics are of major importance. These differences have obvious relevance to the efficacy and side effects profiles. Likewise, different enzyme formations and drug compatibilities play a role [6]. In general, treatment of carotid stenosis depends on the severity of the disease. Conservative treatment of asymptomatic carotid stenosis includes the elimination of cardiovascular risk factors, and medical therapy with antithrombotic platelet aggregation inhibitors and cholesterol lowering statins. More severe disease is treated by interventional or surgical approaches to enlarge vessel lumen. According to the Women’s Health Study, when compared to placebo, the daily intake of a low dose of aspirin Vasa (2016), 45 (1), 11 – 16

K. Stoberock et al.: Gender differences with carotid stenosis

(100 mg) reduces the life-long risk for stroke in women by 17 % (RR 0.76; 95 % CI 0.63 – 0.93; P = 0.04), and for ischemic stroke by 24 % (RR 0.76; 95 CI 0.63 – 0.93; p = 0.009), while the risk of haemorrhagic stroke does not significantly increase (RR 1.24; 95 % CI 0.82 – 1.87; p = 0.31) [16]. Almost identical results were obtained by a study by Berger et al. which concerned the primary prevention of cardiovascular events with aspirin.[17] In contrast, men do not benefit from taking low dose-aspirin at all: it neither affects the total risk of stroke (OR 1.13, 95 % CI, 0.96 – 1.33) nor the risk of ischemic stroke (OR 1.00; 95 %CI 0.72 – 1.41; p = 0.98) but is associated with a significant 69 % increase of haemorrhagic stroke (OR 1.69; 95 % CI 1.04 – 2.73; p = 0.03) [17]. The gender-specific effects of aspirin may at least in part be due to the contrary effects of sex hormones on platelet aggregation which is stimulated by testosterone and inhibited by oestrogen and progesterone, respectively [5]. These observations clearly demonstrate the need for gender-specific treatment of cardiovascular diseases. While the gender-specific effects of aspirin or the contrary effects of sex-hormones on platelet aggregation cannot explain the higher risk for women than men to suffer from stroke, one reason for this difference may simply be that women take less medication (aspirin, statins and ACE-inhibitors) than men. [18] This may lead to insufficient secondary prevention of stroke and therefore be responsible for higher recurrence rates and worse survival in women compared to men [18]. It must be noted, however, that no significant gender differences have been found for aspirin as secondary stroke prevention [5, 19]. Law et al. showed in a large meta-analysis, that statins lower LDL cholesterol concentrations by an average of 1.8mmol/l which reduces the risk of thromboembolic stroke by 17 % but does not affect haemorrhagic stroke. Simvastatin 40mg/d, lovastatin 40 mg/d, and atorvastatin 10mg/d lower LDL cholesterol by about 37 % from all pretreatment concentrations [20]. Therefore, statin therapy might be recommended independent of the basal LDL cholesterol levels. No genderspecific recommendations were found.

Asymptomatic stenosis Two large trials, the North American “Asymptomatic Carotid Atherosclerosis Study” (ACAS) and the European “Asymptomatic Carotid Surgery Trial” (ACST) have been designed for patients with severe asymptomatic carotid stenosis (> 60 % ACI) to evaluate the benefit of CEA. In the ACAS trial, 1659 patients (1091 male/568 female) were enrolled between 1987 and 1993. In the ACST trial, 3120 patients (2044 male/1076 female) were enrolled between 1993 and 2003. Both studies report an identical effectiveness of CEA resulting in a significant overall absolute risk reduction for ipsilateral stroke of 5 – 6 % within 5 years for both genders [21,22]. However, according to the ACAS, the relative risk reduction for ipsilateral stroke provided by Vasa (2016), 45 (1), 11 – 16

surgical therapy is 66 % for men and only 17 % for women (both not significant). Presumably, this difference is due to the higher rate of perioperative complications in women (3.6 % vs. 1.7 % in men). Subgroup analyses in both trials revealed that surgery is significantly more advantageous for men (ARR 4.1 %; 95 % CI 2.5 – 5 %) than for women (ARR 0.2 %; 95 % CI – 2.0 – 2.5 %) [22]. According to ACST, men have a significant lower risk of stroke and perioperative death within 5 years after CEA than women (ARR: 8.2 and 4.1 %) [9, 20, 21]. However, after 10 years, women also benefited (perioperative stroke: 5.5 %, p < 0.02, not perioperative stroke: 6.3 %, p = 0.006 in men; 5.8 %, p = 0.05 and 8.2 %, p = 0.003 in women) [23]. As of now, all German and international guidelines recommend CEA in patients with asymptomatic ACI stenosis (50 – 99 %) regardless of gender, as this procedure slightly but statistically significantly reduces the risk of stroke (Level of Evidence 1) [9]. The guidelines of the German Society of Neurology and the European Society for Cardiology additionally restrict recommendations for CEA to patients with expected risk of perioperative stroke rate/ mortality of < 3 % and life expectancy of > 5 years [24,25]. There are no gender-specific adaptations in these guidelines. Generally for the management of asymptomatic carotid stenosis also the non-invasive treatment with bestavailable medical therapy is an option [26], although at present there is limited evidence that this therapy alone is the best choice [27].

Symptomatic stenosis According to the current European Stroke Organisation (ESO) and AHA guidelines, a CEA is recommended for all patients with symptomatic carotid stenosis of 70 – 99 % and/ or after a transitory ischemic attack (Level of Evidence Ia). Despite a periprocedural risk of 5 – 7 %, CEA is recommended by all guidelines as the gold standard of treatment, while early surgery is desirable [9, 28]. For 50 – 69 % stenosis AHA guidelines recommend CEA after taking into account age, sex and other comorbidities, while ESO guidelines suggest that men with a recent history of ipsilateral symptoms most likely benefit (Level of Evidence Ia) [9]. According to NASCET and ECST men have a better post-operative benefit compared to women, who have a 50 % higher risk of perioperative stroke and perioperative death than men. Men benefit from surgery of a symptomatic > 50 % stenosis, whereas women only reach a significant risk reduction after surgery of a symptomatic stenosis of at least 70 % [29]. A joint analysis of NASCET and ECST confirmed that the CEA of a 70 – 99 % stenosis according to NASCET results in a significant absolute risk reduction of ipsilateral stroke by 16 % within 5 years for both genders. According to NASCET, the treatment of stenoses between 50 – 69 % provides a lower absolute medium advantage of 4.6 % which however differs between genders (ARR: 8.0 % for men, 2.7 % for women) [30]. © 2016 Hogrefe

In a meta-analysis of the ECST and NASCET data by the “Carotid Endarterectomy Trialists Collaboration”, 5,893 patients (29 % women) with 33,000 patient-years of follow-up were evaluated. All ECST and NASCET patients with symptomatic carotid stenosis were treated either conservatively with antiplatelet drugs or additionally underwent CEA. The outcome of CEA was significantly influenced by gender (p = 0.003). Men benefited more than women; best results were reached for men > 7 5 years with a CEA within 2 weeks following an ischemic event. Men with ≥ 70 % stenosis benefited even after > 12 weeks, whereas in case of a moderate 50 – 69 % stenosis benefit for both genders was only observed after a prompt intervention after the first event [29 – 31]. CEA performed at patients with moderate (severe) symptomatic carotid stenosis reduced the risk of stroke within 5 years by 8 % (15 %) for men but only by 2.7 % (9.9 %) for women. In ≥ 50 % stenosis, the number-needed-to-treat to prevent an ipsilateral cerebral infarction within 5 years was 9 for men vs. 36 for women. [30] On the other hand, some studies report a significantly higher overall mortality after CEA in men than in women (hazard ratio: 1.41; 95 % CI 1.01 – 1.98) [5,31]. However, this difference may be explained by the fact that in women, a CEA is performed less frequently and often only at a late stage [32]. A subgroup analysis of the Cochrane database with 5223 patients (1644 women) showed a relative risk reduction for stroke or death by CEA of 51 % for men (RR 0.49; 95 % CI 0.036 – 0.66) but only of 4 % for women (RR 0.96; 95 % CI 0.64 – 1.44) [9,33]. A study by Kapral et al. investigated the gender differences after CEA in 6038 patients (35 % women) with moderate or severe carotid stenosis. Although there was no gender-specific difference in the frequencies of perioperative complications, within a 2-year follow-up, women had a higher risk of recurrent stroke than men, which may be attributable to a higher number of women in this study suffering from arterial hypertension. In contrast, men were at higher risk of mortality, possibly because of a higher prevalence of coronary artery disease [34]. All studies agree that protection from stroke by CEA is significantly higher for men than for women.

Endovascular therapy The ESO and AHA guidelines recommend carotid artery stenting regardless of gender as an alternative to CEA for patients < 70 years with difficult anatomical conditions or with increased medical risk (e.g. very low ejection fraction of the heart, dialysis-dependent renal failure, steroid-requiring respiratory disease). In asymptomatic carotid stenosis a perioperative complication rate of < 3 % is required, in symptomatic carotid stenosis < 6 % [9]. Whether gender plays a role in the endovascular therapy appears to be controversial. The American CREST study © 2016 Hogrefe

K. Stoberock et al.: Gender differences with carotid stenosis

included 2502 patients (40 % women), which received CAS (1271 p.) or CEA (1251 p.) to treat asymptomatic or symptomatic carotid stenosis. After 2.5 years follow up no gender differences between CAS and CEA regarding the primary endpoint (stroke, myocardial infarction, or death from any cause during the periprocedural period [30d]) were found [35]. However, after 4 years follow up a lower periprocedural event rate (stroke, myocardial infarction or death after CAS or CEA) for women undergoing CEA (3.8 %) than for men (4.9 %) but higher for women in CAS (6.8 vs. 4.3 %) was shown [36]. The opposite was found in International Carotid Stenting Trial (ICSS) where women had a higher 120-day event rate for CEA (7.6 % vs. 4.2 %) and a lower rate for CAS (8 % vs. 8.7 %) [37]. Also, a larger meta-analysis combining ICSS and CREST databases did not confirm the findings of the CREST study [38]. A systematic review consisting of 170 studies reported an association of female gender with a higher risk of procedural stroke or death after CEA but not after CAS [39]. These results suggest that the long-term perspective of an increased peri-procedural risk of stroke or death in women after CEA should be taken into account when selecting treatment for carotid artery stenosis. Results from CREST further showed that CAS was more efficient in patients < 70 years and CEA in patients > 70 years. These findings were confirmed by a pooled data analysis from three large randomized clinical trials (EVA3S, SPACE, ICSS) from the Carotid Stenting Trialist Collaboration revealed. This analysis showed that patients > 70 years have a twofold increase in the risk of stroke or death after CAS, compared with CEA (RR: 2.04, 95 %CI = 1.48 – 2.82), whereas there was no significant risk difference for patients < 70y [40]. Jim et al. performed a recent study with 9865 patients (40.6 % women), and demonstrated similar results after CEA or CAS for women and men and reported no statistically significant gender differences in the primary end point (death, stroke, myocardial infarction at 30 days) for CEA (women, 4.07 %; men, 4.06 %) or CAS (women, 6.69 %; men, 6.80 %) [38]. Additional studies found no gender differences between CEA and CAS [42,43]. Unfortunately, thus far, gender issues regarding the comparison of CEA and CAS were not yet fully explored in the SPACE study where women were anyway underrepresented (28 %) [44, 45]. Since the data concerning CEA and CAS remain inconsistent in regard of the impact of gender further research with a focus on the gender aspect is required.

Conclusions Although the surveyed studies come to different conclusions in part, there is general agreement that men benefit more from a CEA than women. Some studies on CEA and CAS find gender differences, while others do not. Vasa (2016), 45 (1), 11 – 16

K. Stoberock et al.: Gender differences with carotid stenosis

Studies comparing CEA to pure medication therapy found less favourable results for women than for men with respect to revascularisation. In particular, men with a severe stenosis (> 70 %) benefit more than women from surgery. With respect to CEA, men have lower peri-procedural stroke and death rates. Also, the 5-year recurrence rate of ipsilateral stroke after surgery is higher in women. The reasons for such differences are not yet clear. They may be caused by biological, anatomical (smaller vessel diameter) or hormonal reasons as well as a protracted development of atherosclerotic changes in women. Also, different plaque morphology may be a cause. Furthermore, the higher age of women at the time of first diagnosis and of surgical treatment can be an influential factor. To reduce the risk of stroke and improve treatment results, especially for women, further research on gender differences and their causes is mandatory and promising.

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14. Ota H, Reeves MJ, Zhu DC, et al. Sex differences in patients with asymptomatic carotid atherosclerotic plaque: in vivo 3.0T magnetic resonance study. Stroke 2010; 41: 1630 – 5. 15. Hellings WE, Pasterkamp G, Verhoeven BA, et al. Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy. J Vasc Surg 2007; 45: 289 – 96. 16. Ridker PM, Cook NR, Lee IM, et al. A randomised trial of lowdose aspirin in the primary prevention of cardiovascular disease in women. N Engl Med 2005; 352: 1293 – 304. 17. Berger JS, Roncaglioni MC, Avanzini F, et al. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. JAMA 2006; 295: 306 – 13. 18. Rother J, Alberts MJ, Touze E, et al. Risk factor profile and management of cerebrovascular patients in the REACH Registry. Cerebrovasc Dis 2008;25(4):366-74. 19. Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirin use in acute ischemic stroke: a combined analysis of 40,000 randomised patients from the Chinese acute stroke trial and the international stroke trial. Stroke 2000; 31 (6): 1240-49. 20. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. Br Med J 2003; 326: 1423. 21. Walker MD; Marler JR, Goldstein M, et al. Endarterectomy for asymptomatic carotid artery stenosis. Journal of the American Medical Association 1995; 273: 1421 – 8. 22. Halliday A, Mansfield A, Marro J, et al. MRC Asymptomatic Carotid Surgery Trial (ACST) Collaborative Group. Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms: randomised controlled trial. Lancet 2004; 363: 1491 – 502. 23. Halliday A, Harrison M, Hayter E, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): a multicentre randomised trial. Lancet 2010; 376: 1074 – 84. 24. Deutsche Gesellschaft für Neurologie. Primär- und Sekundärprävention der zerebralen Ischämie. Gemeinsame Leitlinie der DGN und der deutschen Schlaganfallgesellschaft 2008: 1 – 42. 25. Tendera M, Aboyans V, Bartelink ML, et al. TESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid artery. ESC Committee for Practice Guidelines. Eur Heart J 2011; 32: 2851 – 906. 26. Raman G Moorthy D, Hadar N, et al. Management strategies for asymptomatic carotid stenosis. A systematic review and meta-analysis. Ann Intern Med 2013; 158: 676 – 685. 27. De Rango P, Brown MM, Didier L, et al. Management of carotid stenosis in women. Consensus document. Neurology 2013; 80: 2258 – 68. 28. European Stroke Organisation Writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack. Cerebrovasc Dis 2008; 25: 457 – 507. 29. Rothwell PM, Gutnikov SA, Warlow CP. Reanalysis of the final results of the European carotid surgery trial. Stroke 2003; 34: 514 – 23. 30. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Carotid Endarterectomy Trialists Collaboration. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. Lancet 2004; 363: 915 – 24. 31. Rothwell PM, Eliasziw M, Gutnikov SA, et al. Sex difference in the effect of time from symptoms to surgery on benefit from carotid endarterectomy for transient ischemic attack and non-disabling stroke. Stroke 2004; 35: 2855 – 61. 32. Poisson SN, Johnston SC, Sidney S, et al. Gender differences in treatment of severe carotid stenosis after transient ischemic attack. Stroke 2010; 41: 1891 – 5. 33. Chambers BR, Donnan GA. Carotid endarterectomy for asymptomatic carotid stenosis. Cochrane Database Syst Rev 2005: 1 – 20. © 2016 Hogrefe

34. Kapral MK, Wang H, Austin PC, et al. Sex differences in carotid endarterectomy outcomes results from the Ontario carotid endarterectomy registry. Stroke 2003; 34: 1124 – 25. 35. Brott TG, Hobson RW, Howard G, et al. CREST Investigators. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl J Med 2010; 363: 11 – 23. 36. Howard VJ, Lutsep HL, Mackey A, et al. Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the carotid revascularisation endarterectomy versus Stenting trial (CREST). Lancet Neurol 2011; 10: 530 – 7. 37. International Carotid Stenting Investigators. Ederle J, Dobson J, Featherstone RL, et al. Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial. Lancet 2010; 375: 985 – 97. 38. Touze E, Trinquart L, Chatellier G, et al. Systematic review of perioperative risks of stroke or death after carotid angioplasty and stenting. Stroke 2009; 40: 683 – 693. 39. Touzé E, Trinquart L, Felgueiras R, et al. Carotid Stenting Trialists’ Collaboration. A clinical rule (sex, contralateral occlusion, age, and restenosis) to select patients for stenting versus carotid endarterectomy: systematic review of observational studies with validation in randomised trials. Stroke 2013; 44: 3394 – 400. 40. Carotid Stenting Trialists’ Collaboration, Bonati LH, Dobson J, Algra A,et al. Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a pre-planned meta-analysis of individual patient data. Lancet 2010; 376 (9746): 1062 – 73. 41. Jim J, Dillavou ED, MD, Upchurch GR, et al. Gender-specific 30day outcomes after carotid endarterectomy and carotid artery

K. Stoberock et al.: Gender differences with carotid stenosis

stenting in the Society for Vascular Surgery Vascular Registry. J Vasc Surg 2014; 59: 742 – 8. 42. Park B, Aiello F, Dahn MS, et al. No gender influences on clinical outcomes or durability of repair following carotid angioplasty with stenting and carotid endarterectomy. Vascular and Endovascular Surgery 2008; 42: 321 – 28. 43. Zarins CK, White RA, Diethrich EB, et al. Carotid revascularization using endarterectomy or stenting systems (caress):4 year outcomes. J Endovasc Ther 2009; 16: 397 – 409. 44. Ringleb PA, Allenberg J, Brückmann H, et al. 30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised noninferiority trial. Lancet 2006; 368 (9543): 1239 – 47. 45. Eckstein HH, Ringleb P, Allenberg JR, et al. Results of the stentprotected angioplasty versus carotid endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial. Lancet Neurol 2008; 7: 893 – 902. Submitted: 11.04.2015 Accepted after revision: 24.06.2015 There are no conflicts of interest existing. Correspondence address Dr. Konstanze Stoberock, MD Department of Vascular Medicine University Heart Center Hamburg Martinistraße 52 22529 Hamburg Germany k.stoberock@uke.de

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Review

Inflammatory diseases of the aorta Ludwig Caspary Angiologische Praxis Luisenstraße, Gefäßzentrum Klinikum Hannover, Germany

Summary: Inflammatory aortic diseases may occur with and without dilatation and are complicated by obstruction, rupture and dissection. Infections originate from periaortic foci or septicaemia and tend to result in the rapid development of aneurysms. Large vessel vasculitis due to Takayasu arteritis in younger and giant cell arteritis (GCA) in older patients is located in all layers of the aortic wall and prevails in the thoracic section. GCA patients are prone to developing aortic complications in the late course of disease. In Behçet’s disease, aneurysms may have an unusual morphology and localisation. The diagnosis of aortitis is usually obtained by vascular imaging, but partly made only by biopsy on occasion of an operation, especially in case of isolated aortitis of the ascending aorta which mostly remains inapparent until dissection or large aneurysms have developed. Periaortitis typically occurs in the abdominal aorta and may lead to inflammatory aortic aneurysm (IAA). It is looked upon as a special form of vasculitis, with an overlap to primary retroperitoneal fibrosis (RF). An identical pathology is discussed for the three diseases. On the other hand, about 50 % of isolated aortitides and periaortitides as well as retroperitoneal fibroses can be classed among IgG4related diseases. Periaortitis also is observed after treatment of aortic aneurysms by stent-graft implantation. Special attention should be paid to ureteral obstruction along with RF or IAA. Once infection is ruled out, immunosuppression is applied to all forms of inflammatory aortic diseases, primarily with glucocorticoids. However, after successful surgery for isolated thoracic aortitis or inflammatory aortic aneurysm immunosuppression may be dispensable and it is not required if periaortic tissue enlargement persists in chronic inactive disease. For some patients with periaortitis and RF, tamoxifen may be a valuable alternative. Key words: Aortitis, vasculitis, giant cell arteritis, Takayasu arteritis, periaortitis, inflammatory aortic aneurysm

Introduction Inflammatory diseases of the aorta are rare compared to atherosclerosis, which is the most frequent cause of aortic disease. The underlying pathology is diverse (Tab. I). A clinician is confronted with various kinds of initial symptoms and – in a number of cases – diagnosis is provided by histopathology or made by chance. Inflammation may be located in all layers of the vessel wall or be restricted to the adventitial and periadventitial tissue. It can be found in the thoracic or abdominal part of the aorta only or spread along the entire length of it. It may be restricted to the aorta or appear in other arteries as well. Vessel inflammation is mostly part of systemic disease. In the course of inflammation, aneurysmatic dilatation may occur with the risk of rupture. On the other hand, dissection is possible despite unchanged vessel diameter. In most cases, immunosuppressive treatment is required, sometimes for a long period of time [1].

Diseases Infectious aortitis Vessel infections may be generated by endocarditis, local perivascular foci (such as vertebral osteomyelitis) or septicaemia. The aorta is the most frequent location of bacteriVasa (2016), 45 (1), 17 – 29 DOI 10.1024/0301-1526/a000491

al artery infection [2]. A pre-existing atherosclerotic pathology, in the form of a plaque formation or an aneurysm, may facilitate and subsequently host infection. Certain bacteria are known to affect distinct parts of the aorta. Treponema pallidum, however rare, is almost entirely found in the ascending aorta or the aortic arch. In general, gram-positive bacteria such as Staphylococcus or Enterococcus species and Streptococcus pneumonia have a propensity for the thoracic aorta [3] while gram-negative germs, especially Salmonella species, prevail in the abdominal aorta. Infection generally leads to the formation of an aneurysm very early. Typically, the aneurysms resulting are excentric and sacciform. Due to their fungous aspect they are called mycotic aneurysms. In the aortic arch, aneurysm formation often occurs on the concave side opposite the supra-aortic branches. In the abdomen, it forms similarly, but at the dorsal side opposite the visceral arteries. An infectious aortitis rarely may be detected before vessel wall inflammation leads to an aneurysm [4]. Clinical signs are non-specific. Fever of unknown origin is the most frequent symptom, followed by back pain in the case of abdominal localisation. Laboratory findings include leukocytosis and the elevation of C-reactive protein (CRP) as well as erythrocyte sedimentation rate (ESR). The level of CRP elevation mostly exceeds that of ESR, but this may occur in non-infectious aortic inflammation as well. Samples for blood culture should be drawn repeatedly, but negative results are frequent and do not rule out an infection. In those cases, PCR amplification of the bacterial 16S rRNA gene may be helpful, © 2016 Hogrefe

Table I. Pathology of inflammatory aortic diseases Aortitis due to defined vasculitis Takayasu arteriitis Giant cell arteriitis Behçet’s disease Cogan’s syndrome Polyarteritis nodosa Kawasaki disease Aortitis due to rheumatic diseases Spondylarthritis ankylosans Lupus erythematosus Rheumatoid arthritis Sarcoidosis Ulcerative colitis Psoriatic arthritis Isolated aortitis* Chronic periaortitis* Retroperitoneal fibrosis (Ormond’s disease)* Inflammatory aortic aneurysm* *

may represent IgG4-related disease

proving infection by the detection of a universal conserved region and subsequently identifying the responsible germ by sequence analysis of the variable regions [5]. Echocardiography is crucial to detect an underlying valve endocarditis. Both endocarditis and the aortic infection itself may produce septic embolism with splinter haemorrhages in toes and fingers. The differential diagnosis of bacterial or non-bacterial inflammation may remain difficult. Computerised tomography (CT) or magnetic resonance tomography (MRT) is often the clue to diagnosis [6], mostly performed as angiography (CTA or MRA). It may reveal a perivascular focus of infection. Gas in the aortic wall is an almost certain sign of infection even before aortic dilatation begins [7]. Periaortic lymph nodes may be found to be enlarged. In some cases, repetitive investigation could demonstrate rapid aneurysmal growth [8]. Patients with infective aortitis are in danger of aneurysm rupture but also of the formation of aorto-caval or aorto-enteric fistula. Untreated, the infection tends to generalisation and multiorgan failure [5]. Once the infectious nature of aortitis was identified, antibiotic therapy is introduced. However, if the germ responsible is not known and clinical situation allows for it, spending some time for further sample acquisition might be of value. Untargeted antibiotic treatment will consider the higher prevalence of gram-positive bacilli in the thoracic and enterobacteria in the abdominal part of the aorta. Antibiotic treatment is recommended over a six to eight week period [2]. Aneurysm formation can proceed even after successful antibacterial treatment and regularly leads to rupture. Surgery is always necessary in that case and often demanded as an emergency. With regard to graft infection, resection of the infected aortic section and extra-anatomical artery reconstruction is propagated as the gold standard. However, this approach © 2016 Hogrefe

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is intricate and may not be practical in critical patients. Arterial homografts seem to be an expensive but safer alternative if in situ-reconstruction is chosen. Replacement of the infected aortic segment by autologous femoral vein was tried with low donor-side morbidity and low graft infection rates [2]. Stenting was discussed as an additional option, especially in emergency situations, leaving the perspective of later open reconstruction of the aorta after the patient was stabilised. Planned as a definitive procedure, the method has best results in abdominal aortic infections due to salmonella species. As for persistent infection, antibiotic treatment then must be prolonged beyond 8 weeks to prevent graft infection which may demand open conversion. In a recently published European multicentre study of 123 patients treated with stent grafts, 19 % died of infections, often after antibiotics were withdrawn [9]. Development of aorto-enteric or aorto-bronchial fistula in patients with stents is generally lethal. Long-term monitoring is mandatory, including laboratory controls and imaging, with CT being preferred in the case of stenting. In uncomplicated cases of abdominal repair, CDUS may be sufficient to rule out relapse of infection.

Vasculitis The aorta is involved in several of the vasculitides for which the Chapel Hill nomenclature has recently been revised [10]. Classical diseases affecting large vessels are giant cell arteritis (GCA) and Takayasu arteritis (TA). A new category called variable vessel vasculitides comprises Behçet’s disease (BD) and Cogan’s syndrome (CS), which also affect large vessels including the aorta. In addition, the two types of medium-vessel vasculitis, polyarteritis nodosa (PAN) and Kawasaki disease (KD), may in some cases extend to larger vessels, even the aorta; the same holds true for ANCA-associated vasculitides. Isolated aortic vasculitis is in the category of single organ vasculitis.

Giant cell arteritis (GCA) Giant cell arteritis accounts for the majority of inflammatory aortic diseases [1]. Its annual incidence in persons aged over 50 is variable, ranging from 20/100,000 in European countries (with a preponderance in Northern Europe) to < 1/100,000 in the Far East. In the revised Chapel-Hill nomenclature of vasculitides [10] it is described as vasculitis “that usually affects the aorta and its major branches”. The ACR criteria of 1990 were limited to the cranial form of the disease (former Horton’s disease), including headache and a tenderness of the temporal artery [11]. In recent years, important parts of the pathogenesis have been elucidated [12]: Inflammation begins in the vasa vasorum involving dendritic cells, the activation of which induces lymphocyte invasion to the vessel wall normally free of immunological processes. It has become clear that Vasa (2016), 45 (1), 17 – 29

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GCA often involves the aorta, subclavian arteries and branches of the carotid and vertebral arteries; this condition is named “large-vessel-GCA”. Possibly, the respective patients represent a subgroup, since they are more frequently women (90%) and younger (with a peak between 60-70 years) than those with predominantly cranial symptoms such as ocular symptoms and jaw claudication [13]. However, they still fulfil the ACR criteria of an onset of disease beyond the age of 50 and an increase of (CRP and) ESR, the latter regularly exceeding 40 mm/h. Constitutional symptoms are frequent in the acute form, sometimes with fever of unknown origin in the beginning. There are no specific laboratory tests. Interleukin-6 and Pentraxin-3 are correlated with disease activity but so far have not reached clinical relevance. Temporal biopsy may prove the disease but is less sensitive in case of large vessel GCA. Colour-coded Doppler ultrasound (CDUS) is valuable for detection of vessel inflammation both in the temporal artery and in large vessels, showing homogeneous hypoechogenic vessel wall enlargement (Fig. 1). Typical hypodense enlargement of the vessel wall is seen by CT. MR-angiography may reveal increased perfusion within the aortic wall indicating local inflammation [6]. In patients with a subtype of large vessel GCA, inflammation of the aorta is frequent (especially in the thoracic part). It is, however, still considerable in cranial-type GCA patients. CTA or MRA reveal an aortic involvement in 30 – 65 % of patients [14, 15]. By means of CTA, PrietoGonzales et al. found large vessel vasculitis of the aorta in 26 out of 40 consecutive patients with newly diagnosed biopsy-proven GCA. In all cases, the thoracic aorta was affected, in 19 patients, the abdominal aorta showed vessel wall enlargement as well. In 6 patients there was al-

ready aortic dilation by the time of diagnosis. In all but three patients vessel wall thickening was found in aortic branches as well. On the contrary, there was only one patient with large vessel GCA in whom the aorta was spared [15]. 18 F-fluorodeoxyglucose positron emission tomography (PET) might have a higher sensitivity for aortic involvement in the disease and shows larger extension of inflammatory areas than CT [16]. PET is of special value if isolated GCA-aortitis is considered and if active inflammation is suspected although laboratory inflammation parameters are normal. If used to clarify unexplained general symptoms as fever of unknown origin, 18FDG enrichment in the aortic wall often gives the first hint at an underlying vasculitis. In untreated patients, it has a sensitivity of > 90 %. Apart from that, if the diagnosis of GCA was established by other means, PET is dispensable; the additional information gained is seldom decisive and its sensitivity rapidly decreases once an immunosuppressive therapy is initiated. Moreover, persisting 18FDG enrichment may correspond to vessel wall remodelling and is not proof of active inflammation [14]. Aortic involvement may produce chest or back pain but is more frequently asymptomatic. In rare cases, it represents the only manifestation of GCA. Usually, it is found in complementary investigations after other symptoms gave the clue to diagnosis. Anyhow, its disclosure is of importance since patients with initial aortic involvement tend to more frequently experience cardiovascular complications and a higher rate of recurrence [17], thus probably requiring more intense treatment. On the other hand, aortic manifestation may develop in the course of disease of formerly unaffected patients. García-Martínes et al. per-

Figure 1. Vasculitis of the aortic arch in a 69-year-old woman presenting with atypical chest pain and an ESR of 37 mm/h. CT shows a non-circular vessel wall thickening (A). Diagnosis of GCA was made by the detection of an enlarged vessel wall in the left common carotid artery (B) and subclinical stenosis of the left axillary artery (C).

Vasa (2016), 45 (1), 17 – 29

formed a follow-up study of initially 54 patients who were CT-investigated for structural aortic damage every four years. Morphological abnormalities and growing diameter were detected in an increasing number of patients, with a prevalence of about 20 % after 5 years coming to about 30% after 10 years. Eight of the patients met the criteria for aortic interventions and one died of dissection [18]. Development of aortic sequelae was unpredictable and more pronounced in patients with good clinical response to initial treatment. The percentage of patients in remission of active disease was considerably higher in patients with aortic involvement than in those without. Pathological investigation distinguished loss and disorganisation of elastic fibres in all of 6 cases, but sparse active inflammatory infiltrates in only two of them. Late damage of the aorta in GCA may be due to repairing mechanisms as well as to persistent vasculitis. In patients with aortitis due to RCA, immunosuppression with glucocorticoids is the initial treatment of choice. Although not validated by controlled studies, it is generally suggested to start with 1 mg prednisolone equivalent/kg body weight and a maximum of 60 mg/d. Tapering is begun after 3 – 4 weeks once laboratory parameters greatly improved or normalised. Constitutional symptoms mostly have resolved by this time. According to the European league against rheumatism (EULAR), in uncomplicated cases a stepwise reduction should lead to a level of 10 – 15 mg/d after three months [19]. A slower reduction scheme, by 10 mg every 2 weeks down to 20 mg, then by 2.5 mg down to 10 mg is recommended by the British Society of Rheumatology [20]. Further reduction is slow, with steps of 1 mg every 4 weeks, the treatment thus extending over at least one year. Long-term treatment with glucocorticoids implies considerable side effects, such as a decline of diabetic control, glaucoma, cataract, weight gain and osteoporosis, medication against which is obligatory. There is high interest in steroid sparing co-medication. For this purpose only methotrexate (MTX) is proposed [19], which was effective in a meta-analysis of three studies. However, the effect is small and the substance may have side effects itself. TNF-α-blockers have not been proven to be useful in initial treatments [21]. Positive results in case reports suggests their use if the re-induction of glucocorticoids and MTX is ineffective to control inflammation. Cyclophosphamide also may be useful in this situation [22]. Recently, there were encouraging results with the Interleukin-6-antagonist tocilizumab [23] which is presently tested in larger studies. The risk of infections seems increased under this treatment. Aspirin 100 mg/d is advised in addition. No controlled studies are available, but due to the number of cardiovascular events especially in patients with aortic involvement [17] a benefit of aspirin is expectable. There is no treatment differentiation between patients with or without aortic manifestation. Aortic vessel wall thickening should be controlled and is likely to decrease during treatment. A French study reported permanence of vessel wall thickening in 40 % of 48 GCA patients with aortic involvement after 6 months of treatment. However, inflammatory activity was low in these patients and during © 2016 Hogrefe

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follow up an operation was only necessary in two patients in whom vessel diameter had been increased initially [24]. In the series of Daumas, steroid response in patients with aortitis was better than in those without and time to relapse was more prolonged. PET showed a persisting uptake of 18FDG in patients with reduction of vessel wall diameter assessed by helical CT. This result did not influence the intensity of treatment since no other parameters implied disease activity [14]. However, it is possible that slow inflammation processes mediated by Th1-lymphocytes are responsible for the development of aortic aneurysm in late disease. Inflammation via this mechanism, which is triggered by interleukin-12, is less susceptible to corticosteroid treatment than the variant inflammation pathway in which interleukin-6 induced Th17-lymphocytes account for the acute symptoms of vasculitis [12]. Therefore, a rapid decrease of symptoms due to drugs depressing the IL6-pathway may be treacherous as premature treatment withdrawal could allow parts of the inflammation to persist. Up to now, there is no prognostic criterion for future development of aortic aneurysm or dissection and a favourable initial response to treatment does not rule out these sequelae [18]. To become aware of impending complications, a regular surveillance is demanded during the follow-up of GCA. This led to the advice to perform biannual chest x-ray controls in all patients with GCA. However, this proceeding must be handled with care and restricted to patients whose condition would allow an active treatment in case of aneurysm detection [25]. Surgical repair was possible in a third of patients only [18]. Although aneurysms with underlying vasculitis have a greater tendency for rupture or dissection than atherosclerotic aneurysms, due to advanced age of patients and comorbidities elective surgery in the ascending aorta is only recommended if the vessel diameter exceeds 5 cm or if severe aortic regurgitation develops. In emergency cases, stent graft implantations are performed increasingly more often. If possible, activity of the disease should be minimised in all vasculitis patients by the time of operation. Surgical interventions are preferred because of a better long-term outcome.

Takayasu arteritis (TA) Conversely to GCA, TA is rare in European countries but is the most frequent large vessel vasculitis in Far East and India with a prevalence of 4/100,000 in Japan [26]. The ACR criteria of 1990, still applicable in general, describe TA as vasculitis in younger (predominantly < 40 years at disease onset) patients (female > 90%) with symptoms related to the obstruction of mainly supra-aortic vessels: effort-induced weakness or pain in one or more extremities, reduction of pulses in arm arteries, a pressure difference of more than 10 mmHg between arms, vascular murmurs over one or two subclavian arteries or the abdominal aorta and obstructions or occlusions of the aorta or its branches of primary or secondary order [27]. This last criterion was Vasa (2016), 45 (1), 17 – 29

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originally said to be proven by angiography, which is restricted to patients in whom an intervention is considered necessary. However, along with clinical investigation, other forms of imaging play a crucial role in the diagnosis of TA. CDUS is the method of choice to reveal wall proliferation in supra-aortic vessels ensuring the diagnosis [28]. Once TA is suspected, investigation of all large vessels is mandatory and has to cover the intrathoracic vessels and the aorta which are frequently affected. They can be assessed by CT or MRA [6, 26], the latter being preferred as most patients are women of child-bearing age. As in large vessel GCA, there are a number of TA-patients with constitutional symptoms at onset of disease including fever and an elevation of inflammation indicating laboratory parameters, although less pronounced. Detection of early vessel wall alterations may help with the diagnosis in this initial phase and allow treatment before obstructions occur [28, 29]. At this stage, aortic involvement is already considerable. As in large vessel GCA, aortitis may be first diagnosed by PET [30]. The pattern of occurrence of vasculitis in various vessel sections was the basis for the classification of Hata and Moriwaki [31]. With the exception of Type I, defined as an affection of supra-aortic arteries only, thoracic and/or abdominal aorta are involved in all other types. Type V represents the most extended disease in all parts of the aorta and its branches and is associated with a higher cardiovascular risk and more frequent relapse. Extension of the disease during its course is possible and propagation to aortic affection in former Typ-I-disease is described [32]. On the other hand, the (thoracic rather than abdominal) aorta may be the only site of manifestation. Initial treatment consists of glucocorticoids following the scheme indicated for GCA. However, patients with TA are more prone to relapses and other immunosuppressants added to steroid therapy may be useful from the beginning, at least after recurrence. MTX, azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil have been used. In a second line therapy, TNF-α-antagonists are effective [33]. Patients with TA also benefit from tocilizumab, with a small number of non-responders [34]. Due to a relapse rate of more than 50 %, treatment duration is often more than a decade. As for GCA, interventions are only required in the case of ischemia or impending aneurysm rupture, and surgical interventions show better long term outcomes. Frequency of aortic interventions is low in comparison to other target vessels, especially to proximal subclavian and cerebral arteries in symptomatic patients. Although the aorta is involved in 50 – 60 % of TA patients, interventions are needed only in 3 – 5 %. While operative measures in GCA are mostly required for aneurysms, TA patients may develop severe stenoses up to occlusion, particularly in the infrarenal section. In these cases, stenting has been performed, but recurrences are more frequent than for open surgery. Moreover, renal arteries are often involved which requires complex operations. Relapses are frequent and comprise the formation of aneurysms at anastomoses in up to 25 % Vasa (2016), 45 (1), 17 – 29

of TA patients, but their occurrence is considerably reduced if immunosuppression is continued [26, 35, 36]. Disease activity in the vessel wall may recur without elevation of laboratory inflammation parameters. Therefore, imaging should be regularly controlled as well.

Behçet’s disease (BD) Behçet’s disease has its main prevalence of up to 1:1000 habitants along the ancient “silk route” connecting Turkey and Northern China, but is also frequent in Northern Africa and increasingly diagnosed in Western countries [37]. It mostly affects younger adults at an age of 20 – 40 yrs with a predominance in males. Categorised as vasculitis of a variably sized vessel, in 10– 20 % of patients BD is affecting larger vessels, the majority of which are veins. About 5 % of patients have arterial manifestations which may lead to vessel occlusions, but more frequently result in aneurysmal enlargement of one or sometimes several segments. The aorta is the main site of aneurysm development [38]. Dilation is mostly eccentric, thus formally resembling infectious aneurysms. Also, the increase in diameter may proceed rapidly. In addition to constitutional symptoms, patients often suffer from thoracic, abdominal or back pain. Laboratory inflammation parameters are elevated nonspecifically. A hint to the diagnosis can be obtained from the “pathergy test”, which consists of the intradermal injection of 0.1 ml 0.9 % saline to the forearm skin and is positive if a papule or pustule emerges within 24 – 48 hrs. Specificity of the test is > 90 %, but sensitivity decreases over time, presently rated to be 30 – 50 % in developed countries [39] and less in patients with vascular involvement in comparison to those without (46 vs. 56 % [38]). Typical symptoms such as uveitis and pseudofolliculitis may hint at the diagnosis, but organ involvement in general is very variable – with one exception: Nearly all patients have or had oral ulcers by the time of aneurysm detection. Questioning the presence of oral ulcers may be decisive to obtain the diagnosis and to distinguish the clinical picture from infectious aneurysm. In patients with active BD leading to aortic disease, aneurysm progression may be stopped and even reversed by immunosuppression. Glucocorticoids are the first line treatment and dosage recommendation follows that of large vessel vasculitides [40]. Additionally, cyclophosphamide and azathioprine are frequently used. Treatment duration will take at least two years. If classical inmmunosuppressant drugs are ineffective, biological agents as TNF-α-inhibitors are applied [41]. Nevertheless, interventions are required in a high number of cases with aortic involvement, mainly for aneurysms. Increasingly, stent grafts are used [42]. Operation sites must be regularly controlled for the development of pseudoaneurysms at bypass anastomoses. Both type I and type II endoleaks are described after stent graft repair. Patients with vascular Behçet’s are prone to development of venous thrombosis and coincidence may be more © 2016 Hogrefe

than 50%. Additional venous complications imply a lower remission rate [40]. In patients with vascular lesions, there is a higher incidence of cardiac BD manifestations and a higher mortality rate. Clinical outcome and survival may be improved by continued immunosuppression and a high intensity of follow-up.

Cogan’s syndrome (CS) Originally defined as keratitis and hearing loss caused by immune phenomena, Cogan’s syndrome (CS) meanwhile was recognised to be a form of vasculitis regarding histology and constitutional symptoms. It mostly begins within the 3rd and 4th decade, with equal gender distribution. In 10 % of cases of this rare disease, thoracic or thoraco-abdominal aorta may be involved, sometimes after a large interval [43]. Assessment by CT or MRA shows a homogeneous wall thickening indistinguishable from TA. Aortic involvement may occur years after the onset of disease, without other signs of activity. Vessel wall inflammation can result in aneurysm formation [44]. Presence of ocular and otological symptoms along with improvement during immunosuppressive therapy alleviates the diagnosis. Aortitis in Cogan’s syndrome is mostly treated with glucocorticoids, with a dosage varying between 0.5 and 2 mg/kg/d. In the case of response, tapering over 2 – 6 month is possible. A considerable number of patients do not respond and must be treated by anti-inflammatory agents, preferably methotrexate, otherwise azathioprine, cyclophosphamide or cyclosporine A [43]. Involvement of the ascending aorta requires surgery, often with replacement of the aortic valve. In other locations, endovascular repair was successful, but in case of extended disease surgery is preferred [44].

Other vasculitides and rheumatologic disorders In rare cases, ANCA-associated vasculitides [45] and aneurysm-forming polyangitis nodosa may include the aorta. It can also be involved in autoimmune disorders. In ankylosing spondylitis the aortic root predominantly is concerned [46] and aneurysm formation has been described. Occasionally, aortic inflammation is found associated with rheumatoid or psoriatic arthritis, systemic lupus erythematosus, sarcoidosis and inflammatory bowel diseases. In almost all of these cases, diagnosis of the primary disorder is known by the time aortic inflammation or aneurysm are detected and diagnostic skill lies in the awareness that such complication may occur. Aortic valve regurgitation must be regularly checked for in clinical visits. This and associated symptoms should induce further diagnosis (CT, MRA), revealing the inflammation mostly in the aortic arch. Atypical chest pain or abnormal chest radiography are other findings along with this condition. © 2016 Hogrefe

L. Caspary: Inflammatory diseases of the aorta

Aortitis secondary to other vasculitides or rheumatologic diseases basically is treated by escalation of the medical regimen. Interventions are needed in cases of complication but should be performed only after inflammation has reduced.

Isolated aortitis (IA) Isolated aortitis (IA) is found primarily in the ascending part of the thoracic aorta. As this condition rarely produces clinical symptoms, it is mostly diagnosed during operations prompted by aortic dissection or the formation of aneurysms which are often combined with aortic valve regurgitation. In several published series [47 – 49], it accounts for the majority of inflammatory diseases found in surgery for ascending aortic aneurysm or dissection, which represented about 5 % of the total number of operations. While the inflammatory character of the lesion often is obvious to the vascular surgeon, in some cases diagnosis is only obtained from pathologic specimen. Isolated aortitis is regarded to be a specific clinical entity, which is diagnosed if no infection and no signs of rheumatologic or other systemic diseases are seen and vessel wall inflammation does not extend to other arteries. Accordingly, inflammatory parameters such as ESR and CRP are mostly within normal ranges. Patients in a series of western countries were predominantly female, with a mean age between 63 and 73 years, which is comparable to the distribution in GCA. In a recent Chinese operation series, patients were younger and mostly male [50]. In an Italian study where diagnosis was made by PET with an isolated 18FDG uptake to the aorta, 9/11 patients were male and age at diagnosis with a mean of 62 years was considerably below that of a comparative group of RCA patients [51]. Burke introduced a histological classification based on the presence or absence of media necrosis. [52] Among patients with necrotising aortitis, a bimodal distribution was seen with a cut-off at 65 years. Younger patients were balanced with regard to sex, while the female sex prevailed in older patients. Whether this distinction has an epidemiological or therapeutic impact is not clear. Diagnosis mostly is made after operation which eliminates a great part of the inflamed tissue. In these cases, immunosuppressant drugs do not seem necessary [47]. However, the remaining aorta should be investigated for persisting inflammation in other parts. This condition might require immunosuppression, which is also advised if vessel wall thickening is detected together with constitutional symptoms, chest or back pain. PET may be useful to guide the decision. Inflammation of caudal parts of the aorta can develop in the further course of disease, so regular controls are needed.

IgG4-related aortitis In a certain number of patients, aortitis may be part of the spectrum of IgG4-related diseases. The relevance of the Vasa (2016), 45 (1), 17 – 29

L. Caspary: Inflammatory diseases of the aorta

antibody subclass of IgG4 for the development of fibrous organic diseases was first recognized in Japan regarding autoimmune pancreatitis (AIP; [53]). IgG4-positive AIP had a more benign course and was susceptible to immunosuppressive treatment. Within a short time, a considerable number of organ manifestations were described in which fibrous inflammation could be ascribed to plasmacellular infiltrates staining positive for IgG4. The respective diseases were summarised under the term of IgG4-related diseases (IgG4-RD; [54]). Diagnosis basically is made of pathologic specimen and approved if a proportion of 50 % of plasma cells in the infiltrate is expressing IgG4. Infiltrate architecture resembles the hub of a wire wheel or a woven mat and is therefore termed “storiform”. Typically, serum IgG4 levels are elevated to above 1.35 g/l, albeit found within the normal range of 0.05 – 1.25 g/l in blood samples of more than 20 % of patients. A survey of diseases is given in Table II but must remain incomplete since virtually any organ may be affected. IgG4-related disease has a systemic character and can appear in different organs which may be affected simultaneously or within a longer period of time (e.g. periaortitis and pleuritis; [55]). Thus, a patient in whom an IgG4-RD was diagnosed may develop a similar disease in other organs. After first revealing thoracic aortitis which was IgG4related, Stone et al. came to the assumption that this condition accounts for half of the cases of thoracic lymphoplasmacytic aortitis [56]. Laco et al. found the typical histological aspect with numerous plasmocytes staining for IgG4 in 6 out of 11 patients [57]. Agaimy et al. detected lymphoplasmacytic infiltrates in a high number of specimens among 15 out of 376 patients operated for thoracic aortic aneurysms. In this series, none of the patients had elevated IgG4-antibodies in peripheral blood [58]. As a consequence, aortic specimens yielded during operation should be analysed for IgG4-staining of lymphoplasmacytic cells. Assignment of aortitis to IgG4-RD might be of relevance, since other IgG4-RD manifestations could develop in future. Immunosuppression should be considered if signs of inflammation show postoperatively, but lower steroid doses may be sufficient. Initial doses of 3040 mg prednisolone equivalent/d are efficient in other IgG4-RD [54].

Periaortic inflammation Chronic periaortitis (CP) Chronic periaortitis (CP) generally is located in the abdominal aorta and to variable extent in the iliac arteries. There are no sound epidemiological data, but it is a rare disease predominantly found in men and at ages below 60 years. It often causes abdominal or back pain and can also be accompanied by fatigue and fever [59]. Vessel wall Vasa (2016), 45 (1), 17 – 29

enlargement is almost circular and concerns the adventitial layer. Investigation by CT, MRA and – in most cases feasible – ultrasound reveals hypointense/hypoechoic vessel wall enlargement outside the tunica media which can easily be identified in case of vessel wall calcifications beneath the inflammatory tissue (Fig. 2). The alterations are sometimes found unexpectedly in asymptomatic cases where inflammation may be inactive. Unspecific inflammatory parameters are variably elevated. At the time of diagnosis the aortic diameter often is normal.

Retroperitoneal fibrosis (RF) Retroperitoneal fibrosis (RF), also known as Ormond’s disease (OD), has a prevalence of about 1:100,000 and starts at an age of 40-60 years, with a higher incidence in men (2 – 3:1). Histology of the inflammation is comparable to that of CP. In RF, inflammation exceeds the periaortic area and spreads within the retroperitoneal tissue where it can encompass other structures, especially the vena cava and ureters and also the duodenum. Constriction of the ureter leads to hydronephrosis and possibly renal failure, while obstruction of the vena cava or lymphatic vessels may produce bilateral leg swelling. Both can be the initial symptom of the disease, and may also be detected by general symptoms or accidentally. Back pain or abdominal pain is reported by about 40 % of patients. While in 70 – 80 % of cases RF is regarded as idiopathic, secondary forms may originate from a variety of diseases such as retroperitoneal metastatic tumours or serotonin-excreting carcinoid, drugs (β-blockers, ergotamine-derived drugs, TNF-αblockers), trauma or abdominal surgery, rare histiocytoses and radiotherapy [60]. Histology should be obtained to rule out malignancy in newly diagnosed retroperitoneal tumours. Laboratory testing is demanded, but typical inflammatory parameters are elevated in only half of the cases of primary disease. The diagnosis can be made by ultrasound. For exact documentation of fibrosing tissue extension and follow up, CT or MRT are required. Kidneys should always be controlled for dilated calyces and function.

Inflammatory abdominal aneurysm (IAA) Inflammatory abdominal aneurysm (IAA) describes a condition in which periaortic inflammation is accompanied by aneurysmal dilation. Within the course of CP or RF, this may develop in an initially normal sized abdominal aorta. Perivascular inflammation also can develop in pre-existent degenerative aneurysms [61]. As in CP or RF, active inflammation may generate back pain and abdominal aching. Progression of the inflammatory process to ureter surrounding tissue can result in hydronephrosis and urinary infections. The disease may be inactive and detected by routine ultrasound investigation only. Typical age at onset is in the 6th to 7th decade and most patients are male. Labo© 2016 Hogrefe

L. Caspary: Inflammatory diseases of the aorta

Table II. IgG4-related diseases Disease

Organ involved

Autoimmune pancreatitis (AIP)

Pancreas

Sclerosing cholangitis

Bile duct

Autoimmune esophagitis

Esophagus

IgG4 hepatopathy

Liver

Sclerosing mesenteritis

Mediastinum

Mikulicz’s disease

Lacrimal gland

Küttner tumor

Salivary gland

Riedel’s thyroiditis

Thyroid

Mastitis

Breast

Skin pseudolymphoma

Skin

Membranous nephropathy, tubulointerstitial nephritis

Kidney

Idiopathic segmental ureteritis

Ureter

Prostatitis

Prostate

Retroperitoneal fibrosis

Retroperitoneum

Inflammatory aortic aneurysm, periaortitis

Arteries

Constrictive pericarditis, pseudotumor

Heart

Interstitial pneumonia, hilar lymphadenopathy, pleuritis

Lung

Uveitis, ocular adnexal lymphoma

Eye

Hypophysitis

Pituitary gland

Sclerosing pachymeningitis

Central nervous system

ratory changes are not specific. An increase of CRP and ESR is frequent, but less pronounced than in large vessel vasculitis. Except for continuous expansion to iliac arter-

ies, extra-aortic vessels are rarely clinically involved. In large aneurysms, typical complications such as dissection and rupture can occur. CT or MRA are performed in symptomatic patients. There are several indications suggesting that CP, RF and IAA represent a type of vasculitis with systemic character. Histological studies showed that inflammation starts within the vasa vasorum comparable to large vessel vasculitis. Patients may exhibit signs of generalised disease such as fever, weight loss and fatigue. In some cases perivascular inflammation was found in vessels distant of the abdominal aorta such as renal and celiac arteries and the thoracic part of the aorta (not being isolated thoracic aortitis) and even around the coronary vessels and the mitral valve. Taking into account the similarities in mean age, prevailing male sex, histological features and a possible transition between CP, idiopathic RF and IAA, the three diseases appear as different forms of the same vasculitic disease [62]. Nevertheless, there is no uniform underlying pathology for these relating diseases. In a considerable proportion of CP, RF and IAA histopathology shows lymphoplasmacytic infiltrate staining positive for IgG4. Soon after the first descriptions of these findings it was estimated that about half of the cases of IAA belong to IgG4-RD [63]. Correspondingly, more than 50% of RF may be regarded IgG4-RD [64]. Differing from thoracic manifestations, serum IgG4 level regularly is elevated in these cases and its assessment may allow a distinction between the two forms of periaortic disease. The meaning of this differentiation is not yet clear. Vasculitis-like CP may have another outcome than IgG4-related CP. In the latter, manifestations of IgG4-RD may occur in remote organs [65]. Although under discussion, the hypothesis might be considered that the inflammation resulting in CP and IAA is an allergic reaction to atherosclerotic plaques. Parums reviewed 440 sections of atherosclerotic aortas and arteries presenting with advanced atherosclerotic plaques in 85 % of cases. He found adventitial inflammation com-

Figure 2. Periaortitis in a 58-year-old man. ESR 18 mm/h, CRP not elevated, IgG4 2.24 g/l (normal range: 0.5 – 1.25 mg/l). Inferior mesenteric artery (IMA) is running through the inflammatory tissue.

Vasa (2016), 45 (1), 17 – 29

L. Caspary: Inflammatory diseases of the aorta

Figure 3. Relationship between chronic perioaortitis (CP), retroperitoneal fibrosis (RF) and inflammatory aortic aneurysm (IAA). CP may evolve into RF and IAA. The latter may develop from degenerative aortic aneurysm as well, sometimes after stent graft repair. IgG4-RD may account for all forms of the disease, as well as vasculitis does, which may be primary or associated with other immunological disorders. In RF, secondary forms must be ruled out. Ureteral obstruction can be caused by RF and by IAA.

bined with subclinical chronic periaortitis in nearly half of these cases [65]. Mechanisms of local inflammation may be active when periaortic inflammation develops around pre-existent aneurysms, which was well documented by serial CTs [66]. Moreover, de-novo periaortitis was observed after stent graft repair of atherosclerotic aortic aneurysms [67,68] which must be considered a possible trigger of inflammation. Inflammatory periaortic tissue can be detected in 2-3% of those cases and may even cause ureteral obstruction. In a recent study, significantly higher calcium content in the vessel wall (pointing to atherosclerosis) was noticed in 9 patients with periaortitis due to IgG4-RD compared to 8 patients suffering from idiopathic periaortitis [69]. The authors propose that IgG4 might be involved in autoimmune reaction to atherosclerosis, thus combining the two pathomechanisms and clearly distinguishing this entity from the vasculitis-type of non-IgG4related periaortitis. Remarkably, a number of patients were not included in the analysis because periaortitis was part of other defined vasculitides, IgG4 being elevated in some. In summary, the distinction between CP, RF and IAA basically is made on the grounds of morphology, but there are different types of underlying pathological conditions which can be found in all three forms of disease (Fig. 3). Similar modes of treatment seem adequate for CP, RF and IAA. If an idiopathic form of disease with clinical activity is diagnosed, most authors would start prednisolone at doses of 60 mg/d tapering over 3 – 6 months. Beyond that other anti-inflammatory drugs are applied, such as cyclophosphamide, mycophenolate mofetil, methotrexate and azathioprine, partially for resistance against glucocorticoids or in clinical need of reducing them [59]. Vasa (2016), 45 (1), 17 – 29

Tamoxifen, an anti-oestrogen agent developed for the treatment of gynaecological tumours, has proven to be efficient in patients with RF [70]. In more than 80 %, substantial symptom resolution was seen within 3 weeks of a monotherapy with 2 × 20 mg tamoxifen/d which was continued over two years. In a third of patients, complete resolution could not be obtained and immunosuppression was introduced, to which half of them responded well. In a double-blind study, Vaglio et al. compared prednisone to tamoxifen for eight months after an initial successful 4-week-treatment with prednisone 40 mg/d. A third of the patients in the tamoxifen group relapsed in form of mass progression, ESR increase, clinical symptoms or ureter obstruction, compared with one of 20 patients on prednisone following a reduction scheme [71]. Admittedly glucocorticoids were more successful, but tamoxifen had few and tolerable side effects (mainly hot flashes, fatigue/asthenia, and libido loss in men). Thus, it seems to be a valuable alternative for first line treatment at least in patients with concerns about steroid medication to which it might be switched in case of non-response. Caution is indicated if propensity for thromboembolism is assumed which may be propagated by tamoxifen (but can also be induced by glucocorticoids). Tamoxifen has not been studied in IAA. Whether its efficacy is depending on the involvement of IgG4 is not known. In order to spare glucocorticoids, cyclophosphamide may be used as well [72]. Ureter involvement is the most important complication of RF and IAA and the patient’s kidneys require our utmost attention [60]. However, hydronephrosis should be treated first by the insertion of ureteral stents which can mostly be removed once the retroperitoneal mass diminished. © 2016 Hogrefe

© 2016 Hogrefe Antibiotics preferably according to resistogram Surgery nearly always required Stent graft in special cases (e.g. treated salmonellosis) or as bridging procedure Prednisolon 60 mg/d, cautious tapering MTX may spare glucocorticoids AZT, CYP, TNF-α-blockers in case of frequent relapse (Tocilizumab in second line?) Aspirin 100 mg/d recommended Surgery in case of dissection or exceeding of critical size Prednisolon 60 mg/d initially, low doses over long time Additional anti-inflammatory treatment often required, frequent relapses Surgery/endovascular treatment in case of symptomatic distal ischemia, dissection or exceeding of critical size

Prednisolon 60 mg/d, tapering, often combined with AZT, MTX, CYP, MMF, CsA Surgery/endovascular treatment in case of symptomatic distal ischemia, dissection or exceeding of critical size Continuation of anti-inflammatory treatment after interventions

Escalation of specific treatment Surgery in case of dissection or exceeding of critical size Preferably glucocorticoids, dosage depending on inflammation activity Possibly reduced initial dosage sufficient in case of active IgG4-RD

Prednisolone 40 – 60mg/d, tapered according to inflammation activity and decrease of retroperitoneal mass. Possibly reduced initial dosage sufficient in case of IgG4-RD For steroid replacement, CYP, MTX, MMF, AZT may be used Tamoxifen 2 x 20 mg/d may be tried in first line Preferably glucocorticoids, dosage depending on inflammation activity Prednisolon 30 mg/d as starting dose in case of active IgG4-RD Surgery or stent-graft repair if critical diameter is exceeded Possible persistence of inflammation after stent-graft implantation

Endocarditis Paraaortic infection Rapid growth of aneurysm Septic digital embolism Age at onset of disease > 50 years Association with polymyalgia rheumatica Vessel wall inflammation in primary or secondary branches Late aneurysm formation Age at onset of disease < 50 years Vessel wall inflammation in primary or secondary branches

Former or present oral ulcerations in nearly all patients Specific pathergy test positive in 30-40% of patients Concomitant superficial phlebitis or deep vein thrombosis Ocular and inner ear symptoms Occurrence of aortitis in late course of disease

Mostly diagnosed on occasion of operation Possibly IgG4-related disease Rheumatic disease normally known by the time of detection May evolve into retroperitoneal fibrosis May evolve into inflammatory aneurysm Possibly IgG4-related disease Secondary diseases and malignancy must be ruled out Possibly IgG4-related disease Ureteral obstruction may occur

May develop after stent-graft for non-inflammatory aneurysm Possibly IgG4-related disease Ureteral obstruction may occur

Fever of unknown origin Abdominal or back pain Aneurysm rupture or fistulation

Extended investigation after diagnosis Vasculitis-type lesions in peripheral arteries Positive temporal biopsy Imaging for fever of unknown origin

Extended investigation after diagnosis Pulse deficit Vasculitis-type lesions in peripheral arteries Imaging for fever of unknown origin

Abdominal or back pain Imaging for fever of unknown origin Rupture of aneurysm

Aortic valve regurgitation

Acute thoracic dissection Aortic valve regurgitation

Extended investigation after diagnosis Abdominal or back pain

Imaging for constitutional symptoms Abdominal or back pain Routine ultrasound screening

Imaging for constitutional symptoms Renal failure due to hydronephrosis Leg swelling

Imaging for constitutional symptoms Abdominal or back pain Routine ultrasound screening

Infectious aortitis

Giant cell arteritis

Takayasu arteritis

Behçet disease

Cogan Syndrome

Isolated aortitis

Rheumatic diseases

Periaortitis

Retroperitoneal fibrosis

Inflammatory aortic aneurysm

Surgery Prednisolone 30-40 mg/d if inflammatory activity persists

Prednisolon 60 mg/d initially, in case of non-response (frequent): MTX, AZT, CYP, CsA Replacement of aortic valve and/or ascending aorta, if indicated Surgical repair for extended aneurysm development

Treatment

Specific features

Occasion of detection

26 L. Caspary: Inflammatory diseases of the aorta

Vasa (2016), 45 (1), 17 – 29

L. Caspary: Inflammatory diseases of the aorta

Ureterolysis or other reconstructive operations may be necessary if medical treatment is insufficient. Normally, end-stage renal disease can be avoided. If the periaortic disease is associated with IgG4, initial steroid dosage may be lower than in case of vasculitis. An observational study in IgG4-positive periaortitis showed a significant reduction of inflammatory parameters and vessel wall enlargement under variable prednisolone treatments, initiated with 15 – 50 mg/d and tapered to 5 – 10 mg/d during 6 – 12 months. Aortic wall diameter decreased by 50 % within the first two months of treatment; after that a further decrease was observed in half of the patients [73]. There were a few patients with IAA in whom aneurysmatic dilation increased despite reduction of the adventitial inflammatory border. Interventions in IAA should be restricted to aneurysm diameters exceeding 5 – 5.5 cm or rapid diameter increase (> 1 mm/month) accompanied by clinical symptoms. Danger of rupture is not higher than for atherosclerotic aneurysms of equal size. Open surgery, consisting of graft inclusion with minimal dissection of the surrounding structures, is challenging but may be definite and cause periaortic inflammation to subside. This is comprehensible for those particular cases in which inflammation stands for an immune reaction to atherosclerosis and an aneurysm had already formed before adventitial enlargement began. However, inflammation may also continue and resuming immunosuppressive treatment seems particularly important if ESR elevation persists after the intervention. In IgG4-RD, disease activity cannot be deduced from antibody titres [54]. It must be further assessed by organ function or, in case of vessels, changes in vessel wall diameter. For abdominal aortic aneurysm, stent-graft insertion is increasingly preferred to open intervention but applied with restraint in the case of IAA. There is some concern since adventitial inflammation is unaffected by the procedure. Progress [74] and even de-novo-evolution of retroperitoneal inflammation were observed after stent-graft insertion [68]. Additionally, open surgery allows repair of ureteral obstruction which inevitably persists after endovascular stenting. Nevertheless, recent validations suggest that stent-graft implantation is safe and in the majority of cases follow-up has shown an improvement both in terms of aortic diameter reduction and in reduction of periaortic fibrosis [75]. Stenting, as well as open surgery, is not an exhaustive therapy for IAA. The course of development of periaortic thickening, laboratory parameters, encompassed structures and a patient’s constitutional symptoms determine the necessity and intensity of a further anti-inflammatory treatment. On the other hand, inflammatory activity may cease, following treatment or even spontaneously. Hence, periadventitial tissue enlargement detected occasionally does not necessarily require medication. This holds true even if IgG4 antibodies are detected since these do not directly mirror disease activity. If no concomitant clinical symptoms are noticed and ureteral obstruction is ruled out, watchful waiting is adequate. Vasa (2016), 45 (1), 17 – 29

Conclusions Inflammatory aortic diseases comprise a broad spectrum of underlying pathologies. Although rare, they should be regarded in patients with constitutional symptoms. Imaging (CT, MRT) is often the clue to revealing this condition; PET may be even more sensitive. Local symptoms such as abdominal, chest or back pain may guide the attention but are frequently missing. Distinction of infectious from noninfectious inflammation is crucial, the former characterised by rapid growth of aneurysm. Findings outside the aorta itself are helpful for disease classification such as valve endocarditis in case of infectious aortitis, wall thickening in primary or secondary aortic branches in the case of large vessel vasculitis and oral ulcers in cases of BD (Table III). On the other hand, aortitis may develop in the course of various diseases. In the case of large vessel vasculitides, it must be searched for actively, while in BD and a number of rheumatologic diseases, especially ankylosing spondylitis, the awareness of its possible occurrence is decisive. Aortic valve regurgitation may be a hint at dilating aortitis of the ascending aorta. Isolated aortitis is seldom diagnosed before complications demand an emergency intervention, mostly for aortic dissection. Inflammatory diseases of the periaortic tissue (CP, RF and IAA) are increasingly regarded as parts of one pleomorphic vasculitis. On the other hand, up to half of these cases, as well as cases of isolated aortitis, may belong to the spectrum of IgG4-related diseases. Antibody determination is suggested, although consequences of the differentiation are uncertain. IgG4-related diseases may need a lower dosage of steroid treatment. Glucocorticoids are the first line treatment for virtually all types of non-infectious aortitis but development of new forms of treatment is desirable to reduce their considerable side effects. Unless in an emergency, interventions should be performed restrainedly and under immunosuppression, which mostly must be continued postoperatively. Surgery in general yields more durable results, but stenting procedures are increasingly applied due to lower periprocedural morbidity. Sustained follow-up is necessary to recognise disease relapse which is often revealed only by laboratory parameters or imaging. The management of patients with inflammatory aortic diseases requires an interdisciplinary approach.

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66. Hayashi H, Hidaka F, Kumazaki T, et al. Serial assessment of the development of inflammatory abdominal aortic aneurysm from ordinary atherosclerotic abdominal aortic aneurysm using multidetector-row computed tomographic angiography. Heart Vessels 2006; 21: 334 – 7. 67. Vijaynagar B, McMahon GS, McCarthy MJ. Periaortic inflammation after endovascular aneurysm repair. Ann Vasc Surg 2011; 25: 558. 68. Alomran F, de Blic R, Mallios A, et al. De novo periaortic fibrosis after endovascular aortic repair. Ann Vasc Surg 2014; 28: 493. 69. Castelein T, Coudyzer W, Blockmans D. IgG4-related periaortitis vs idiopathic periaortitis: is there a role for atherosclerotic plaque in the pathogenesis of IgG4-related periaortitis? Rheumatology 2015; 54: 1250 – 6. 70. van Bommel EF, Pelkmans LG, van Damme H, et al. Long-term safety and efficacy of a tamoxifen-based treatment strategy for idiopathic retroperitoneal fibrosis. Eur J Intern Med 2013; 24: 444 – 50. 71. Vaglio A, Palmisano A, Alberici F, et al. Prednisone versus tamoxifen in patients with idiopathic retroperitoneal fibrosis: an open-label randomized controlled trial. Lancet 2011; 378: 338 – 46. 72. Binder M, Uhl M, Wiech T, et al. Cyclophosphamide is a highly effective and safe induction therapy in chronic periaortitis: a long-term follow-up of 35 patients with chronic periaortitis. Ann Rheum Dis 2012; 71: 311 – 2. 73. Mizushima I, Inoue D, Yamamoto M, et al. Clinical course after corticosteroid therapy in IgG4-related aortitis/periaortitis and periarteritis: a retrospective multicentre study. Arthritis Res Ther 2014; 16: R156. 74. van Bommel EF, van der Veer SJ, Hendriksz TR, Bleumink GS. Persistent chronic peri-aortitis (‘inflammatory aneurysm’) after abdominal aortic aneurysm repair: systematic review of the literature. Vasc Med 2008; 13: 293 – 303. 75. Stone WM, Fankhauser GT, Bower TC, et al. Comparison of open and endovascular repair of inflammatory aortic aneurysms. J Vasc Surg 2012; 56: 951 – 5, discussion 955 – 6. Submitted: 12.06.2015 Accepted after revision: 30.08.2015 There are no conflicts of interest existing. Correspondence address PD Dr. med. Ludwig Caspary Angiologische Praxis Luisenstr. 10/11 30159 Hannover Germany lcaspary@t-online.de

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Original communication

Predicting the prevalence of peripheral arterial diseases: modelling and validation in different cohorts Yiqiang Zhan1, Jie Zhuang2, Ying Dong3, Hong Xu4, Dayi Hu5, and Jinming Yu1 School of Public Health, Fudan University, Shanghai, P. R. China Leibniz Institute for Plasma Science and Technology, Greifswald, Germany 3 Department of Preventive Medicine, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, P. R. China 4 Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention, and Technology, and Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden 5 Heart Center, Peking University People’s Hospital, Peking, P. R. China 1 2

Summary: Background: To develop models for prevalence estimation of peripheral arterial disease (PAD) and to validate them in an external cohort. Methods: Model training cohort was a population based cross-sectional survey. Age, sex, smoking status, body mass index, total cholesterol (TC), high density lipoprotein (HDL), TC/HDL ratio, low density lipoprotein, fasting glucose, diabetes, hypertension, pulse pressure, and stroke history were considered candidate predicting variables. Ankle brachial index ≤ 0.9 was defined as the presence of peripheral arterial disease. Logistic regression method was used to build the prediction models. The likelihood ratio test was applied to select predicting variables. The bootstrap method was used for model internal validation. Model performance was validated in an external cohort. Results: The final models included age, sex, pulse pressure, TC/HDL ratio, smoking status, diabetes, and stroke history. Area under receiver operating characteristics (AUC) with 95% confidence interval (CI) of the final model from the training cohort was 0.74 (0.70, 0.77). Model validation in another cohort revealed AUC (95% CI) of 0.72 (0.70, 0.73). P value of Hosmer-Lemeshow’s model goodness of fit test was 0.75 indicating good model calibration. Conclusions: The developed model yielded a moderate usefulness for predicting the prevalence of PAD in general population. Key words: Ankle brachial index, peripheral arterial diseases, model predicting, validation

Introduction Peripheral arterial disease (PAD), an obstructive atherosclerotic disease in the lower extremities, was repeatedly found to be associated with cardiovascular diseases, stoke, mortality, and poor quality of life in different populations [1 – 3]. The prevalence of PAD has been of increasing concern around the world for the last decades. It was reported that in the general population, around 10 % of people younger than 70 years and 20 % of people aged 70 years and over had PAD [4, 5]. However, only 10 % of PAD patients had typical intermittent claudication and asymptomatic PAD accounted for up to 75 % of total PAD [6]. The National Institute for Health and Clinical Excellence (NICE) published guidelines on the diagnosis of PAD as well as assessment of patients with suspected PAD [7]. It recommends that people with PAD should be offered a wide range of information regarding the condition including on key modifiable risk factors like smoking, diabetes, Vasa (2016), 45 (1), 31 – 36 DOI 10.1024/0301-1526/a000492

dyslipidaemia, obesity, and physical activity, whereas epidemiology studies on PAD are much fewer than those of other cardiovascular diseases. Thus, there is an urgent need for PAD surveillance, to investigate the aetiology, and to develop preventive and treatment strategies. To assess the prevalence of PAD, thorough examinations using ankle brachial index (ABI) or combing clinical symptoms are the typical methods for most of the current clinical and epidemiological studies [5, 7]. However, because these methods are sometimes expensive, time consuming, and resource and labour demanding, many epidemiological cohorts do not have these measurements, which might be a hurdle to further examine the risk factors of PAD or its predictive performance for other outcomes. Consequently, alternative cost-effective, reliable, and valid instruments for PAD prevalence surveillance at the national or regional level, such as scales or other routine examinations in epidemiological studies, are on the agenda of the scientific community. © 2016 Hogrefe

Y. Zhan et al.: Predicting peripheral arterial disease

In the present study, we aimed to (1) develop models for current population prevalence of PAD using a combination of self-reported questions and routine clinical metabolic biomarkers from a community based population; (2) to externally validate these models in another cohort.

Methods

in our survey, and 2998 were recruited (participation rate, 83.53 %). Among the recruited participants, we excluded 16 individuals who had disabilities making them unable to attend physical examinations or interviews; thus, data from 2982 participants were used in the final analysis. All participants provided written informed consent, and ethical approval was obtained from the Ethics Committee of the Beijing Municipal Science and Technology Commission.

Study population

Model validation cohort

Model training cohort The training cohort was a cross-sectional chronic disease and risk factor survey conducted in Beijing from May 2007 to August 2007. The details of the study design were reported elsewhere [8]. Briefly, 3589 community-dwelling adults aged 60 years and over were invited to participate

Table I. Basic characteristics of study participants in each cohort (mean ± SD) Variables

Training cohort (n = 2982)

Validation cohort (n = 6250)

Age (years)

68.1 ± 6.0

67.1 ± 11.1

Pulse pressure (mm Hg)

57.14 ± 17.25

58.77 ± 18.18

TC/HDL ratio

3.99 ± 1.10

4.18 ± 1.66

BMI(Kg/m )

25.31 ± 3.89

24.23 ± 3.67

Glucose(mmol/L)

5.39 ± 1.82

6.50 ± 4.75

TC(mmol/L)

5.09 ± 0.96

4.63 ± 1.17

HDL(mmol/L)

1.33 ± 0.31

1.20 ± 0.43

LDL(mmol/L)

2.67 ± 0.69

2.74 ± 0.90

male

1155 (38.7)

2909 (46.5)

female

1827 (61.3)

3341 (53.5)

yes

1088 (36.5)

2495 (39.9)

1894 (63.5)

3766 (60.1)

yes

566 (19.0)

2130 (34.1)

2416 (81.0)

4120 (65.9)

yes

348 (11.7)

2022 (32.4)

2634 (88.3)

4228 (67.6)

yes

1789 (60.0)

5022 (80.4)

1193 (40.0)

1228 (19.6)

Sex, n (%)

Smoking, n (%)

Diabetes, n (%)

Stroke, n (%)

Hypertension, n (%)

The validation cohort was originally designed to investigate the risk factors of PAD in patients with a higher cardiovascular disease risk. Details of the study design were previously described [9]. Six thousand four hundred and forty nine participants were recruited from collaboration hospitals in Beijing and Shanghai. Among them, 199 were excluded due to missing values in ABI measurements or other covariates, resulting in a study sample of 6250 for the present analysis. This study was approved by the ethics committee of Tongji University, and written informed consent was obtained from all the participants.

PAD ascertainment Doppler ultrasound (Nicolet Vascular, Elite 100R) was used to measure systolic blood pressure (SBP) at bilateral brachial, positional tibial and dorsal pedal arteries in the supine position after 5 minutes rest. The Doppler probe was used at a frequency of 5 MHz. Right and left ABI were calculated by the highest pressure at the dorsal or posterior tibial arteries on the corresponding sides, respectively, and by the highest brachial pressure on either side. PAD was defined as an ABI ≤ 0.9 in either leg.

Covariates Pulse pressure was calculated as the systolic blood pressure minus the diastolic blood pressure. Hypertension was defined as SBP ≥ 140 mm Hg, DBP ≥ 90 mm Hg, or current medication for hypertension and diabetes mellitus was defined as fasting glucose ≥ 7.0 mmol/L or current medication for diabetes. TC/HDL-C ratio was calculated by TC divided by HDL-C. Pulse pressure and TC/HDL-C were new variables that were considered here compared with previous models.

Statistical analysis Basic characteristics of the two study samples were shown as mean (± standard deviation) and numbers (proportions). Multivariable logistic regression models were Vasa (2016), 45 (1), 31 – 36

Y. Zhan et al.: Predicting peripheral arterial disease

Table II. Univariate analysis by peripheral arterial disease (PAD) in training cohort (mean ± SD) Variables

Non-PAD (n = 2776)

PAD (n = 206)

OR (95 % CI)

Age (years)

67.88 ± 6.01

71.69 ± 6.01

1.10 (1.08, 1.12)

Pulse pressure (mm Hg)

56.63 ± 17.25

64.00 ± 17.25

1.02 (1.01, 1.03)

TC/HDL ratio

3.96 ± 1.10

4.32 ± 1.10

1.24 (1.12, 1.38)

BMI(Kg/m )

25.31 ± 3.89

25.20 ± 3.89

0.99 (0.96, 1.03)

Glucose(mmol/L)

5.35 ± 1.82

5.98 ± 1.82

1.14 (1.08, 1.22)

TC(mmol/L)

5.08 ± 0.96

5.24 ± 0.96

1.18 (1.02, 1.35)

HDL(mmol/L)

1.34 ± 0.31

1.28 ± 0.31

0.52 (0.32, 0.86)

LDL(mmol/L)

2.66 ± 0.69

2.79 ± 0.69

1.30 (1.06, 1.58)

Sex, n (%)

1.14 (0.85, 1.53) male

1081 (38.9)

74 (35.9)

female

1695 (61.1)

312 (64.1)

Smoking, n (%)

1.35 (1.02, 1.80) yes

999 (36.0)

89 (43.2)

1777 (64.0)

117 (56.8)

Diabetes, n (%)

2.15 (1.58, 2.92) yes

500 (18.0)

66 (32.0)

2276 (82.0)

140 (68.0)

Stroke, n (%)

2.82 (2.02, 3.96) yes

296 (10.7)

52 (25.2)

2480 (89.3)

154 (74.8)

Hypertension, n (%)

1.81 (1.32, 2.48) yes

1640 (59.1)

149 (72.3)

1136 (40.9)

57 (27.7)

applied to develop the prediction models in the model training cohort. Likelihood ratio tests were used to determine which variables were included in the models. Harrell’s Concordance-statistics (C-statistics), equivalent to area under receiver operating characteristics curve in logistic regression, and Hosmer–Lemeshow’s model goodness-of-fit test [10] were used to evaluate model discrimination and calibration, respectively. C-statistics between 0.7 and 0.9 were considered moderately useful [11]. Bootstrap methods were used for internal model validation and over-optimism estimation [12]. Bootstrap analysis was replicated on 200 different samples of the same sample size drawn with replacement from the original training cohort. All of the 7 selected predictors were in the 200 bootstrap samples. Optimism, a measurement of internal model validation, equals the difference between respective statistics of the bootstrap sample and the original sample [12]. Optimism-corrected C-statistics were calculated as C-statistics from the original sample minus optimism. We also applied decision curve analysis and studied clinical usefulness of our models [13]. We externally validated the final model in the validation cohort. Vasa (2016), 45 (1), 31 – 36

Table III. Model coefficients based on training cohort Variables

Coefficients

Standard error

Intercept

–11.72

0.96

Age

0.09

0.01

Pulse pressure

0.01

0.004

TC/HDL ratio

0.19

0.05

female

0.38

0.18

yes

0.52

0.17

yes

0.54

0.16

yes

0.97

0.18

Sex (reference: male)

Smoking (reference: no)

Diabetes (reference: no)

Stroke (reference: no)

Y. Zhan et al.: Predicting peripheral arterial disease

Table IV. Model performance for peripheral arterial disease Performance measurements

Results

Results X2

5.06

P value

0.75

AUC

0.74 (0.70; 0.77)

Internal validation optimism

0.0015

optimismcorrected AUC

0.74

AUC

0.72 (0.70, 0.73)

External validation

Basic characteristics of study participants are shown in Table I. In the modelling training cohort, the average age was 68.1 ± 6.0 years with men comprising 38.7 % of the study population, while in the model validation cohort, the average age was 67.1 ± 11.1 years with men comprising 46.5 %. The prevalence of PAD was 6.9 % in the model training cohort and 22.1 % in model validation cohort. The univariate analysis by PAD in the training cohort was presented in Table II. The final model included age, sex, pulse pressure, TC/ HDL ratio, smoking, diabetes, and stroke history as predicting variables (Tab. III). The C-statistics and 95 % confidence interval (CI) was 0.74 (0.70, 0.77) in the training cohort (Tab. IV and Fig. 1). Optimism from Bootstrap internal validation was 0.0015 and optimism-corrected Cstatistics was comparable to the previous uncorrected one. Hosmer-Lemeshow goodness of fit test revealed P value of 0.75 indicating very good model calibration in the training cohort. In terms of model external validation, the C-statistics was 0.72(0.70, 0.73) as shown in Figure 1. The decision curve analysis (Fig. 2) showed that our prediction model could offer benefit if the threshold probability were from 2 % and onwards.

Discussion

Figure 1. The Area under the receiver’s curve for the model in training cohort and validation cohort.

Figure 2. Net benefit for the model.

In the present study, we developed a population prevalence prediction model for PAD in a training cohort and externally validated it in another cohort. We found that the models based on self-reported questionnaires and routine clinical metabolic biomarkers had a good discrimination capacity with C-statistics of 0.74 and 0.72 in the training and validation cohort, respectively. These results suggest that the model performance was moderately good and might be useful in PAD surveillance and epidemiological studies. Until now, several groups have proposed PAD prevalence estimation algorithms, of which the predictors in the models varied among different studies. For instance, the Netherland PREVALENT score [14] model included age, smoking behaviour, hypertension, coronary heart disease, and cerebrovascular disease (CVD) in the final models using stepwise logistic regression models. Likewise, the Spain REASON risk score included age, sex, smoking status, pulse pressure, and diabetes in the final model, which yielded AUC of 0.76 in both the training and validation samples [15]. Later, the same group compared the performance of two prediction scores and found that REASON had better performance in Spanish populations [16]. Another group developed a PAD score in a US cohort [17] and selected age, sex, race/ethnicity, smoking status, BMI, hypertension, heart failure, CVD, coronary artery disease, and diabetes in the final models with a moderate discrimination performance (C-statisVasa (2016), 45 (1), 31 – 36

Y. Zhan et al.: Predicting peripheral arterial disease

tics:0.61 – 0.64 in the training and validation samples). Because most of these models were based on samples from different regions and populations, they might not be applicable to the other cohorts, especially non-European populations. An approach for predicting the prevalence of PAD in communities is multivariable modelling using self-reported questionnaires combining some routine examination measurements. In our study, we developed a model in the training cohort considering several potential variables including age, sex, BMI, pulse pressure, fasting glucose, TC, HDL, LDL, TC/HDL ratio, smoking, diabetes, hypertension, and stroke history. Most of the variables were regarded as risk factors of PAD. Consistent with previous research results, age, sex, smoking, and pulse pressure were selected in the final model. Nevertheless, we considered more possible variables to be selected for model development. In addition to common lipid biomarkers (TC, HDL and LDL), we considered TC/HDL ratio as one of the candidate predicting variables because several studies had found a strong association between TC/HDL ratio and PAD independent of other conventional risk factors [18, 19]. In parallel with previous findings, TC/HDL showed a strong association with PAD and was superior to other lipid biomarkers; thus, it was selected in the final models via likelihood ratio test. Some more variables were also taken into account of model training in the present study. However, they did not show any significant improvement in model performance and were not included in the final model. Our results demonstrated that the prevalence prediction model we developed might be a promising PAD surveillance instrument for the community-based population. In the first place, internal validation analysis was conducted to avoid over-fitting of the prediction models. Bootstrap methods were used to estimate the over-optimism, and the optimism-corrected C-statistics were still good. Next, external validation analysis was performed in a different population. Although the source populations of the training cohort and validation cohort might be different, the model still performed well in the validation sample. The results of the external validation analyses ascertained the performance of our prediction model.

Limitations The definition of PAD was solely based on ABI. Further information regarding intermittent claudication would definitely reduce information bias. Secondly, although the model we developed was validated in an external cohort, the cohort was based on hospital participants rather than community people. Thus, additional community-based cohorts used for validation might provide robust evidence for the model performance. Vasa (2016), 45 (1), 31 – 36

Conclusions We developed a PAD prevalence model based on self-reported questions, demographic characteristics, and routine metabolic biomarkers that moderately predicted the population prevalence of PAD. This model was validated in an external sample in different times and regions and showed a moderate discriminatory power. Our findings may be helpful to assess PAD prevalence and surveillance and to track susceptible populations. In the future, the proposed model should be validated in other communitybased cohorts to evaluate their external performance.

Acknowledgements We would like to thank all participants involved in these two cohorts.

References 1. Banerjee A, Fowkes FG, Rothwell PM. Associations between peripheral artery disease and ischemic stroke: implications for primary and secondary prevention. Stroke 2010; 41 (9): 2102 – 2107. 2. Feringa HH, Bax JJ, Hoeks S, et al. A prognostic risk index for long-term mortality in patients with peripheral arterial disease. Arch Intern Med 2007; 167 (22): 2482 – 2489. 3. Regensteiner JG, Hiatt WR, Coll JR, et al. The impact of peripheral arterial disease on health-related quality of life in the Peripheral Arterial Disease Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) Program. Vasc Med 2008; 13 (1): 15 – 24. 4. Shammas NW: Epidemiology, classification, and modifiable risk factors of peripheral arterial disease. Vasc Health Risk Manag 2007; 3 (2): 229 – 234. 5. Fowkes FG, Rudan D, Rudan I, et al. Comparison of global estimates of prevalence and risk factors for peripheral artery disease in 2000 and 2010: a systematic review and analysis. Lancet 2013; 382 (9901): 1329 – 1340. 6. Beckman JA, Jaff MR, Creager MA. The United States preventive services task force recommendation statement on screening for peripheral arterial disease: more harm than benefit? Circulation 2006; 114 (8): 861 – 866. 7. Peach G, Griffin M, Jones KG, et al. Diagnosis and management of peripheral arterial disease. BMJ 2012; 345: e5208. 8. Zhan Y, Yu J, Chen R, et al. Prevalence of low ankle brachial index and its association with pulse pressure in an elderly Chinese population: a cross-sectional study. J Epidemiol 2012; 22 (5): 454 – 461. 9. Zhan Y, Dong Y, Tang Z, et al. Serum Uric Acid, Gender, and Low Ankle Brachial Index in Adults With High Cardiovascular Risk. Angiology 2015; 66 (7): 687 – 691 10. Archer KJ, Lemeshow S. Goodness-of-fit test for a logistic regression model fitted using survey sample data. Stata J 2006; 6 (1): 97 – 105. 11. Swets JA: Measuring the accuracy of diagnostic systems. Science 1988; 240 (4857): 1285 – 1293. 12. Steyerberg EW, Harrell FE, Jr., Borsboom GJ, et al. Internal validation of predictive models: efficiency of some procedures for logistic regression analysis. J Clin Epidemiol 2001; 54 (8): 774 – 781. © 2016 Hogrefe

13. Calster BV, Vickers AJ. Calibration of risk prediction models: impact on decision-analytic performance. Med Decis Making 2015; 35 (2): 162 – 169. 14. Bendermacher BL, Teijink JA, Willigendael EM, et al. A clinical prediction model for the presence of peripheral arterial disease--the benefit of screening individuals before initiation of measurement of the ankle-brachial index: an observational study. Vasc Med 2007; 12 (1): 5 – 11. 15. Ramos R, Baena-Diez JM, Quesada M, et al. Derivation and validation of REASON: a risk score identifying candidates to screen for peripheral arterial disease using ankle brachial index. Atherosclerosis 2011; 214 (2): 474 – 479. 16. Grau M, Baena-Diez JM, Felix-Redondo FJ, et al. Estimating the risk of peripheral artery disease using different population strategies. Prev Med 2013; 57 (4): 328 – 333. 17. Duval S, Massaro JM, Jaff MR, et al. An evidence-based score to detect prevalent peripheral artery disease (PAD). Vasc Med 2012; 17 (5): 342 – 351. 18. Zhan Y, Yu J, Ding R, et al. Triglyceride to high density lipoprotein cholesterol ratio, total cholesterol to high density lipopro-

Y. Zhan et al.: Predicting peripheral arterial disease

tein cholesterol ratio and low ankle brachial index in an elderly population. Vasa 2014; 43 (3): 189 – 197. 19. Pradhan AD, Shrivastava S, Cook NR, et al. Symptomatic peripheral arterial disease in women: nontraditional biomarkers of elevated risk. Circulation 2008; 117 (6): 823 – 831. Submitted:09.04.2015 Accepted after revision: 31.05.2015 There are no conflicts of interest existing. Correspondence address Dr. Yiqiang Zhan, MD or Dr. Jinming Yu, PhD Key laboratory of Public Health Safety Ministry of Education, School of Public Health Fudan University Dong’an Road 130 200032 Shanghai China zhany09@fudan.edu.cn

Vasa (2016), 45 (1), 31 – 36

Original communication

Knowledge about ankle-brachial index procedure among residents: being experienced is beneficial but is not enough Ségolène Chaudru1, Pierre-Yves de Müllenheim2, Alexis Le Faucheur1, 2, 3, Vincent Jaquinandi4, Adrien Kaladji4, 5, and Guillaume Mahe1, 4 Inserm, Centre d’Investigation Clinique 1414, Rennes, France Movement, Sport and Health Laboratory, University of Rennes 2, France 3 Department of sport sciences and physical education, ENS Rennes, Campus de Ker Lann, Rennes, France 4 Cabinet d’Angiologie, University of Rennes, France 5 Inserm U1099, Signal and Image Processing Laboratory, University of Rennes 1, France 6 University Hospital, University of Rennes, France 1 2

Summary: Background: Ankle-brachial index (ABI) at rest is the main clinical tool to diagnose the presence of lower extremity peripheral artery disease (PAD). The method for ABI procedure (i.e., measurement, calculation and interpretation) is standardised and guidelines were published in 2012. This study sought to: i) assess knowledge about the three major steps of the ABI procedure (i.e., measurement, calculation and interpretation) among residents from different medical schools, ii) compare the ABI knowledge of experienced residents (i.e., who have already performed ABI procedure more than 20 times) with the knowledge of inexperienced residents, and iii) describe the most common errors by residents. Methods: Residents from six medical schools were invited to complete a questionnaire about the ABI procedure. Results: Sixty-eight residents completed the questionnaire. None of them knew how to perform the entire ABI procedure. Overall, 22 %, 13 % and 41 % of residents correctly answered questions about ABI measurement, ABI calculation and ABI interpretation, respectively. Score comparisons underlined the fact that experienced residents (n = 26) answered ABI measurement questions to a significantly better level and had a significantly higher total score than inexperienced residents (n = 42) (P = 0.0485 and P = 0.0332, respectively). Errors were similar for most of the residents. Conclusions: Our study confirms that experienced residents have significantly better ABI procedure knowledge than inexperienced residents. However, none of them are able to perform the entire ABI procedure without any mistake with regard to current guidelines. It is important that training be given to residents in medical schools in order to improve their ABI procedure knowledge. Key words: Peripheral artery disease, competency, teaching, diagnosis, vascular medicine

Introduction Ankle-brachial index (ABI) at rest is the main clinical tool to diagnose the presence of lower extremity peripheral artery disease (PAD) [1, 2]. Although some physicians screen patients for PAD on the basis of finding a complaint of intermittent claudication, fewer than 10 % of PAD patients will provide symptoms consistent with the Rose criteria for intermittent claudication [3, 4]. Therefore, international vascular societies [5 – 7] recommend a screening of PAD using ABI at rest but the interest of a screening is still debated [8]. The method for measuring, calculating and interpreting the ABI is standardised and guidelines were published in 2012 aiming to homogenise the procedure [6]. Several studies have also shown that ABI is not accurately perVasa (2016), 45 (1), 37 – 41 DOI 10.1024/0301-1526/a000493

formed in general practice [9 – 11]. A possible explanation may be a lack of knowledge about the ABI procedure caused by poor educational processes [12]. Only a few studies [13, 14] have addressed the basic knowledge of the ABI procedure among residents and/or students, whereas these results may provide recommendations for optimal medical educational processes. Only one study has addressed knowledge of the entire ABI procedure among a small group of residents in one centre [14]. Our study sought to: i) assess basic knowledge about the three major steps of ABI procedure (i.e., measurement, calculation and interpretation) among residents from different French medical schools, ii) compare the ABI knowledge of experienced residents with the knowledge of inexperienced residents, and iii) describe the most common errors by residents. © 2016 Hogrefe

S. Chaudru et al.: Knowledge about ABI procedure

Figure 1. Questionnaire (translated from the French version).

Methods Residents in cardiology and vascular medicine from six French medical schools were invited during an annual seminar to complete a questionnaire about ABI procedure knowledge. No selection criterion was used. Based on previous studies [13, 14], this questionnaire was designed to assess whether the three fundamental tasks of the ABI procedure, namely measurement, calculation and interpretation, were assimilated by residents. A score assessing the individual performance of each resident was developed. A scoring sheet was established for each answer, awarding the same number of points to each task (Fig. 1). Three points were awarded for the measurement task (i.e., one-and-a-half point was awarded for each of the following: utilisation of a hand-held Doppler for ankle and brachial systolic blood pressure measurement, assessment of three systolic ankle pressures in each ankle). Three points were awarded for the calculation task (i.e., one-and-a-half point was awarded for each of the following: selection of the higher of the two systolic brachial pressures; selection of the higher of the systolic ankle pressures to define patient diagnosis). Three points were awarded for the interpretation task (i.e., one-half point for each correct interpretation). The sum of the three tasks defined the total score (maxi© 2016 Hogrefe

mum rating nine points). The higher the total score, the higher the resident’s knowledge about ABI procedure. An experienced resident was considered as a resident who declared having performed more than 20 ABI measurements in clinical practice. This cut-off of 20 measurements was based on a previous study by Georgakarakos et al. [15]. This study was conducted according to the French Health laws.

Statistical analyses Scores comparisons between experienced residents and inexperienced residents were performed using a MannWhitney test because distributions were not normal (Shapiro-Wilk’s test). A Chi-square test was performed to compare qualitative values between groups. Statistical analysis was performed with the programming language R version 3.1.3. A two-tailed probability level of P < 0.05 was used to indicate significance.

Results All residents (n = 68) completed the questionnaire. Participants included 44 residents in cardiology and 24 vascular Vasa (2016), 45 (1), 37 – 41

S. Chaudru et al.: Knowledge about ABI procedure

medicine residents. Nine (13 %) reported knowing the current American Heart Association (AHA) guidelines concerning ABI procedure but none of them knew how to perform the entire ABI procedure (ESM 1, Figure). Forty-seven (69 %) residents did not feel adequately trained to perform ABI, and 53 (78 %) would like more practical training. Among these 68 residents, 15 (22 %), 9 (13 %) and 28 (41 %) correctly answered the questions about ABI measurement, ABI calculation and ABI interpretation, respectively. Score comparisons (ESM 2, Table) underlined that experienced residents (n = 26) answered ABI measurement questions significantly better and had a significantly higher total score, compared with inexperienced residents (n = 42) (P = 0.0485 and P = 0.0332, respectively, MannWhitney test). The most common errors were: • Using an automatic blood pressure measurement device for the brachial systolic pressure assessment: 21 out of 68 residents (31 %); • Measuring the systolic brachial pressure in only one arm: 11 out of 68 residents (16 %); • Assessing only one systolic ankle pressure (tibial posterior or dorsalis pedis or fibular arteries): 20 out of 68 residents (29 %); • Calculating the ABI using the lowest ankle systolic pressures: 36 out of 68 residents (53 %); • Interpreting ABI = 0.60 as severe: 33 out of 68 residents (48 %). No significant difference existed between inexperienced and experienced residents’ common errors except for two criteria. First, inexperienced residents were significantly more likely to use an automatic blood pressure measurement device to measure pressure at both brachial and ankle levels than experienced residents (P = 0.0027). Second, experienced residents were significantly more likely to measure three ankle pressures in each leg (tibial posterior, dorsalis pedis, and fibular arteries), than inexperienced residents (P < 0.0001).

Discussion ABI is an important and widely used non-invasive tool for the diagnosis of PAD. This study showed that i) deviations from the ABI procedure guidelines are commonplace among French medicine residents, ii) experienced residents have better results about ABI procedure knowledge than inexperienced residents, and iii) common errors are similar for most of the residents. First, we demonstrated that French residents in the cardiovascular field have poor knowledge about ABI procedure. None of them obtained the maximal total score and knew the entire ABI procedure. These results obtained from residents from six different French medical schools showed that this lack of knowledge was not restricted to only one medical school but was more generalised. Wyatt et al., using a point based scoring system, assessed the perVasa (2016), 45 (1), 37 – 41

formance of twenty-nine internal medicine residents [14]. As shown in the present study, the authors observed a poor level of competency, showing that only 4 % of the residents correctly measured the ankle pressures, 10 % correctly performed the ABI, and 45 % correctly interpreted the ABI. These similarities between these two studies suggest an educational medical problem worldwide. We believe that this poor knowledge might explain the underutilisation and/or the incorrect use of the ABI in primary care settings such as other common barriers advocated in the literature (e.g., time consuming or expensive equipment) [4, 10, 16]. Second, we highlighted that experienced residents were more likely to follow ABI procedure guidelines. Experienced residents tended to obtain higher scores for ABI calculation and interpretation. They also had significantly higher ABI measurement and total scores (P = 0.0485 and P = 0.0332, respectively). These results are in accordance with previous literature that showed that practical training improved the compliance with guidelines [14, 15]. Indeed, Georgakarakos et al. (2013) showed that the completion of 20 measurements in patients was required to achieve enough competency level to avoid misdiagnosing of PAD [15]. However, even among experienced residents, none of them knew how to perform the entire ABI procedure without any mistake with regard to current guidelines. Third, common errors were similar for most of the residents. Three deviations (e.g., using automatic blood pressure measurement devices, measuring the brachial pressure in only one arm, and assessing only one ankle pressure on each leg) may more likely be attributed to the residents’ willingness to reduce the time procedure than a real lack of knowledge about ABI procedure. Although the use of automatic devices is not admitted in the ACC/AHA guidelines [6], the use of such devices at the brachial level could be discussed, especially for PAD screening. Gardner and Montgomery (1998) compared three brachial blood pressure measurement methods and concluded that the accuracy of ABI measurement in PAD patients with intermittent claudication was not affected by the method used to obtain brachial systolic blood pressure (P = 0.92) [17]. Furthermore, we showed that experienced residents were significantly more likely to measure three artery pressures in each ankle (tibial posterior, dorsalis pedis and fibular arteries), than inexperienced residents (P < 0.0001). The reason for this is that, in the French health care system, reimbursement for ABI measurement is offered only if three different artery (tibial posterior, dorsalis pedis and fibular arteries) pressures are measured [11]. Another common error among residents was interpreting an ABI = 0.60 as severe PAD whereas normally an ABI equal to 0.60 is interpreted as mild to moderate PAD. This is not a major deviation since the patient will be classified as a PAD patient. The explanation could be that, in France, PAD severity indicators are rarely used [6, 14]. Finally, according to the French specificities previously mentioned, if we accept i) the use of automatic brachial blood pressure device, ii) the measurement of the three artery pressures in each ankle, and iii) the interpretation of © 2016 Hogrefe

ABI = 0.60 as PAD without any judgment about the severity, 23.1 % (6/26) of the experienced residents performed the entire ABI procedure without any mistake, against 2.4 % (1/42) of novice residents (P = 0.0063, Chi-square test). This study highlighted poor knowledge about the ABI procedure among French residents. Given the fact that teaching in French medical schools generally takes the form of lectures with very few practical training sessions, these results were not surprising [18]. The opportunity to have practical training should be offered, since the majority of residents (78 %) stated that they would like to receive more practical training. Finally, on the basis of these findings, we recommended, as previously suggested by Ray et al. (1994), that junior doctors should not perform ABI measurements alone until they have performed several ABI procedures under supervision with an appropriately experienced instructor [12, 19].

Limitations This study had several limitations. First, we did not evaluate whether residents knew which pressures have to be used as numerator and as denominator. As shown by Wyatt et al. (2010), such a question would have induced many errors [14]. Second, we assessed the residents’ knowledge about the ABI measurement task through a questionnaire and not through a direct supervision, which was used by Wyatt et al. [14]. As shown by the authors, the advantage of direct supervision is that respondents currently reported difficulties regarding skills or technical aspects of the procedure such as locating pulses in the ankle, or maintaining the position of the Doppler probe while inflating the blood pressure cuff [14, 15, 19]. However, our aim was to assess a high number of residents from different French medical schools and not to focus on one, as reported by Wyatt et al. [14]. In their limitations section, Wyatt et al. did not know whether their results were generalisable to a broader population or not. According to our results, it seems that this poor knowledge about ABI procedure is a global issue. Last, the experience of the residents was based on the answer to the question about the declarative number of ABI previously performed (n > 20) [15].

Conclusions Our study confirms that experienced residents (i.e., who have already performed more than 20 ABI procedures) had significantly better knowledge of the ABI procedure than inexperienced residents. It is important that training be offered to residents in medical schools in order to improve their ABI procedure knowledge. Identifying the best way to teach the ABI procedure requires other studies such as randomised controlled trials, which have not yet been conducted. © 2016 Hogrefe

S. Chaudru et al.: Knowledge about ABI procedure

Electronic Supplementary Material The electronic supplementary material is available with the online version of the article at http://dx.doi.org/ 10.1024/0301-1526/a000XXX ESM 1. Figure. Flow of the residents that gave cumulative right answers throughout the entire questionnaire (5 questions). ESM 2. Table. Score comparisons for each task between experienced and inexperienced residents (mean±SD).

References 1. Dachun X, Jue L, Liling Z, et al. Sensitivity and specificity of the ankle-brachial index to diagnose peripheral artery disease: a structured review. Vasc Med 2010; 15 (5): 361 – 9. 2. Winsor T, Hyman C, Payne JH. Exercise and limb circulation in health and disease. AMA Arch Surg 1959; 78 (2): 184 – 92. 3. Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull World Health Organ 1962; 27: 645 – 58. 4. Belch JJF, Topol EJ, Agnelli G, et al. Critical issues in peripheral arterial disease detection and management: a call to action. Arch Intern Med 2003; 163 (8): 884 – 92. 5. Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA Focused Update of the Guideline for the Management of Patients With Peripheral Artery Disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2011; 58 (19): 2020 – 45. 6. Aboyans V, Criqui MH, Abraham P, et al. Measurement and Interpretation of the Ankle-Brachial Index A Scientific Statement From the American Heart Association. Circulation 2012; 126 (24): 2890 – 909. 7. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for the management of peripheral arterial disease. Int Angiol 2007; 26 (2): 81 – 157. 8. Alahdab F, Wang AT, Elraiyah TA, et al. A systematic review for the screening for peripheral arterial disease in asymptomatic patients. J Vasc Surg 2015; 61 (3S): 42S – 53S. 9. Haigh KJ, Bingley J, Golledge J, et al. Barriers to screening and diagnosis of peripheral artery disease by general practitioners. Vasc Med 2013; 18 (6): 325 – 30. 10. Davies JH, Kenkre J, Williams E. Current utility of the anklebrachial index (ABI) in general practice: implications for its use in cardiovascular disease screening. BMC Family Practice 2014; 15 (1): 69. 11. Meyer D, Bureau JM, Vu Tri D. [Ankle brachial index: motivations, training, and practices among 165 general practitioners in Île-de-France]. J Mal Vasc 2014; 39 (1): 18 – 25. 12. Chaudru S, de Müllenheim PY, Le Faucheur A, et al. Training to perform Ankle-Brachial Index_Systematic Review and perspectives to improve teaching and learning. European Journal of Vascular and Endovascular Surgery. (Submitted). 13. Chaudru S, de Müllenheim PY, Le Faucheur A, et al. Ankle brachial index teaching: A call for an international action. Int J Cardiol 2015; 184: 489 – 91. 14. Wyatt MF, Stickrath C, Shah A, et al. Ankle brachial index performance among internal medicine residents. Vascular Medicine 2010; 15 (2): 99 – 105. 15. Georgakarakos E, Papadaki E, Vamvakerou V, et al. Training to Measure Ankle-Brachial Index at the Undergraduate Level: Can It Be Successful? The International Journal of Lower Extremity Wounds 2013; 12 (2): 167 – 71.

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16. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286 (11): 1317 – 24. 17. Gardner AW, Montgomery PS. Comparison of three blood pressure methods used for determining ankle/brachial index in patients with intermittent claudication. Angiology 1998; 49 (9): 723 – 8. 18. Mahé G. Ankle-brachial index: methods of teaching in French medical schools and review of literature. JMV 2015. 19. Ray SA, Srodon PD, Taylor RS, et al. Reliability of ankle:brachial pressure index measurement by junior doctors. Br J Surg 1994; 81 (2): 188 – 90.

Submitted: 26.06.2015 Accepted after revision: 20.07.2015 No conflicts of interest. SC received a grant «BOURSE ARED» from the «Région Bretagne» Correspondence address Dr. Guillaume Mahe, MD, PhD Pôle imagerie médicale et explorations fonctionnelles CHU Rennes 2 rue Henri Le Guilloux 35033 Rennes France maheguillaume@yahoo.fr

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Original communication

Accuracy of in-patients ankle-brachial index measurement by medical students Matteo Monti1*, Luca Calanca2*, Adriano Alatri2, and Lucia Mazzolai2 1 2

Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland Division of Vascular medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Summary: Background: Ankle brachial index (ABI) is a first line non-invasive screening tool for peripheral arterial disease (PAD) in at risk populations. The need to extend ABI use in large population screening has urged its use by professionals other than vascular physicians. As advocated by the American Heart Association, ABI teaching is part of medical curriculum in several countries. We determine accuracy in ABI measurement by trained medical students compared with an experienced angiologist. Methods: Twelve 6th year medical students underwent 9 days of training at Lausanne University Hospital. Students and an experienced angiologist, blinded to students’ results, screened consecutive hospitalised patients aged ≥ 65 or ≥ 50 with at least one cardiovascular risk factor during a 6-week period. Results: A total of 249 patients were screened of whom 59 (23.7 %) met the inclusion criteria. Median age was 80, 45.8 % were women, and 6.8 % were symptomatic. In total, 116 ABIs were available for analysis. Agreement between students and angiologist was moderate with a k-value of 0.498 (95 % confidence interval: 0.389 – 0.606). Overall accuracy and precision of PAD screening performed by students showed sensitivity of 73.2 % and specificity of 88.0 %. Positive and negative predictive values were 76.9 % and 85.7 %, respectively; positive and negative likelihood ratios were 6.3 and 3, respectively. Conclusions: A nine day training program on ABI measurement is not sufficient for inexperienced medical students to achieve an acceptable diagnostic accuracy in detecting PAD in at risk populations. Key words: Ankle brachial index, ABI, peripheral arterial disease, screening, accuracy, medical students

Introduction Peripheral arterial disease (PAD) is common, affecting an estimated 27 million individuals in Europe and North America [1, 2]. Its prevalence reaches 20 % in unselected populations [3], but can be as high as 30 % in patients with cardiovascular (CV) risk factors [1]. Patients with PAD are at increased risk of myocardial infarction or stroke [2, 4, 5], as well as CV and overall mortality [4, 6]. Consequently, accurate PAD diagnosis and management is needed. Measurement of ankle-brachial index (ABI; ratio of lower limb systolic pressure over the higher systolic brachial pressure) is an accurate, simple, and inexpensive vascular tool allowing PAD diagnosis and severity assessment. ABI measurement is recommended as initial vascular examination for PAD detection and diagnosis [2, 7, 8]. Additionally, ABI is an indicator of atherosclerosis in other vascular sites and is a useful predictor of CV morbidity and mortality in both symptomatic and asymptomatic PAD patients [4, 9]. When performed by qualified personnel, ABI showed good accuracy and reproducibility with a sensitivity and specificity of 89 – 95 % and 95 – 100 %, respectively [8, 10].

Reproducibility was, however, lower when performed by non-skilled personnel [11]. Higher inter-observer difference was found between “inexperienced” and skilled personnel when ABI was performed in PAD patients rather than in healthy people [10]. ABI use in primary care is highly recommended [1, 2]. Few studies have investigated PAD prevalence among hospitalised internal medicine patients using standardised methods. A 36% prevalence of low ABI has been described when ABI was measured by pulse palpation [12]. Hand held Doppler measurements recently showed a 29 % PAD prevalence [13], similar to that observed among patients hospitalised for acute coronary and cerebrovascular events [14, 15], and in those hospitalised for non-vascular causes in a tertiary care hospital [16]. Initial ABI PAD screening among hospitalised internal medicine patients is limited by unavailability of well trained personnel. To overcome this drawback, we investigated accuracy of PAD diagnosis by ABI measurements performed by 6th year medical students receiving a short training period during their internship in internal medicine. This approach may additionally favour the imple-

Matteo Monti and Luca Calanca contributed equally to this research paper.

Vasa (2016), 45 (1), 43 – 48 DOI 10.1024/0301-1526/a000494

mentation of recent recommendation from the AHA advocating measure and interpretation of ABI to be part of standard curriculum for medical students [10]. ABI was measured in consecutive internal medicine in-patients of a tertiary hospital and compared with those obtained by an experienced angiologist. To our knowledge, diagnostic accuracy of ABI measurement by medical students in hospitalised internal medicine patients has been described only in one small-size study evaluating 28 limbs in 18 patients [17].

M. Monti et al.: ABI accuracy by medical students

dents and angiologist. Medical history and demographic data were collected by the students and verified by the angiologist. Symptomatic PAD was defined by the presence of intermittent claudication. History of CV disease (previous myocardial infarction, angor, heart failure, stroke or transient cerebral ischemic attack) was recorded together with drug treatment (lipid lowering drugs, antihypertensive drugs, anti-diabetic drugs, anti-platelets drugs). The study protocol was accepted by the local ethic committee.

Students training

Methods Study population and selection During a 6-week period (February-March 2012), consecutive patients admitted to the internal medicine division of the university hospital of Lausanne, Switzerland, were screened. Inclusion criteria were as follows: age ≥ 65 or ≥ 50 with at least 1 CV risk factor (CVRF): diabetes (patient on anti-diabetic treatment), hypertension (patient on antihypertensive treatment), dyslipidaemia (patient on lipid lowering drugs), and history of smoking (self-reported present or past smoking habit). Patients were excluded if one of the following occurred: presence of recent below the knee lower extremity arterial bypass (risk of bypass damage), presence of open wounds and ulcers contraindicating cuff placement in both legs, participation to other research protocols, or inability to give informed consent. During the 6-week period, a study nurse extracted a list of all potentially eligible patients from the institutional electronic medical database on a daily basis. The list was then verified with medical supervisor for potential exclusion criteria. All eligible patients received oral and written information and an informed consent form for signature. Finally, list of participants was transmitted to study stu-

Figure 1. Screening of patients.

For this study, 6th year undergraduate medical students received a specific training by an experienced angiologist during their internship in internal medicine prior to the start of the study. Each student participated to a 3-hour teaching session including 30 minutes of theoretical introduction to PAD and ABI measurement/calculation, followed by practical training. During the practical session, students received instructions on the use of handheld Doppler flow-meters and practiced ABI measurements on healthy volunteers under the angiologist’s supervision. Students were then invited to perform independently ABI measurements on hospitalised patients during a 7-day period. Following this practice period, a second 90-minute session was scheduled, where all students performed ABI measurements and calculations on patients under the supervision of the angiologist. Therefore, overall, students received nine days’ training in total.

ABI measurement and calculation ABI measurements were performed in supine patients following guidelines of the AHA [10] using a vascular handheld 5-MHz Doppler flow meter (Nicolet-EliteTM100 Doppler, Natus Medical Incorporated, San Carlos, CA 94070 USA). ABI was calculated separately for each leg by dividing the higher of the posterior tibialis or dorsalis pedis systolic blood pressure (SBP) by the higher of the right or left arm SBP. Highest ABI value for each leg was used to stratify patients within 6 categories: no-PAD (ABI 0.91 – 1.40), PAD (ABI <= 0.9), mild PAD (ABI 0.90 – 0.71), moderate PAD (ABI 0.70 – 0.51), severe PAD (ABI ≤ 0.50), high abnormal ABI (ABI > 1.40). ABI values > 1.4 are considered to be pathological and correlate with increased CV morbidity and mortality [8]. Therefore, in the manuscript, abnormal ABI refers to values either < 0.9 or > 1.4. Each student used the same Doppler throughout the study period. Students recorded patient’s ABI values on specific report forms. As already mentioned, the literature has shown a good accuracy and reproducibility in ABI measurement, compared with angiography, when performed by qualified personnel [8, 10]. We therefore chose an experienced angiologist, with more than 15 years of clinical experience, as reference for comparison of students’ measures. Vasa (2016), 45 (1), 43 – 48

M. Monti et al.: ABI accuracy by medical students

Table I. ABI measurements performed by the angiologist and classified according to PAD severity ABI

All (n = 116)

Men (n = 64)

Women (= 52)

2 (1.7)

2 (3.8)

12 (10.3)

7 (10.9)

5 (9.6)

9 (7.8)

5 (7.8)

4 (7.7)

Normal, no-PAD (0.91 – 1.40), No. (%)

72 (62.1)

38 (59.4)

34 (65.4)

Abnormally high (> 1.40), No. (%)

21 (18.1)

14 (21.9)

7 (13.5)

Severe PAD (≤ 0.50), No. (%) Moderate PAD (0.70 – 051), No. (%) Mild PAD, (0.71 – 0.90), No. (%)

The angiologist repeated ABI measurements the same day using, for each patient, the same Doppler used by the student. The angiologist reported measured ABI values on separate forms. All forms were collected by the study nurse on a daily basis. Students and the angiologist were instructed not to communicate results among each other and were blinded to ABI results.

Analysis of continuous variables (duration of ABI measurements) are summarised as mean ± standard deviation (SD) and differences were compared using the unpaired ttest (p < 0.05). Analysis of categorical data (frequencies of CVRF) is represented as the percentage of total occurrence. Differences in frequencies of CVRF between normal and abnormal ABI groups are compared using the Fisher’s exact test (p < 0.05). All statistical analysis was performed with the statistical software Stata (version 12.1, StataCorp LP, College Station, Texas, USA).

Statistical analysis ABI values were calculated separately for each limb. Students’ measurements were compared with those obtained by the angiologist. Concordance between students’ and angiologist’s ABI measurements were evaluated by interrater agreement Kappa test [18] and by concordance correlation coefficient [19]. In the kappa test, agreement was defined whenever the ABI measurements of the student and the angiologist resulted within the same category (see stratification described above) otherwise, values were considered as disagreeing. The strength of agreement (k value) was interpreted as follows: < 0.20: Poor agreement; 0.21 – 0.40: Fair agreement; 0.41 – 0.60: Moderate agreement; 0.61 – 0.80: Good agreement; 0.81 – 1.00: Very Good agreement. Furthermore, we evaluated inter-observer variability by Bland-Altman method [20] by analysing the difference between student and angiologist ABI within the same patient. A difference of 0.15 or more was considered significant. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and positive (+LHR) and negative likelihood ratio (-LHR) were calculated.

Results Study population In total, 249 consecutive patients were screened. Of them, 190 were excluded (130 did not fulfil the inclusion criteria or met the exclusion criteria and 60 declined enrolment). Fifty-nine patients were finally included (Fig. 1). The median age was 80 years (range 60 – 96 years, interquartile 71 – 86 years), and 45.8 % were women. No significant difference was found between men and women included in the study concerning CVRF, co-morbidities, and reasons for hospitalisation. Only six patients (10.2 %) presented symptoms of lower limb intermittent claudication and 6.8 % underwent prior lower limb revascularisation. Severe renal insufficiency (ClCreat < 30 ml/min) was present in 5.1 %. The distribution of reasons for hospitalisation was as follows: 32.2 % cardiac, 35.6 % pulmonary, 11.9 % onco-

Table II. Inter-rater agreement between ABI measurements obtained by students and angiologist. Values reported in the diagonal correspond to agreement. Kappa value (95%C.I.) = 0.498 (0.388 – 0.608) Angiologist Students

≤ 0.50

0.51 – 0.70

0.71 – 0.90

0.91 – 1.40

> 1.40

Overall

≤ 0.50

0.51 – 0.70

0.71 – 0.90

0.91 – 1.40

> 1.40

Overall

116

Vasa (2016), 45 (1), 43 – 48

M. Monti et al.: ABI accuracy by medical students

Table III. Accuracy and precision of ABI measurements (students vs angiologist) considering either all abnormal ABI values (ABI ≤ 0.9 and > 1.4), only the abnormally low ones (ABI ≤ 0.9)

ABI ≤ 0.9 and > 1.4

ABI ≤ 0.9

Sensitivity, %

Specificity, %

PPV, %

NPV, %

+LHR

-LHR

K value

75.0

87.5

78.6

85.1

6.0

0.29

0.498

(59.7 – 86.8)

(77.6 – 94.1)

(63.2 – 89.7)

(75.0 – 92.3)

(3.2 – 11.3)

(0.17 – 0.48)

(0.389 – 0.606)

82.6

90.3

73.1

94.2

8.5

0.19

0.505

(61.2 – 95.0)

(81.0 – 96.0)

(52.2 – 88.4)

(85.8 – 98.4)

(4.1 – 17.6)

(0.08 – 0.47)

(0.370 – 0.641)

Results are expressed as value and (95% confidence interval). PPV: Positive predictive Value. NPV: Negative Predictive Value. +LHR: Positive likelihood ratio. –LHR: Negative likelihood ratio.

Figure 2. Correlation between students› and expert›s ABI measures.

Figure 3. Bland-Altman graphic correlation between students’ and expert’s measures along ABI values. Differences > 0.15 (red lines) are considered significant.

logical, 10.2 % gastrointestinal, 8.5 % haematological, and 3.4 % acute renal failure).

ABI measurements For each patient, ABI was calculated separately in the two legs. However, in 2 patients, because of skin wounds and amputation, ABI was calculated in one leg only. Therefore, a total of 116 ABIs were available for analysis. A total of 12 © 2016 Hogrefe

medical students participated in the study; 6 of them performed more than 10 ABI measurements. According to measurements obtained in the reference group (angiologists), ABI results were stratified as follows: normal no PAD in 72 cases (62.1 %), mild PAD in 9 (7.8 %), moderate PAD in 12 (10.3 %), severe PAD in 2 cases (1.7 %), and abnormally high ABI in 21 (18.1 %; maximal ABI value measured was 1.86) (Tab. I). Therefore, there were a total of 44 abnormal values and 72 normal ones. Concerning CVRF distribution, only hypertension was significantly more frequent both in PAD and abnormally high ABI than in normal ABI (p = 0.001). Interestingly, hypertension was found in 100 % of ABI ≤ 0.9 and in 97.7 % of total abnormal ABI. Of the 21 abnormally high ABI, thirteen (61.9 %) were associated with chronic renal insufficiency (25 % in the normal ABI group, p = 0.003), and 8 of them (62 %) also presented with diabetes (37.5 % in the normal ABI group, not statistically significant). Among the 72 normal ABI (> 0.9 – 1.4), only 63 measured by the students showed agreement. Among the 9 patients with mild PAD, only 3 were concordant with the angiologist’s measure. Of the 12 ABI in the moderate PAD class, 6 showed agreement, and only one of the 2 severe PAD cases was correctly identified by students. Concerning the 21 abnormally high ABI, only 10 students’ measures were concordant (Tab. II). Therefore, the agreement between angiologists and students was moderate, with a k value of 0.498 (95% confidence interval: 0.389 – 0.606). Agreements remained moderate if only ABI ≤ 0.9 were considered (k = 0.505, 95%CI 0.370 – 0.641, Tab. III). A difference > 0.15 in ABI values was significantly more frequent in students’ measures compared to the angiologists in patients with abnormal ABI (≤ 0.90 or > 1.40) rather than in patients with normal ABI (> 0.9 – 1.4) (38.6% vs 12.5 %, respectively, p = 0.002). Further analysis among patients with abnormal ABI revealed that this difference was only significant (p = 0.001) in patients with abnormally high ABI (ABI > 1.4) but not (p = 0.058) in those with PAD (ABI ≤ 0.90). Concerning overall accuracy and precision of PAD diagnosis performed by students, sensitivity, specificity, PPV, NPV, +LHR, and -LHR were 73.2 %, 88.0 %, 76.9 %, 85.7 %, 6.3 and 3.0, respectively. Accuracy and precision were no better when only abnormally low ABI (ABI ≤ 0.9) were evaluated Vasa (2016), 45 (1), 43 – 48

M. Monti et al.: ABI accuracy by medical students

(Tab. III). We found no correlation between the number of exams performed and mean ABI difference (correlation coefficient 0.101) and, when considering only ABI values obtained by the six medical students having performed more than 10 ABI measures, no significant difference was observed in data analysis (73.3 % sensitivity, 87.9 % specificity, 73.3 % PPV, 87.9 % NPV, 6.05 +LHR, and 0.3 -LHR). The concordance correlation coefficient between students and the expert was also fair (rho 0.62 [95 % CI 0.52 – 0.73]). Figure 2 shows the moderate correlation of measures between students and experts with a high rate of discordant results, either under- or overestimations. The Bland-Altman graphic (Fig. 3) highlights that significant differences (> 0.15) between students’ and expert’s measures exist for every ABI value. Mean duration time needed to perform ABI measurement by medical students and angiologists was 17m15s (± 5m58s), and 11m16s (± 2m17s), respectively (p < 0.001). No significant difference in agreement between angiologists and students was found if data from the posterior tibial artery and the dorsalis pedis artery were analysed separately (data not shown).

Discussion The performance of ABI measurement by 6th year medical students following a 9 day training period was evaluated. Compared to an angiologist with 15 years of clinical experience, medical students performed poorly in PAD screening using the ABI measure. Inter-observer agreement was moderate with a k value of 0.498. Furthermore, in 38 % of PAD patients the difference was greater than 0.15 (clinically relevant and frequently associated with a change in PAD class severity). An ideal screening test should be highly sensitive to avoid false negative values. In our study, because of the consistent number of false negative and false positive results, sensitivity and NPV were low (75.0 % and 85.1 %, respectively), while specificity and PPV were equally modest. To the best of our knowledge, only one study involving medical students in ABI measurement has been published [17]. In this small study (only 28 limbs examined), medical students underwent a basic training course over a period of two weeks. No difference in ABI measures was found between trainees and trainers for patients with mild-tomoderate PAD. However, significant students’ underestimation was observed in patients without PAD and overestimation in patients with severe PAD. This difference became non-significant with advanced training. Other studies evaluated ABI performance in other professional categories including general practitioners (GPs) [10, 21 – 23], nurses [22, 23], and internal medicine residents [24]. Only studies with well trained personnel showed good agreement between vascular physicians and other health professional categories [24]. Our results also confirmed high PAD prevalence among medical in-patients aged 50 – 65 years with at least one Vasa (2016), 45 (1), 43 – 48

CVRF, or older than 65. Abnormal ABI (determined by the experienced angiologist) was found in 37.9 % of screened patients. Of these, PAD (ABI <=0.9) was diagnosed in 19.8 % while 18.1 % showed an abnormally high ABI (> 1.4). These data are in agreement with those published in the literature [14 – 16]. Interestingly, patients with an ABI > 1.4 presented with either diabetes (61.9 %), renal insufficiency (38.1 %), or were aged > 80 years (38 %), all of which are conditions associated with increased arterial stiffness.

Limitations A high number of patients (24 %) refused to participate. This is likely due to the predominantly older age population hospitalised in our department and compares to that observed in other studies of frail, elderly patients [25]. A lack of perceived immediate benefits, difficulty in reading and understanding the consent form, co-morbidity, mobility problems, distrust and unfamiliarity with the research are described as the main challenges in recruiting elderly people in research studies [26]. A second limitation may be the lack of objective arterial imaging to ensure PAD diagnosis. However, good diagnostic accuracy for ABI has been shown when compared to angiography, digital subtraction angiography (DSA), or CT-Angiography [2, 10, 27]. Therefore, it would have been unethical for the present study to submit patients to side effects of contrast media. The length of training period in our study could be interpreted as a limitation. However, the rotation of medical students in internal medicine wards is on a 1 – 3 month basis in most countries including ours. Therefore, nine days represents a realistic training period.

Conclusions Our study further contributes to the finding that ABI measurements require well trained personnel. Furthermore, the results highlight that a short training period in inexperienced medical students is not sufficient to guarantee adequate accuracy. Although the AHA advocates ABI measurement and interpretation as part of standard undergraduate medical students’ curriculum [10], caution should be paid to the type and length of training.

Acknowledgement We are grateful to Professor Pedro Manuel Marques-Vidal for his help in the statistical analysis and for his critical revision of the manuscript. This paper has been presented as an oral presentation at 1st annual congress of European Society for Vascular Medicine (ESVM), Berlin-Potsdam, 10 – 12 May 2015. © 2016 Hogrefe

References 1. Hirsch AT, Criqui MH, Treat-Jacobson D, et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA 2001; 286: 1317 – 24. 2. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007; 45 Suppl S: S5 – 67. 3. Diehm C, Schuster A, Allenberg JR, et al. High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study. Atherosclerosis 2004; 172: 95 – 105. 4. Criqui MH, Langer RD, Fronek A, et al. Mortality over a period of 10 years in patients with peripheral arterial disease. N Engl J Med 1992; 326: 381 – 6. 5. Murabito JM, Evans JC, Larson MG, et al. The ankle-brachial index in the elderly and risk of stroke, coronary disease, and death: the Framingham Study. Arch Intern Med 2003; 163: 1939 – 42. 6. Heald CL, Fowkes FG, Murray GD, et al. Risk of mortality and cardiovascular disease associated with the ankle-brachial index: Systematic review. Atherosclerosis 2006; 189: 61 – 9. 7. Hirsch AT, Haskal ZJ, Hertzer NR, et al. ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic). Circulation 2006; 113: e463 – 654. 8. 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: 2851 – 906. 9. Diehm C, Allenberg JR, Pittrow D, et al. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120: 2053 – 61. 10. Aboyans V, Criqui MH, Abraham P, et al. Measurement and interpretation of the ankle-brachial index: a scientific statement from the American Heart Association. Circulation 2012; 126: 2890 – 909. 11. Ray SA, Srodon PD, Taylor RS, et al. Reliability of ankle:brachial pressure index measurement by junior doctors. Br J Surg 1994; 81: 188 – 90. 12. Antonopoulos S, Kokkoris S, Stasini F, et al. High prevalence of subclinical peripheral artery disease in Greek hospitalised patients. Eur J Intern Med 2005; 16: 187 – 91. 13. Pasqualini L, Schillaci G, Pirro M, et al. Prognostic value of low and high ankle-brachial index in hospitalised medical patients. Eur J Intern Med 2012; 23: 240 – 4. 14. Busch MA, Lutz K, Rohl JE, et al. Low ankle-brachial index predicts cardiovascular risk after acute ischemic stroke or transient ischemic attack. Stroke 2009; 40: 3700 – 5. 15. Dieter RS, Tomasson J, Gudjonsson T, et al. Lower extremity peripheral arterial disease in hospitalised patients with coronary artery disease. Vasc Med 2003; 8: 233 – 6.

M. Monti et al.: ABI accuracy by medical students

16. Lacroix P, Aboyans V, Voronin D, et al. High prevalence of undiagnosed patients with peripheral arterial disease in patients hospitalised for non-vascular disorders. Int J Clin Pract 2008; 62: 59 – 64. 17. Georgakarakos E, Papadaki E, Vamvakerou V, et al. Training to measure ankle-brachial index at the undergraduate level: can it be successful? Int J Low Extrem Wounds 2013; 12: 167 – 71. 18. Altman DG. Practical statistics for medical research. Chapman and Hall, London ; New York [etc.]; 1991. 19. Lin LI. A concordance correlation coefficient to evaluate reproducibility. Biometrics 1989; 45: 255 – 68. 20. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1: 307 – 10. 21. Nicolai SP, Kruidenier LM, Rouwet EV, et al. Ankle brachial index measurement in primary care: are we doing it right? Br J Gen Pract 2009; 59: 422 – 7. 22. Holland-Letz T, Endres HG, Biedermann S, et al. Reproducibility and reliability of the ankle-brachial index as assessed by vascular experts, family physicians and nurses. Vasc Med 2007; 12: 105 – 12. 23. Nexoe J, Damsbo B, Lund JO, et al. Measurement of blood pressure, ankle blood pressure and calculation of ankle brachial index in general practice. Fam Pract 2012; 29: 345 – 51. 24. Wyatt MF, Stickrath C, Shah A, et al. Ankle-brachial index performance among internal medicine residents. Vasc Med 2010; 15: 99 – 105. 25. Harris R, Dyson E. Recruitment of frail older people to research: lessons learnt through experience. J Adv Nurs 2001; 36: 643 – 51. 26. Provencher V, Mortenson WB, Tanguay-Garneau L, et al. Challenges and strategies pertaining to recruitment and retention of frail elderly in research studies: a systematic review. Arch Gerontol Geriatr 2014; 59: 18 – 24. 27. Xu D, Zou L, Xing Y, et al. Diagnostic value of ankle-brachial index in peripheral arterial disease: a meta-analysis. Can J Cardiol 2013; 29: 492 – 8. Submitted: 25.06.2015 Accepted after revision: 20.07.2015 There are no conflicts of interest existing. Correspondence address Dr. Matteo Monti Internal Medicine Centre Hospitalier Universitaire Vaudois Rue du Bugnon 44 BH 10-640 1011 Lausanne Switzerland matteo.monti@chuv.ch

Vasa (2016), 45 (1), 43 – 48

Original communication

Percutaneous mechanical thrombectomy in the treatment of acute and subacute occlusions of the peripheral arteries and bypasses Frantisek Stanek1, 2, Radoslava Ouhrabkova1, and David Prochazka1 1 2

Department of Radiology, District Hospital Kladno, Czech Republic Department Cardiology, 3rd Faculty of Medicine, Charles University, Prague, Czech Republic

Summary: Background: The aim of this prospective single-centre study was to analyse the immediate results, failures and complications of percutaneous mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of peripheral arteries and bypasses, as well as to evaluate long-term outcomes of this method. Patients and methods: Patients with acute (duration of symptoms < 14 days) or subacute (duration of symptoms > 14 days and < 3 months) occlusions of peripheral arteries and bypasses were selected consecutively for treatment. The cohort consisted of 113 patients, aged 18 – 92 years (median 72 years). In all, 128 procedures were performed. Results: Angiographic success was obtained in 120 interventions (93.8 %). Reasons for failures were rethrombosis of a partially recanalised segment in six procedures, and embolism into crural arteries in one intervention – percutaneous aspiration thromboembolectomy (PAT) and/or thrombolysis were ineffective in all these cases. Breakage of the Rotarex catheter happened in one procedure. Embolisation into crural arteries as a transitory complication solvable with PAT and/or thrombolysis occurred in four cases. Rethrombosis was more frequent in bypasses than in native arteries (p = 0.0069), in patients with longer occlusions (p = 0.026) and those with poorer distal runoff (p = 0.048). Embolisation happened more often in patients with a shorter duration of symptoms (p = 0.0001). Clinical success was achieved in 82.5 %. Major amputation was performed in 10 % of cases. Cumulative patency rates were 75 % after one month, 71 % after six months, 38 % after 12 months, 33 % after 18 months and 30 % after 24, 30, 36 and 42 months. Conclusions: Rotarex thrombectomy has excellent immediate results with a low rate of failures and complications. In comparison to thrombolysis, it enables the fast and efficient treatment of acute and subacute occlusions of peripheral arteries in one session. Key words: Rotarex thrombectomy, thromboembolic occlusions, peripheral arteries

Introduction Percutaneous mechanical thrombectomy using the Rotarex catheter represents a relatively new method of treating acute and subacute occlusions of the peripheral arteries and bypasses. In comparison to intra-arterial thrombolysis, recanalisation of arteries is achieved faster and during one session. A shorter hospital stay is necessary and intensive care after the procedure can be avoided. For these reasons, thrombectomy should be preferred to thrombolysis, especially in older and polymorbid patients [1 – 5]. Although complications of Rotarex thrombectomy are relatively rare and are not as serious as in thrombolysis, they may also happen and may limit the success of this method [1, 3, 6 – 8]. The aim of this prospective single-centre study was to analyse immediate results, failures and complications of Rotarex thrombectomy in the treatment of acute and subacute occlusions of peripheral arteries and bypasses. In addition, another goal of the study was the evaluation of long-term outcomes. Vasa (2016), 45 (1), 49 – 56 DOI 10.1024/0301-1526/a000495

Patients and methods Patients Patients with acute or subacute occlusions of the peripheral arteries were selected consecutively for treatment with the Rotarex system from May 2007 to November 2014. Acute patients were considered those presenting with duration of symptoms < 14 days and subacute patients with duration of symptoms > 14 days and < 3 months [9 – 11]. Patients with acute occlusions were classified according to the modified Rutherford classification for acute occlusions and those with subacute occlusions according to the Rutherford classification for peripheral arterial disease [9]. The cohort consisted of 113 patients (60 men and 53 women), aged 18 – 92 years (median 72 years). In our patients, the duration of symptomatology ranged from 1 – 90 days (median 14 days). In all, 128 procedures were performed in these patients; of these, 63 procedures (49 %) were completed in patients with acute © 2016 Hogrefe

F. Stanek et al.: Rotarex thrombectomy in limb arteries

Table I. Clinical classification of patients before the procedure and causes of arterial obstruction Acute occlusions (n = 63)

No. of procedures

Category I

14 (22 %)

Category IIa

32 (51 %)

Category IIb

16 (25 %)

Category III

1 (2 %)

Subacute occlusions (n = 65) Category Rutherford 2

4 (6 %)

Category Rutherford 3

19 (29 %)

Category Rutherford 4

24 (37 %)

Category Rutherford 5

18 (28 %)

Causes of arterial obstruction

No. of procedures

Embolisation to lower limb arteries

59 (46 %) {36 acute, 23 subacute}

Thrombosis of lower limb arteries

57 (45 %) {25 acute, 32 subacute}

Thrombotic reocclusion after previous percutaneous intervention

12 (9 %) {4 acute, 8 subacute}

symptoms and 65 procedures (51%) were carried out in patients with subacute symptoms. Table I presents the distribution of the patients according to the clinical classification before intervention. Based on clinical and angiographic findings, occlusions of the peripheral arteries were divided as either embolic or thrombotic, see also Table I. The Rotarex system is approved for use in our country. All of the patients from our cohort were fully informed about the procedure and possible complications, and written informed consent was obtained. The local Ethics Committee gave its approval for this study.

The Rotarex system The Rotarex system (Straub Medical, Wangs, Switzerland) consists of a catheter, motor, control console and collecting bag. The catheter is connected by an electromagnetic clutch to the motor, which powers the spiral within the catheter. The 40 W motor is coupled to the control console, which regulates the number of rotations. The catheter itself is supplied as a 6F or 8F calibre and its braided multi-layer tubing is made of polyimide and Pebax. The catheter contains a steel spiral coated with anti-thrombogenic material that rotates at 40,000 rotations per minute. The tip of the catheter consists of two superimposed cylinders, each having two lateral slits. The inner cylinder (the so-called stator) is connected to the catheter shaft or wall. The outer cylinder (the so-called rotor) is connected to the rotating spiral and forms the cutting head, which “drills” © 2016 Hogrefe

the occluding material within the artery. The rotating spiral produces a permanent vacuum (the Archimedes effect) and the material is suctioned through the slits into the catheter. The aspiration efficacy is approx. 0.75 ml/s in the case of the 6F system and 1.25 ml/s in the case of the 8F system. The suctioned material is fragmented in the slits and transported by the spiral to the external collecting bag. The Rotarex catheter is inserted over a 0.018” guidewire. The detailed technique of thrombectomy using the Rotarex catheter is well known and has been described in the literature [4, 5, 8, 12 – 14]. At the start of each procedure, all patients received 5,000 IU of heparin intraarterially. Following the procedure, unfractionated heparin was administered, either at 5,000 IU subcutaneously every eight hours for 24 hours or as a continuous intravenous infusion of 30,000 IU for 24 hours with monitoring of aPTT. In some patients, a preventive dose of low molecular weight heparin was given once a day. Patients were discharged with chronic anti-aggregant therapy consisting of 100 mg of acetylsalicylic acid daily. If a stent had been placed, 75 mg of clopidogrel daily was added to acetylsalicylic acid for a period of six weeks. If atrial fibrillation was present as the probable cause of embolism to the lower limb peripheral arteries, the patients were started on chronic anticoagulation with warfarin.

Patient follow-up The ankle/brachial index (ABI) was determined before and after the procedure. All patients who returned for follow-up as outpatients were assessed through clinical examination, ABI measurement and duplex ultrasonography of the intervened segment. A new angiography was performed if restenosis or reocclusion was identified and relevant clinical symptomatology was present. Medical check-ups took place one month after the procedure and then at six-month intervals after the intervention. Primary endpoints of our study included: angiographic success, clinical success, amputation rate and primary patency rates 1, 6, 12, 18, 24, 30, 36 and 42 months after the procedure.

Definitions Angiographic (immediate, technical) success: recanalization of the occlusion (residual stenosis < 30 %) with restoration of antegrade blood flow in the whole lower limb. Clinical success: an upward shift of at least one category of the Rutherford classification; concurrently, an increase of the ankle/brachial index (ABI) of > 0.1 must be present (9). Major amputation: any amputation above the level of the ankle. Vasa (2016), 45 (1), 49 – 56

F. Stanek et al.: Rotarex thrombectomy in limb arteries

Amputation rate: number of patients who underwent major amputation divided by the total number of procedures. Early reocclusion: reocclusion within 30 days after procedure (< 30 days). Late reocclusion: reocclusion more than 30 days after procedure (> 30 days). Primary patency: uninterrupted lasting patency following mechanical thrombectomy with residual restenosis < 50 %. Duplex criterion for haemodynamically significant restenosis (> 50 %): peak systolic velocity ratio (PSVR) > 2 .4 [13]. Adjunctive treatment: techniques performed, when needed, after successful Rotarex recanalisation during one session. These are integral components of percutaneous mechanical thrombectomy and they include PTA and/or stenting. PTA is completed if a significant residual stenosis remains despite repeated Rotarex passages. A stent is implanted in the case of flow limiting dissection or if thromboemboli persist after repeated Rotarex passages. A reason for stenting lies in fixing thromboemboli to the arterial wall. Secondary interventions: interventions performed due to reocclusion after mechanical thrombectomy to restore new patency (“secondary patency”). It involves, e.g., repeated Rotarex thrombectomy, PTA, stenting, thrombolysis, surgical thromboembolectomy, bypass etc.

Statistics Categorical variables are expressed as a percentage of a certain whole. Continuous data are presented as a range of values with the median and as mean ± standard deviation. Fisher’s exact test was used to compare categorical variables between the two groups. The means ± standard deviations of continuous data were compared using the twosample t-test. P-values < 0.05 were considered to represent statistical significance. Patency rates were calculated using the life table method.

Results To date, we have conducted 128 interventions in 113 patients. The procedure was repeated because of early or late reocclusion in ten patients, and in two patients the intervention was repeated twice for the same reason. The median interval between two repetitions of interventions was 124 days. Both lower limbs were treated in one patient. The procedure details are summarised in Table II. Angiographic success was obtained in 120 of a total of 128 interventions (93.8 %). Eight procedures were unsucVasa (2016), 45 (1), 49 – 56

Table II. Procedure details – Intervened arterial segments

No. of procedures

Native arteries (iliac, femoropopliteal, proximal crural)

115 (90 %)

–S uperficial femoral artery + popliteal artery

– Superficial femoral artery + popliteal artery + crural arteries

– Superficial femoral artery

– Popliteal artery + crural arteries

– Popliteal artery

– Crural arteries

– Iliac artery

– Deep femoral artery

Bypasses

13 (10 %)

- Femoropopliteal

– Popliteopopliteal

– Femorocrural

Length of occlusions

1 – 60 cm, median 12.5 cm

Number of Rotarex passages

1 – 8, median 2

– Arterial access

No. of procedures

Ipsilateral

115 (90 %)

Cross-over

10 (8 %)

Perioperative

3 (2 %)

– Used Rotarex catheter 8 F Rotarex

16 (12.5 %)

6 F Rotarex

112 (87.5 %)

– Adjunctive treatment – Without (Rotarex alone)

37 (29 %)

– Rotarex & stenting

63 (49 %)

– Rotarex & PTA

28 (22 %)

cessful. Reasons for failures of Rotarex thrombectomy were as follows: • Irreversible rethrombosis of a partially recanalised segment occurred in six interventions (4.7%) – in native arteries three times and in bypasses three times. Interventions in native arteries involved two procedures in the superficial femoral, popliteal and crural arteries concurrently, and one intervention in the popliteal artery. Interventions in bypasses included femoropopliteal prosthetic grafts twice and popliteopopliteal venous graft once. PAT and/or thrombolysis had no effect in these rethromboses. • Repeated embolism to crural arteries appeared in one intervention (0.8 %) in the superficial femoral and pop© 2016 Hogrefe

F. Stanek et al.: Rotarex thrombectomy in limb arteries

Figure 1. Primary patency curve after Rotarex thrombectomy by life table method.

liteal artery. PAT was ineffective and thrombolysis had to be interrupted due to agitation. • Breakage of the tip of the Rotarex catheter happened in one procedure (0.8 %) in a tortuous external iliac artery during a cross-over approach.

Fate of patients after angiographically unsuccessful procedures Bypasses were implanted three times (one femoropopliteal, two femorocrural). Two patients (one with an acute occlusion of the popliteal artery and the other with an acute occlusion of the popliteopopliteal bypass) underwent thrombolysis, which was not effective, and the progression of ischemia necessitated lower limb amputation in both cases. Amputation without thrombolysis had to be performed in one patient. Exitus letalis due to a poor general condition occurred after a couple of days in a patient where thrombol© 2016 Hogrefe

ysis could not be completed because of agitation. Surgical extraction of the catheter tip was accomplished due to the broken catheter. Transitory complications of the Rotarex thrombectomy involved the following: embolism into crural arteries, minor perforation of the crural arteries, reversible rethrombosis following balloon dilatation and Rotarex passage, retroperitoneal bleeding and pseudoaneurysm of the common femoral artery. These complications could be solved during one session or immediately after it. The most frequent transitory complication in our group was peripheral embolisation. This occurred in a total of 4 out of 128 procedures (3.1 %). It appeared twice following Rotarex passage and twice following subsequent balloon angioplasty with a dilatation of the artery to the nominal diameter. It was resolved with percutaneous aspiration thromboembolectomy (PAT) in two cases, with thrombolysis in one patient and a combination of PAT together with embolus infiltration using the glycoprotein IIb/IIIa Vasa (2016), 45 (1), 49 – 56

F. Stanek et al.: Rotarex thrombectomy in limb arteries

Figure 2. An example of Rotarex thrombectomy of a subacute occlusion of the left superficial femoral artery (SFA). A 68-year-old male patient with a history of peripheral arterial disease underwent PTA of the left femoral artery 12 years prior to this intervention and was then free of symptoms. Two months before this procedure, he suddenly developed new intermittent claudication in the left calf with walking distance of 30 metres. Figure 2a: The length of the obstruction of the SFA was 7 cm. Thrombus with contrast medium flowing around was probably present at the origin of the occlusion (at the digit 31). Figure 2b: It was possible to pass the occlusion easily with the guide-wire and the occlusion was recanalised after one passage of the 8F Rotarex catheter. The tip of the Rotarex catheter can be seen above the occlusion. Figure 2c, d, e: Final result after second passage of the Rotarex catheter. No adjunctive PTA or stent placement was necessary. The crural and pedal arteries showed no signs of peripheral embolisation.

antagonist eptifibatide (single bolus dose of 15 mg) in one procedure. In three procedures (2.3 %), minor perforation of the proximal segments of the calf arteries (twice in the peroneal arteries, once in the posterior tibial artery) occurred after Rotarex passage. It was possible to proceed conservatively in all of these cases and extravasate was reabsorbed. During two interventions (1.6 %), there was an immediate reversible rethrombosis of the popliteal artery following PTA, which was resolved by a new Rotarex passage. New reversible thrombotic occlusion of the femoropopliteal bypass after Rotarex passage occurred in one intervention (0.8 %); subsequent PAT with infiltration with the glycoprotein IIb/IIIa antagonist eptifibatide was used. Retroperitoneal hematoma after the puncture in one intervention (0.8 %) had to be operated upon and pseudoaneurysm of the common femoral artery in one procedure (0.8 %) was successfully compressed using an ultrasound probe. Analysis of main procedure failures and complicationsrethrombosis during intervention and distal embolisation included the following: Rethrombosis during intervention (both irreversible and reversible rethromboses): We studied whether a number of factors may have influenced the incidence of rethrombosis, Vasa (2016), 45 (1), 49 – 56

including intervention in bypasses vs. intervention in native arteries, the length of the occlusion before the procedure, distal runoff, and aetiology of the occlusion (embolic or thrombotic). Intervention in bypasses vs. intervention in native arteries: The incidence of rethrombosis was higher in bypasses (33.3 %) than in native arteries (4.9 %). The difference was statistically significant (p = 0.0069). The length of the occlusion before the procedure: The length of the occlusion ranged from 6 to 60 cm (median 20 cm) in patients with rethrombosis, while it ranged from 1 to 52 cm (median 11  cm) in patients without rethrombosis (statistically significant, p = 0.026). Distal runoff: The number of patent crural arteries varied from 0 to 3 (median 1) in the group with rethrombosis and from 0 to 3 (median 2) in the group without rethrombosis. This was statistically significant (p = 0.048). Aetiology of the occlusion – embolic vs. thrombotic: The incidence of rethrombosis in embolic occlusions was 5.9 % whilst the incidence was 9.5 % in thrombotic obstructions. Statistical significance was not found (p = 0.36). © 2016 Hogrefe

Distal embolisation: The duration of symptoms, the length of the occlusion before the procedure and the aetiology of the occlusion were also assessed with regard to distal embolisation. Duration of symptoms: The mean duration of clinical symptomatology before the procedure ranged from 2 to 13 days (median 10 days) in the subgroup with peripheral embolism and from 0 to 90 days (median 15 days) in the subgroup without embolism. The difference was statistically significant (p = 0.0001). The length of the occlusion before procedure: The average length of the occlusion varied from 2 to 22 cm (median 4 cm) in patients with distal embolisation while it varied from 1 to 60 cm (median 12 cm) in patients without embolism (statistically non-significant, p = 0.357). Aetiolog y of the occlusion – embolic vs. thrombotic: The incidence of distal embolism in embolic occlusions was 5.9 % whilst it was 3.2 % in thrombotic obstructions. Statistical significance was not found (p = 0.40). Patient follow-up Clinical success following 120 technically successful procedures was achieved after 99 interventions (82.5 %). The ankle/brachial index (ABI) before interventions ranged from 0 to 0.86 (median 0.50). It increased at a statistically significant level (p < 0.001) to 0 – 1.44 (median 0.95) after mechanical thrombectomy. Major amputation was required 13 times out of 128 procedures; thus, the amputation rate was 10 %. The reasons for amputation were as follows: angiographically unsuccessful intervention in three patients, early reocclusion in five patients, sepsis caused by diabetic gangrene in four patients, and primarily poor distal runoff in one patient. The ultimate time at which it was necessary to carry out an amputation was 95 days after the procedure. Cumulative patency rates at 1, 6, 12, 18, 24, 30, 36 and 42 months after Rotarex thrombectomy are plotted in Figure 1. Only primary patency was assessed, so the secondary interventions using the Rotarex catheter were excluded. Overall, 114 procedures were involved at the beginning of the life table analysis: interventions in 113 patients, with both legs treated in one patient, resulted in 114 procedures altogether. Secondary interventions in patients with restenosis and reocclusion during follow-up included PTA/PTA plus stenting in 18 patients, new Rotarex thrombectomy 14 times, bypasses seven times (femoropopliteal - in four patients, femorocrural – in three patients), thrombolysis as secondary treatment four times and surgical embolectomy of the common femoral artery in one case. The rest of the patients with restenosis or reocclusion were managed conservatively. Twenty patients died from unrelated causes during the follow-up period and 12 patients did not come in for scheduled check-ups. © 2016 Hogrefe

F. Stanek et al.: Rotarex thrombectomy in limb arteries

In our cohort, thrombolysis was totally performed in 12 procedures (9 %) – three times after angiographically unsuccessful procedures, four times for early reocclusion (secondary interventions) and five times for distal runoff disease (adjunctive treatment). One example of a typical Rotarex thrombectomy is shown in Figure 2.

Discussion Rotarex thrombectomy has a very high angiographic success rate, of more than 90%, which is in agreement with other authors [4, 5, 8, 12, 14, 15]. As explained in the Introduction, the method is capable of replacing intra-arterial thrombolysis in most cases. The immediate results of rotational thrombectomy are probably more favourable than those following thrombolysis and the complication rate is lower [1, 3, 6, 7]. Nevertheless, we are aware that the comparison of these results with large thrombolytic studies (e.g. STILE, TOPAS) may be misleading as these studies have a completely different design, since they compare thrombolytic treatment with surgical treatment [6, 7]. Randomised, multicentre trials comparing thrombolysis with Rotarex mechanical thrombectomy are not yet available. There is only one exception when thrombolysis cannot be substituted with Rotarex thrombectomy, which is in cases involving the crural arteries. Due to the catheter size of the Rotarex, it is not possible to use it in the middle and distal parts of the crural arteries. We consider this fact to be the main limitation of this method. Thus, thrombolysis may be a very important adjunct to mechanical thrombectomy in some cases. Generally, thrombolysis is either an adjunctive treatment or a secondary intervention. Adjunctive treatment comes in case of, e.g., femoropopliteal occlusions combined with distal occlusions of crural arteries where thrombolysis can be used to improve distal runoff after successful Rotarex thrombectomy. Thrombolysis may also be the secondary intervention when it is performed to restore blood flow in acute reocclusion after mechanical thrombectomy. The same as for thrombolysis is valid for percutaneous aspiration thromboembolectomy, but this method is restricted only for very acute lesions [1, 4]. We recorded only a low number of perforations caused by the Rotarex catheter. These perforations resolved spontaneously without the necessity of stentgraft placement. Some investigators report a somewhat higher incidence of arterial perforations, but their studies were based on the use of only an 8F Rotarex catheter [8, 18]. In our cohort, the main cause of failure of the percutaneous mechanical thrombectomy was rethrombosis of the intervened segment. We registered both irreversible rethrombosis, as the reason for failure of the procedure, and reversible rethrombosis, which could be solved during the same session. Irreversible rethrombosis occurred a couple of minutes after initial successful recanalisation of an occluded segment. Percutaneous aspiration thrombectomy Vasa (2016), 45 (1), 49 – 56

F. Stanek et al.: Rotarex thrombectomy in limb arteries

and thrombolysis had no lasting effect in these rethromboses. The patients with rethrombosis had the same peri-interventional and interventional anticoagulant regimen as others without rethrombosis. Additionally, in the occurrence of rethrombosis, a new intra-arterial bolus of 2,500 IU of heparin was administered to the usual dose of 5,000 IU of heparin given at the beginning of the intervention. The activated clotted time (ACT) assay was not performed in our laboratory. We can only presume that rethrombosis may be related to a greater initial thrombus load, as rethrombosis was more frequent, at a statistically significant level, in bypasses than in native arteries. In our study, the incidence of rethrombosis was also significantly higher in patients with a longer occlusion and poorer distal runoff. However, some authors did not confirm a worse primary success rate of Rotarex thrombectomy in bypasses compared to native arteries [16, 17]. Embolisation into the crural arteries was the major complication of thrombectomy, and was fortunately only transitory in most cases. The frequency of peripheral embolism in our study is comparable with data from the literature, citing an incidence from 0 % to 24 % [4, 5, 8, 12, 14, 15, 18]. The low incidence of peripheral embolism in these soft thromboembolic occlusions is probably due to the considerable suction power of the Rotarex system. Embolisation occurred more often in patients with a shorter duration of symptoms, such as in more acute occlusions when the thrombi and emboli are not yet organised. It is recommended to very slowly advance the catheter in such cases to enable the full suctioning power of the system, especially when reaching the distal portion of the occlusion. Also, the application of embolic protective devices might be taken into consideration in fresh lesions [19]. Breakage of the catheter can happen in tortuous iliac arteries during a crossover approach, mainly with a sharp aortic bifurcation. To prevent breakage of the Rotarex catheter, it is necessary to advance the sheath so that the Rotarex catheter can exit the sheath without bending at a significant angle. Remaining complications, including retroperitoneal hematomas and pseudoaneurysms of the common femoral artery, were not specific to Rotarex thrombectomy and can occur in other types of catheterisations.

months after the procedure [5]. Zeller reports a 33 % restenosis/reocclusion rate in native arteries after six months and a 37 % restenosis/reocclusion rate after 12 months. The restenosis/reocclusion rate after 12 months significantly increases in the case of in-stent recanalisation (81%) and bypasses (86 %) [8]. Duc reported a primary patency of 62 % after six months and 39 % after one year, respectively [14]. In a retrospective analysis, Wissgott described a 49 % annual restenosis/reocclusion rate in the group of acute occlusions and a 54 % restenosis/reocclusion rate per year in the group of subacute occlusions [15]. Berczi described primary cumulative patency of 39 % at 6, 12 and 19 months after intervention [18]. Because there was a relative decrease in the primary cumulative patency in our cohort after six months, we can only speculate that it is due to the complexity of lesions where common adjunctive treatment (PTA or stenting) was necessary. It is well known that the rate of restenosis after femoropopliteal PTA varies between 40 – 60 % at 12 months [20]. Generally, in cases of recurrent limb ischemia during follow-up, it was often possible to perform a new successful secondary procedure. In some patients with restenosis/reocclusion, their mild symptoms allowed for conservative treatment. The incidence of amputations was slightly higher in our group compared to the results obtained from other authors [8, 14, 15]. Amputation was always performed as ultimum refugium in cases with very advanced limb ischemia. Amputations mostly followed some angiographically unsuccessful interventions or early reocclusions, especially when thrombolysis failed. In four patients, however, the limb was also amputated after technically successful interventions. The cause was diabetic gangrene-associated sepsis. On comparing the long-term results of our cohort with the aforementioned studies involving thrombolysis, our results are either superior or comparable. The TOPAS study described a 65 % amputation-free survival rate at one year in the urokinase group. In the STILE study, ischemia recurred in 64 % of patients at one year in the thrombolysed group, with an incidence of amputations in 10 % of patients during the first year after the procedure [6, 7]. However, as mentioned above in the discussion of immediate results, any comparison must be made very carefully

Follow-up Long-term results of all techniques treating acute and subacute occlusions of peripheral arteries must be assessed from several points of view that comprise not only cumulative patency rates but also amputation rates (salvage of limbs) and the possibility of performing any secondary intervention after initial procedure averting an amputation. If we compare our cumulative patency rates with other studies dealing with Rotarex thrombectomy, it is apparent that these studies report the results of follow-up lasting less than 19 months after intervention [8, 14, 15, 18]. The exception is the reference 5, which presents data 36 Vasa (2016), 45 (1), 49 – 56

Conclusions Rotarex thrombectomy has excellent immediate results with a low rate of failures and complications. In our cohort, rethrombosis was more frequent in bypasses than in native arteries, in patients with longer occlusions and those with poorer distal runoff. Embolisation happened more often in patients with a shorter duration of symptoms. In comparison to thrombolysis, Rotarex thrombectomy enables the fast and efficient treatment of acute and subacute occlusions of peripheral arteries in one session. © 2016 Hogrefe

References 1. Zeller T, Tepe G. Treatment of acute limb ischemia with focus on endovascular techniques. Vasa 2009; 38: 123 – 33. 2. Wissgott C, Kamusella P, Richter A, et al. Treatment of acute femoropopliteal bypasses graft occlusion: Comparison of mechanical rotational thrombectomy with ultrasound-enhanced lysis. Rofo 2008; 180: 547 – 52. 3. Karnabatidis D, Spiliopoulos S, Tsetis D, et al. Quality improvement guidelines for percutaneous catheter-directed intra-arterial thrombolysis and mechanical thrombectomy for acute lower limb ischemia. Cardiovasc Intervent Radiol 2011, 34: 1123 – 36. 4. Stanek F, Ouhrabkova R, Prochazka D. Mechanical thrombectomy using the Rotarex catheter – safe and effective method in the treatment of peripheral arterial thromboembolic occlusions. Vasa 2010; 39: 334 – 40. 5. Stanek F, Ouhrabkova R, Prochazka D. Mechanical thrombectomy using the Rotarex catheter in the treatment of acute and subacute occlusions of peripheral arteries: immediate results, long-term follow-up. Int Angiol 2013; 32: 52 – 60. 6. Ouriel K, Veith FJ, Sasahara AA. A comparison of recombinant urokinase with vascular surgery as initial treatment for acute arterial occlusion of the leg. Thrombolysis of peripheral arterial surgery (TOPAS) investigators. N Eng J Med 1998; 338:1105 – 11. 7. Weaver FA, Comerota AJ, Youngblood M, et al. Surgical revascularisation versus thrombolysis for non-embolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE Investigators. Surgery versus Thrombolysis for Ischemia of the Lower Extremity. J Vasc Surg 1996; 24: 513 – 21. 8. Zeller T, Frank U, Bürgelin K, et al. Long-term results after recanalization of acute and subacute thrombotic occlusions of the infraaortic arteries and bypass-grafts using a rotational thrombectomy device. Rofo 2002; 174: 1559 – 65 9. Rutherford RB, Baker JD, Ernst C, et al. Recommended standards for reports dealing with lower extremity ischemia: Revised version. J Vasc Surg 1997; 26: 517 – 38. 10. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-society consensus for management of peripheral arterial disease (TASC II). J Vascular Surg 2007; 45 Suppl S: 5 – 67. 11. Dosluoglu HH, Harris LM. Endovascular management of subacute lower extremity ischemia. Semin Vasc Surg 2008; 21: 167 – 79.

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12. Schmitt HE, Jäger KA, Jakob AL, et al. A new rotational thrombectomy catheter: System design and first clinical experience. Cardiovasc Intervent Radiol 1999; 22: 504 – 9. 13. Schlager O, Francesconi M, Haumer M, et al. Duplex sonography versus angiography for assessment of femoropopliteal arterial disease in a „real-word“ setting. J Endovascular Ther 2007; 14 (4): 452 – 9. 14. Duc SR, Schoch E, Pfyffer M, et al. Recanalization of acute and subacute femoropopliteal artery occlusions with the Rotarex catheter: one year follow-up, single center experience. Cardiovasc Intervent Radiol 2005; 28: 603 – 10. 15. Wissgott C, Kamusella P, Richter A, et al. Mechanical rotational thrombectomy for treatment thrombolysis in acute and subacute occlusion of femoropopliteal arteries: retrospective analysis of the results from 1999 to 2005. Rofo 2008; 180: 325 – 31. 16. Lichtenberg M., Käunicke M, Hailer B. Percutaneous mechanical thrombectomy for treatment of acute femoropopliteal bypass occlusion. Vascular Health and Risk Management 2012; 8: 283 – 9. 17. Wissgott C, Kamusella P, Andresen R. Recanalisation of acute and subacute venous and synthetic bypass-graft occlusions with a mechanical rotational catheter. Cardiovasc Intervent Radiol. 2013; 36: 936 – 42. 18. Berczi V, Deutschmann HA, Schedlbauer P, et al. Early experience and midterm follow-up results with a new, rotational thrombectomy catheter. Cardiovasc Intervent Radiol 2002; 25: 275 – 81. 19. Müller-Hülsbeck S, Schäfer PJ, Hümme TH, et al. Embolic protection devices for peripheral application: wasteful or useful? J Endovasc Ther 2009; 16 Suppl 1: 163 – 9 20. Schillinger M, Minar E. Percutaneous treatment of peripheral artery disease: novel techniques. Circulation 2012; 126(20): 2433 – 40. Submitted: 17.06.2015 Accepted after revision: 19.07.2015 There are no conflicts of interest existing. Correspondence address Dr. Frantisek Stanek, MD, PhD Department Cardiology 3rd Faculty of Medicine, Charles University Srobarova 50 100 34 Prague 10 Czech Republik stanek.f@tiscali.cz

Vasa (2016), 45 (1), 49 – 56

Original communication

Paroxysmal finger haematoma – a benign acrosyndrome occurring in middle-aged women Patrick H. Carpentier1, Hildegard R. Maricq2, Christine Biro1, Myriam Jiguet1, and Christophe Seinturier1 1 2

Department of Vascular Medicine, Grenoble University Hospital, France Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, USA

Summary: Background: Paroxysmal finger haematoma (PFH) is an under-recognised vascular acrosyndrome with no epidemiological description to date. The aim of this work was to evaluate the prevalence, risk factors and clinical correlates of PFH in a population-based sample of subjects and to describe their semiological characteristics. Patients and methods: This cross-sectional study of random samples of the general population in three geographic areas of France involved 802 subjects, 548 women and 254 men, aged 18 to 84 years. The diagnosis of PFH was made from a report by the subject of a history of recurrent haematoma in the fingers with a sudden, painful and unexpected occurrence. Diagnosis of associated conditions and evaluation of lifestyle variables were obtained through standardised medical interview and examination. Results: A history of PFH was detected in 71 subjects, with a prevalence of 1.2 % in men and 12.4 % in women; there was no significant regional variation. Onset before 40 years of age was rare. Besides female sex and age, no socio-economical nor lifestyle risk factors were detected. PFH was associated with Raynaud phenomenon and a history of chilblains, but no link with any health threatening disease was found. In addition to the sudden onset of pain and hematoma, the main clinical features were a frequent digital swelling during the painful attack, and their predominant location on the volar side of the first and second phalanges of the third or second fingers of the dominant hand. Conclusions: PFH is a benign phenomenon, frequently found in middle-aged women, to be classified among the vascular acrosyndromes. Patients seeking medical evaluation for this disorder should be reassured. Key words: Haematoma, finger, Raynaud’s disease, epidemiology, prevalence, risk factors

Introduction Paroxysmal finger haematoma (PFH), also called spontaneous finger haematoma, finger apoplexy or Achenbach syndrome, is usually described by the patient to the consulting physician as recurring episodes characterised by unexpected, painful and sudden onset of a swelling of a finger with subsequent appearance of a deep ecchymosis most often predominant on the volar side of the proximal phalanx (Fig. 1a and 1b). This painful attack suggests a problem of vascular rupture to the patient who seeks medical advice, and his/her main concern is the potential risk of haemorrhages in other sites such as the brain or other vital organs. The first accurate description of this syndrome was given by Achenbach in 1955 (quoted in [1]). Since that time, it has remained ignored in most medical textbooks and fewer than 100 cases have been reported in the medical literature [1 – 23]. According to those publications, paroxysmal finger haematoma is a rare and benign condition of unknown aetiology. An epidemiological study of Raynaud phenomenon in the general population [24 – 26] provided us with the opVasa (2016), 45 (1), 57 – 62 DOI 10.1024/0301-1526/a000496

portunity to estimate the prevalence, risk factors and associated conditions of PFH, and to analyse its usual semiological features in a population-based sample of subjects.

Patients and methods This study was carried out as an offshoot of an AmericanFrench epidemiological study of Raynaud phenomenon in three geographic areas in the South-East of France with different climates (Grenoble in the Alps Mountains, Nyons in the plateau of Haute Provence and Toulon on the Mediterranean Sea shore). The sampling procedure was detailed in previous publications [24 – 26] and can be briefly summarised as follows: Random samples from households of the selected geographic areas were obtained from telephone lists. Every subject aged 18 years or over and living in the selected households was included in the survey until the planned sample size of 2000 subjects per region was reached. The subjects were interviewed by phone (Phase I) about demographic and socioeconomic data and the occurrence of symptoms in their hands suggesting Raynaud © 2016 Hogrefe

P. Carpentier et al.: Paroxysmal finger haematoma

Figures 1. Paroxysmal finger haematoma as shown the day after onset in a 56 years old woman (A,B).

phenomenon, which was the primary aim of the original study. This was based on two key questions: • Are your fingers unusually sensitive to cold? (Q ) • Do your fingers sometimes show unusual colour changes? (C) Subjects were classified as QC+ when they answered yes to either question or QC- when both answers were no. All QC+ subjects and a random sample of QC- cases were invited to a face-to-face interview and medical examination (Phase II), where diagnoses of Raynaud phenomenon and other vascular acrosyndromes were made.

Figure 2. Venectasia in a 62 years old woman with paroxysmal finger haematoma.

Evaluation of vascular acrosyndromes This medical interview evaluated the diagnosis of Raynaud phenomenon and other acrosyndromes through a standardised colour chart-assisted diagnostic procedure that had been previously validated. The following criteria were used: • The diagnosis of Raynaud phenomenon was made from a previous procedure [26 using a standardised questionnaire assisted by colour scales and charts. • The diagnosis of acrocyanosis was based on symmetrical coldness and cyanosis of the hands at the time of examination, being present most of the time according to the information given by the subject. • A positive history of chilblains was accepted when the subject described red, purple or blue palpable skin lesions of the feet and/or hands, giving itching or burning sensations and related to known cold exposure or to the cold season. • A history of paroxysmal finger haematoma (PFH) was recognised when the patient described recurrent haematoma of the fingers occurring with an unexpected, sudden and painful onset, spontaneously or after minimal physical trauma (Fig. 1a and 1b). • The presence of venectasia was evaluated only in two regions (Nyons and Toulon). Venectasia were recognised as prominent visible small veins in the volar side of the finger, mainly in the periarticular area (Fig. 2).

Evaluation of other medical conditions During the same examination, potential risk factors such as cigarette smoking, alcohol consumption, occupation and occupational exposure to vibration or hand trauma were evaluated in a standardised fashion 24], as were other conditions such as migraines, varicose veins and atopy. Any other history of a medically significant health episode was also recorded and coded in a standardised way according to a pre-established diagnostic list for statistical analysis.

Statistical analysis Prevalence estimates for each geographic area were calculated from age-standardised data to the whole population. Due to the sampling procedure, estimates of prevalence were computed by multiplying the proportion of the population in the QC+ and QC- groups (from Phase I) by the proportion of each class that was found to have the condition examined in Phase II. Adding the two resulting products gave the estimated prevalence of the condition in the whole sample; 95 % confidence intervals were calculated using the Poisson law assumptions. Further statistical analysis was restricted to women, as too few cases of paroxysmal finger haematoma were diagnosed in men. As no link was found with QC status, no adjustment for the sampling procedure was performed in these analyses, which were performed with SPSS software Vasa (2016), 45 (1), 57 – 62

P. Carpentier et al.: Paroxysmal finger haematoma

for Windows (version 11.0). The chi-square test was used for categorical data, with a Mantel-Haenszel test for ordinal association when appropriate.

Results Prevalence by sex, age and geographic area The prevalence of paroxysmal finger haematoma for men and women of the three investigated regions are shown in Table I. The syndrome was found in as many as 12.4 % of women compared to only 1.2 % in men, which is a 10-fold difference. No conspicuous geographical differences were found among the three regions with different climates, but there was a strong relationship with age, paroxysmal finger haematoma being mainly found in women over 40 years of age (Fig. 3).

Risk factors and associated conditions As 68 of the 71 subjects reporting PFH were women, the risk factors and associated conditions were evaluated only in the subsample of women. No relation was found with the body mass index, educational level, marital status, skilled/unskilled work nor with an occupational exposure to vibrating tools or to palmar trauma. Apparently significant relationships were found with cigarette smoking, oestrogen treatment and low alcohol consumption that were not confirmed after adjusting for age.

As the syndrome was mainly found in women over 40 years, particular attention was paid to a potential relationship to menopause and oestrogen-related variables (Tab. II), but no significant relationship was documented. No relationship was shown with the number of pregnancies. An apparent relation was found with menopausal status, but it could not be confirmed after adjustment for age; the age of menopause was similar for women with (48.9 + 0.7 years) or without (48.1 + 1.8 years) paroxysmal finger haematoma Table I. Prevalence of paroxysmal finger haematoma in the general population of three French regional areas (FDDs = number freezing degrees days) Geographic areas

Number of subjects with paroxysmal finger haematoma

Adjusted prevalence* (%)

Men Grenoble (73 FDDs per year) Women

0/78

0.0 [0.0; 4.7]

21/189

P < 0.001 11.1 [6.9; 16.9]

Men Nyons (39 FDDs per year) Women

2/119

1.7 [0.8; 6.1]

31/226

P = 0.008 13.3 [9.3; 19.5]

Men Toulon (4 FDDs per year) Women

1/57

1.8 [0.1; 9.8]

16/133

P = 0.004 12.0 [6.9; 19.5]

Men 3 areas combined Women

3/254

0.8 [0.2; 3.5]

68/548

P < 0.001 12.2 [9.3; 15.9]

Regional variations: men (P = ns); women (P = ns). (*) aged standardized prevalence estimates adjusting for the sampling procedure

Figure 3. Prevalence of paroxysmal finger haematoma in women and men as a function of age.

Vasa (2016), 45 (1), 57 – 62

P. Carpentier et al.: Paroxysmal finger haematoma

Table II. Estrogen related variables and prevalence of paroxysmal finger haematoma (PFH) in 548 women. Estrogen related variables

Prevalence of PFH N (%)

Number of pregnancies 0 (n = 100) 1 (n = 87) 2 (n = 205) 3 (n = 89) > 4 (n = 65)

11 (11.0) 13 (14.9) 21 (10.2) 14 (15.7) 9 (13.4)

Menopause (total) (5th decade) (6th decade)

46 (15.8) 22 ( 8.6) 2 (10.0) 14 (12.8) 12 (12.1) 3 (14.3)

yes no yes no yes no

(n = 292) (n = 256) (n = 20) (n = 109) (n = 99) (n = 21)

Hormone replacement therapy yes (n = 35) no (n = 257)

2 ( 5.7) 46 (17.9)

P Value

.013 ns Ns Ns

(P = ns), and no correlation was found when comparing the age of onset of the haematoma and the age of menopause (Fig. 4). Neither was a significant relationship found with the use of hormone replacement therapy. Regarding the associated medical conditions, most subjects with PFH did not report any diagnosis of health threatening conditions, and their self-perceived health status was rated accordingly. No link was found with clinically overt atherosclerosis, varicose veins in the lower limbs, manifestations of atopy, migraine, or with a history of previous internal haemorrhage or of any haematological disorder. Concerning vascular acrosyndromes, a significant association was found with Raynaud phenomenon and a history of chilblains (Tab. III). Clinical venectasia of the fingers were systematically recorded only in the last two regions investigated (Nyons and Toulon). They were found in 11 of 39 women reporting

Figure 4. Relationship between the age at menopause and the age of onset of Paroxysmal finger haematoma in 45 menopausal women with PFH no significant correlation was found (r = –.23 ; P = .12).

paroxysmal finger haematoma vs 9 of 287 women who did not (P < 0.001; Tab. III).

Clinical description Main features of the paroxysmal finger haematoma, as found in our series of 71 subjects, are summarised in Tables IVa and IVb. The median age of onset, as reported by the patients, was 48 years (66 answers, inter-quartile range [40, 55]). The median frequency of attacks was 1.2 per year (interquartile range [0.8 – 2.9], and interestingly, eight patients (11.3 %) reported clusters of 2 to 4 attacks within a single month.

Table III. Associated conditions in the women with and without paroxysmal finger haematoma (PFH). When restricting the comparison to the women aged 40 years or more, associations with palmar hyperhidrosis, raynaud phenomenon, history of chilblains and digital venectasia remain significant. Please also note that the high proportion of women with raynaud or with history of chilblain in this study group is related to the sample procedure favoring cold sensitive subjects; these are not prevalence data Associated conditions in women

PFH+ (n = 68) (%)

PFH(n = 480) (%)

P Value

Purpura simplex (History of spontaneous ecchymoses in the lower limbs)

34.8

24.8

History of visceral bleeding

0.0

0.4

Any health threatening condition

52.9

62.3

Acrocyanosis

17.9

12.1

Raynaud phenomenon

23.9

13.1

.025

History of chilblains

55.2

37.4

.007

Digital venectasia (tested only in 2 geographic areas)

28.2 (11/39)

3.1 (9/287)

< .001

Vasa (2016), 45 (1), 57 – 62

P. Carpentier et al.: Paroxysmal finger haematoma

Table IV. (A) Fingers involved by paroxysmal finger haematoma in the series of 71 subjects Most frequently involved finger (n = 40) N (%)

Right hand

Fingers reported as involved at least once (n = 71) N (%)

1 2 3 4 5

12 (16.9) 26 (36.6) 31 (43.7) 22 (31.0) 15 (21.1)

1 (2.5) 5 (12.5) 14 (35.0) 1 (2.5) 1 (2.5)

Left hand

Fingers involved

1 2 3 4 5

10 (14.1) 27 (38.0) 32 (45.1) 27 (38.0) 14 (19.7)

0 (0.0) 5 (12.5) 8 (20.0) 4 (10.0) 1 (2.5)

Every finger could be involved, but the most frequently affected was the third one, followed by the second, and the right hand was more often involved than the left (Tab. IVa). The volar side was the most often affected (81.7 % of subjects) compared to the dorsal (11.3 %) and lateral (4.2 %) sides. Pain and ecchymosis were present by definition in 100 % of cases. Local swelling was reported as usually associated with attacks in 47.6 % of PFH patients, and pruritus in 27.8 % (Tab. IVb). Occasional complications of the attacks such as transient hypoesthesia of the fingertip and white finger (unrelated to cold exposure), were reported by respectively 11.2 % and 4.2 % of subjects with PFH. The median duration of visible ecchymoses, as reported by the subjects, was 3 days (inter-quartile range [2 – 3]).

Discussion This paper reports the first epidemiological evaluation of the paroxysmal finger hematoma (PFH), which allows an appraisal of prevalence and risk factors unbiased by the numerous factors influencing the referral of a patient to a specialised centre. The potential drawback of this approach is that the diagnosis had to be made retrospectively, from the descriptions reported by the study subjects. However, we are confident that our diagnostic classification was sound, due to the very accurate description of their attacks the PFH subjects were able to provide, and that we report here in detail. Indeed, the semiological description of the paroxysmal finger haematoma by Achenbach [1, was already quite similar to that which we found in this work. It was obtained from a series of patients (6 women and one man), and the author had already noted the predominance in middle-aged women, and insisted on the absence of associated disorder, except for finger venectasia, and a possible “neurotonic complexion”. Since then, the consistency of the description of the attacks throughout the case reports and small series of Vasa (2016), 45 (1), 57 – 62

Table IV. (B) Signs and symptoms related to the attacks of finger haematoma (n = 71) Never occurs (%)

Sometimes occurs (%)

Occurs most often (%)

Ecchymosis

0.0

2.8

97.2

Pain

2.7

4.2

93.1

Swelling

47.2

5.6

47.2

Pruritus

69.4

2.8

27.8

Hypoesthesia

88.8

5.6

White finger

95.8

4.2

0.0

Detectable Triggering factor

57.7

19.7

22.5

Signs and symptoms occurring during the attacks

the literature is quite remarkable, even when the authors were not aware of previous publications [3; 5; 11]. Regarding the aetiology and pathophysiology of this phenomenon, few investigations were performed, mainly looking for haemostatic disorders, and were negative. Singer [19] favoured the hypothesis of a vasomotor disorder, and the association of PFH with Raynaud phenomenon was recently brought into focus by Thies et al. [21] who found three patients with Raynaud in a series of eight women with PFH. This is consistent with the epidemiological associations we found, both with Raynaud phenomenon and with a history of chilblains. The female predominance and the striking similarity of age of onset of PFH and the menopause would point to potential hormonal factors; we were not able to find clearer epidemiological associations favouring this hypothesis, but that does not mean that it can be ruled out. Local mechanical factors could also be involved, as suggested by the association with venectasia, and the minor mechanical stresses sometimes reported as triggers by the subjects. There are few reports on paroxysmal finger haematoma in the literature, totalling less than 100 observations, and several authors have suggested it was rare. It is clear from our data, however, that this phenomenon is underestimated rather than rare. Few patients seek medical evaluation for it and those are probably more anxious and diseasecentred than subjects obtained from screening of the general population, as suggested by the “neurotonic complexion” described by the early reports [1] and the absence of discrepancy between the health status and the self-perception of it in our series. The association of psychological disorders reported in clinic-based series might very well be related mainly to the decision to seek medical advice rather than to the acrosyndrome itself. Finally, the absence of a literature report of any case of paroxysmal finger hematoma where an association was found of visceral bleeding or bleeding diathesis is impressive, and consistent with our findings. As patients who seek medical evaluation are often afraid of visceral (mainly cerebral) vascular rupture, effort should be made by the consulting physician to reassure them. © 2016 Hogrefe

Conclusions Paroxysmal finger haematoma is a benign phenomenon frequently affecting women over 40 years of age. It is associated with other benign acrosyndromes such as primary Raynaud phenomenon and history of chilblains and should be classified among them. It is not associated with health threatening conditions and patients consulting for this disorder should be reassured, since they might be frightened by a possible risk of visceral bleeding which has not been documented neither in the literature nor in this series.

Acknowledgments The authors express their appreciation to Sophie Bouton for organising the field studies.

References 1. Achenbach W. Das paroxysmale Handhämatom. Medizinische 1958; 52: 2138 – 40. 2. Bossong W. Achenbachsyndrom (paroxysmales Handhämatom). Z Hautkr 1973; 48: 582 – 3. 3. Cowen R, Richards T, Dharmadasa A, et al. JM. The acute blue finger: management and outcome. Ann R Coll Surg Engl 2008; 90: 557 – 60. 4. Danilov M. Contributij la sindromul W. Achenbach. Chirurgia 1978; 27: 311 – 2. 5. Deliss L.J., Wilson J.N. Acute blue fingers in women. J Bone Joint Surg (Br) 1982; 64: 458 – 9. 6. Eikenboom JC, Cannegieter SC, Briet E. Paroxysmal finger haematoma: a neglected syndrome. Thromb Haemost 1991; 66: 266. 7. Hornemann M Achenbach-Syndrom. Arch Dermatol Forsch 1972; 244: 603. 8. Huikeshoven M, de Priester JA, Engel AF. A case of spontaneous wrist haematoma in Achenbach syndrome. J Hand Surg Eur Vol 2009; 34: 551 – 2. 9. Jadassohn W, Paillard R, Hunziker N, et al. Hémorragie douloureuse du doigt. Dermatologica 1966; 133: 91. 10. Jung E.G. Das paroxysmale Fingerhämatom. Schweiz Med Wschr 1964; 94: 458 – 60. 11. Khaira HS, Rittoo D, Vohra RK, et al. The non-ischaemic blue finger. Ann R Coll Surg Engl 2001; 83: 154 – 7.

P. Carpentier et al.: Paroxysmal finger haematoma

12. Kluger N, Serres-Cousiné A, Girard C, et al. Hématomes digitaux spontanés (Syndrome d’Achenbach). Presse Med 2011; 40: 326 – 7. 13. Layton A. M., Cotterill JA. A case of Achenbach’s syndrome. Clin Exp Dermatol 1993; 18: 60 – 1. 14. Lazareth I Hématome paroxystique des doigts. Rev.Prat 1998; 48: 1644 – 5. 15. Marx R. Leitsymptom “Hautblutungen”. Münch Med Wschr 1960; 102: 1537 – 41. 16. Nietzschner H. Zur Aetiologie des Fingerapoplexie. Zschr Haut-Geschl Krkh 1967; 42: 141 – 4. 17. Parslew R, Verbov JL. Achenbach syndrome. Br J Dermatol 1995; 139: 319. 18. Robertson A, Liddington MI, Kay SP. Paroxysmal finger haematomas (Achenbach’s syndrome) with angiographic abnormalities. J Hand Surg [Br] 2002; 27: 391-3. 19. Singer R. Über die Symptome und die Diagnose des Fingerapoplexie (paroxysmales Hanhämatom). Wien klin Wschr 1962; 74: 741 – 3. 20. Stiegler W., Heinze-Werlitz C. Paroxysmales Fingerhämatoma (Achenbach-Syndrome). Hautarzt 1990; 41: 270 – 1. 21. Thies K., Beschorner U., Noory E., et al. Achenbach’s syndrome revisited. Vasa 2012; 41: 366 – 70. 22. Van Dijk E., Koopmans-van Dorp B., Pothuizen L.M. Het paroxysmale vingerhematoom. Ned T Geneesk 1973;117:982-4. 23. Zimmerli L, Dobler C, Aschwanden M. Wiederholte schmerzhafte Blaufarbung der Finger und Handinnenfläche. Praxis 2002; 91: 1664 – 6. 24. Carpentier PH, Biro C, Jiguet M, et al. Prevalence, risk factors, and clinical correlates of ulnar artery occlusion in the general population. J Vasc Surg 2009; 50: 1333 – 9. 25. Maricq H. R., Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: Charleston, SC, USA, vs Tarentaise, Savoie, France. J Rheumatol 1993; 20: 70 – 6. 26. Maricq HR, Carpentier PH, Weinrich MC, et al. Geographic variation in the prevalence of Raynaud’s phenomenon: a 5 region comparison. J Rheumatol 1997; 24: 879 – 89. Submitted: 18.07.2012 Accepted after revision: 08.07.2015 There are no conflicts of interest existing. Correspondence address Dr. Patrick H. Carpentier, MD Vascular Medicine Genoble University Hospital Hopital Michallon 38043 Grenoble France pcarpentier@chu-grenoble.fr

Vasa (2016), 45 (1), 57 – 62

Original communication

Risk factors for superficial vein thrombosis in patients with primary chronic venous disease Dalibor Musil1, Marketa Kaletova1, and Jiri Herman2 1 2

Department of Internal Medicine I, Cardiology, Teaching Hospital, Olomouc, Czech Republic Department of Surgery II – Vascular and Transplantation Surgery, Teaching Hospital, Olomouc, Czech Republic

Summary: Background: Primary chronic venous disease (CVD) is associated with an increased risk of superficial vein thrombosis (SVT). While CVD is a predominant factor in SVT, there is a range of additional predisposing factors. The objective was to investigate the association between age, gender, BMI, smoking, oestrogen hormone therapy, family history of venous thromboembolism (VTE) and CEAP clinical classification in patients with CVD and a history of SVT. Patients and methods: In a retrospective observational study on consecutive patients with primary CVD, 641 outpatients were enrolled (152 men, 23.7 %; 489 women, 76.3 %). The prevalence of SVT was evaluated according to age, BMI, smoking, presence of family history of VTE, use of hormone therapy, and clinical class of CVD. Results: Risk of SVT was significantly increased in women (OR 1.68, 95 % CI = 1.02 – 2.76; p = 0.041), older patients (46 – 69 years, OR 1.57, 95% CI = 1.03 – 2.4; p = 0.036, ≥ 70 years, OR 2.93, 95 % CI = 1.5 – 5.76; p = 0.001), smokers (OR 1.69, 95 % CI = 1.1 – 2.58; p = 0.015) and in persons with first-degree siblings diagnosed with VTE (OR 2,28, 95 % CI = 1.28 – 4.05; p = 0.004). The risk was significantly increased in older male smokers (p – 0.042). In women, smoking and oestrogen therapy (p = 0.495) did not increase the risk of SVT even older women or in those with increased BMI. In CVD (C0 – C3), a history of episodes of SVT was found in 103/550 (18.7 %), in chronic venous insufficiency (CVI) in 27/91 (29.7 %). There was a significantly higher prevalence of SVT in patients with CVI (OR 1.70, 95% CI = 1.1 – 2.5; p = 0.016). Conclusions: In patients with primary CVD, SVT was significantly associated with female gender. In men, older age, smoking and positive family history of VTE were relevant SVT risk factors. In women, risk factors were older age, BMI ≥ 25 kg/m2 and positive family history of VTE. Compared with C0 – C3 clinical classes, CVI significantly increases the risk of SVT. Key words: Primary chronic venous disease, superficial vein thrombosis, BMI, smoking, oestrogen hormone therapy, family history

Introduction

Patients and methods

Superficial vein thrombosis (SVT) is a very common condition most often associated with chronic venous disease (CVD) [1]. In the Calisto trial, for example, almost 90 % of patients with acute, symptomatic SVT suffered from varicose veins [2]. SVT is related to one of the components of the Virchow triad: intimal damage, stasis or turbulent blood flow, and increased coagulability, all of which are present in CVD. Varicose veins are a risk factor for both SVT and deep vein thrombosis (DVT) separately [3]. Many additional risk factors and underlying conditions (e.g. malignancy, thrombophilia, and autoimmune disease) are also described in relation to idiopathic, migrant or recurrent SVT [1]. Apart from CVD, obesity, older age, female sex, cigarette smoking, oral contraceptives and hormone replacement therapy are other frequently recognised risk factors [4]. Could these factors modify the risk of SVT in patients with CVD? The objective of this study was to investigate the association between age, sex, BMI, smoking habits, oestrogen hormone therapy, family history of venous thromboembolism (VTE) and CEAP clinical classes in patients with CVD and a history of episodes of SVT.

This was a retrospective observational study on consecutive patients in an angiology outpatient clinic. All patients had objectively confirmed primary CVD, with clinical classes from C0 to C6. In total, 641 patients were enrolled (152 men, 23.7 %; 489 women, 76.3 %), with a mean age 49.1 years (± 13.5). Data were collected from patient files. These included age, gender, weight (kg), height (cm), clinical class of CVD (C) according to the CEAP classification, smoking, family history of VTE, and use of oral contraceptives/hormone replacement therapy. BMI was calculated as: BMI = weight/height2. BMI < 25 kg/m2 was classified as normal weight, BMI 25 – 29 kg/m2 as overweight, and BMI ≥ 30 kg/m2 as obese [10] (Tab. I). The clinical signs and symptoms of venous disease have been widely assessed by means of the CEAP classification. We distinguished patients with CVD of clinical classes C0 to C3 and chronic venous insufficiency (i.e., classes C4 to C6) [5,6]. The subgroup C0 – C3 included 550 patients and the subgroup of chronic venous insufficiency included 91 patients. All of these patients underwent duplex ultrasound examination of the leg veins.

Vasa (2016), 45 (1), 63 – 66 DOI 10.1024/0301-1526/a000497

D. Musil et al.: Additional RF for SVT in pts with CVD

Results

Table I. Baseline characteristics of the patients with CVD N (%) Male

152 (23.7)

Female

489 (76.3)

Mean age (SD)

Male 47.2 (±13.3) years Female 49.6 (±13.6) years

Mean BMI (SD)

Male 28.01 (±3.7) kg/m2 Female 27.0 (±5.1) kg/m2

Number of episodes of SVT

1 episode 2 episodes More than 2 episodes

118 (18.4) patients 8 (1.3) patients 4 (0.6) patients

BMI recorded

641 patients (100 %)

Smoking status recorded

614 patients (95.8 %)

Hormone therapy recorded

418 women (85.5 %)

Family history of VTE recorded

444 patients (69.3 %)

The prevalence of SVT of the lower legs was retrospectively evaluated according to sex, age in three age groups (≤ 45 years, 46 – 69 years and ≥ 70 years), and BMI in three groups (normal weight, overweight, and obese), according to smoking habit, use of oral contraceptives/hormone replacement therapy, presence of first-degree siblings diagnosed with VTE in the family history and clinical classes of CVD according to CEAP classification.

Statistics Comparisons between groups were made using the MannWhitney U test. Pearson’s X2 (Chi-square) test was used to check associations between qualitative variables. The odds ratios were calculated for the risk estimation of variables of interest. Logistic regression analysis was carried out to determine the relationship between different variables and risk of disease. All tests were performed using the statistical analysis software SPSS version 15.0 (SPSS, Inc., Chicago, IL). p < 0.05 was taken to be statistically significant.

The data presented in Table I show a significant prevalence of female patients (76.3 %) over male patients (p < 0.001). There were no significant differences in mean age (p = 0.320) or mean BMI (p = 0.125) of females and males. Table II shows the relationship between gender, age and risk of SVT in patients with CVD. In men, a history of episodes of SVT was found in 22/152 (14.5 %), in women in 108/489 (22.1 %). There was a statistically significantly higher prevalence of SVT in women than men (p < 0.01). In the logistic regression analysis, the risk of SVT was significantly increased in women. SVT was associated with female gender (odds ratio (OR) 1.68, 95 % CI = 1.02 – 2.76; p = 0.041). A history of episodes of SVT was found for each age group: in 15.4 % of patients aged ≤ 45 years, in 22.2 % of patients in the age group 46 – 69 years, and in 34.7 % of patients in the age group ≥ 70 years. In the logistic regression analysis, the risk of SVT increased with age (p = 0.001) in both sexes. In the age group 46 – 69 years, the risk of SVT was almost 1.6 times higher and in patients 70 years and older was about 3 times higher than in patients aged ≤ 45 years. We investigated the relationship between selected lifestyle factors (BMI, smoking, oral contraceptives/hormone replacement therapy), family history of VTE in first-degree siblings in patients with CVD and risk of SVT (Tab. III). A history of episodes of SVT was found in 14.9 % in the group with a BMI < 25 kg/m2, in 21.3 % in the group with a BMI 26 – 29 kg/m2 and in 35.8 % of those with a BMI ≥ 30 kg/m2. The risk of SVT rose significantly in overweight patients (p = 0.039) and very significantly in obese patients (p = 0.003) with CVD. In smokers, the risk of SVT was 1.69 times higher than in non-smokers (p = 0.015). In women, oestrogen therapy was not related to the increased risk of SVT (p = 0.495). The prevalence of SVT in women on oestrogen hormone therapy was 22.6 % and in women without hormone therapy it was 19.6 %. In all groups of patients with CVD, those with a family history of VTE in first-degree siblings had a significantly increased risk of SVT compared to patients without a VTE family history (p = 0.004). We evaluated the relationship between gender and other factors - age, BMI, smoking and risk of SVT (Tab. IV). All patients with a history of SVT were significantly older than SVT-negative patients (p = 0.001). This correlation was found in men (p = 0.022) and women (p = 0.018). The BMI

Table II. Estimation of SVT risk by sex and age in patients with CVD (n = 641) N

SVT n/N (%)

95 % CI

p value

Sex Male Female

152 489

22/152 (14.5) 108/489 (22.1)

1.68

1.02-2.76

0.041

Age ≤ 45 years 46 – 69 years ≥ 70 years

267 325 49

41/267 (15.4) 72/325 (22.2) 17/49 (34.7)

1.00 1.57 2.93

– 1.03 – 2.4 1.5 – 5.76

– 0.036 0.001

OR = odds ratio, CI = confidence interval

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D. Musil et al.: Additional RF for SVT in pts with CVD

Table II. Estimation of SVT risk for lifestyle factors in patients with CVD (n = 641) N

SVT n/N (%)

95 % CI

p value

BMI < 25 kg/m2 26 – 29 kg/m2 ≥ 30 kg/m2

248 207 186

37/248 (14.9) 44/207 (21.3) 49/137 (35.8)

1.00 1.54 2.04

– 0.95 – 2.49 1.27 – 3.29

– 0.039 0.003

Smoking No Yes

455 159

82/455 (18) 43/159 (27)

1.69

1.1 – 2.58

0.015

Hormone therapy No Yes

312 106

61/312 (19.6) 24/106 (22.6)

1.20

0.71 – 2.05

0.495

Family history of VTE No Yes

378 66

68/378 (18) 22/66 (33.3)

2.28

1.28 – 4.05

0.004

OR = odds ratio, CI = confidence interval

was much higher in SVT-positive patients than SVT-negative patients (p = 0.001) but only in women, not in men (p = 0.889). In all patients with CVD, the risk of SVT was very significantly increased in older non-smokers (p < 0.001) with a BMI ≥ 25 kg/m2 (p = 0.001). In smokers, an increased risk of SVT was associated with a BMI ≥ 25 kg/m2 (p = 0.033). In smoking men, the risk was significantly elevated with older age (p = 0.042) but not in those with a BMI ≥ 25 kg/m2 (p = 0.988). In women, cigarette smoking did not increase the risk of SVT even in older age (p = 0.854) or with a BMI ≥ 2 5 kg/m2 (p = 0.174). We investigated and compared the risk of SVT in patients with CVD in clinical classes C0 to C3 and patients with chronic venous insufficiency (i.e., classes C4 to C6) (Tab. V). In CEAP clinical classes C0 – C3, a history of episodes of SVT was found in 103/550 (18.7 %), in chronic venous insufficiency in 27/91 (29.7 %). There was a statistically significantly higher prevalence of SVT in patients with chronic venous insufficiency (p = 0.016). In the logistic regression analysis, the risk of SVT was significantly increased in patients with chronic venous insufficiency (OR 1.70, 95 % CI = 1.1 – 2.5; p = 0.016).

Discussion Until recently, the literature on risk factors for SVT in CVD patients (so called varicose SVT) has been relatively poor.

Most authors focused on SVT accompanying VTE, malignancies, vasculopathies, autoimmune diseases, drug intake and other factors [4]. Our study was designed to evaluate the contribution of gender, age, some lifestyle factors (BMI, cigarette smoking habit, oral contraceptives and hormone replacement therapy) and family history of VTE as additional risk factors for SVT in patients with objectively confirmed primary CVD clinical classes C0 to C6 assessed by means of the CEAP classification [6]. First, we assessed the role of gender and age as risk factors of SVT. In patients with CVD, the risk was significantly associated with female gender in all three age groups and seven classes C0 to C6. Older age was found to be connected with SVT episodes in men and women. This age-related risk was comparable for both genders. In the age group 46 – 69 years, the risk of SVT was 1.57 times higher and in the age group ≥ 70 years almost 3 times higher than young adults aged ≤ 45 years (Tab. II). Age is a well-known risk factor for the development of CVD [7], DVT [11] and also SVT [1,4]. Two recent prospective studies revealed age as a risk factor for SVT in CVD but only in patients with varicose veins. There were no significant differences in patients with chronic venous insufficiency (i.e., classes C4 to C6) [8, 9]. Second, in patients with CVD, we investigated the association between some lifestyle factors (BMI, smoking, oestrogen hormone therapy), family history of VTE of firstdegree siblings and risk of SVT. Of the long list of additional risk factors for SVT (43 items) recently published on Medscape, in the first four places were varicose veins, obesity,

Table IV. Age and lifestyle as risk factors in patients with CVD according to gender Risk factor

Men (n = 152)

Women (n = 489)

All patients (n = 641)

Age

Yes (p = 0.022)

Yes (p = 0.018)

Yes (p = 0.001)

BMI ≥25 kg/m2

No (p = 0.889)

Yes (p < 0.001)

Yes (p = 0.001)

Smoking

Yes in older age (p = 0.042)

No (p = 0.391)

Yes with BMI ≥25 kg/m2 (p = 0.083)

Vasa (2016), 45 (1), 63 – 66

D. Musil et al.: Additional RF for SVT in pts with CVD

Table V. Estimation of SVT risk by CEAP clinical classification (C0 –6) in patients with CVD N

SVT n/N (%)

103/550 (18.7)

1.0

95 % CI

p value

CEAP clinical classification 550 C0 – C3

1.7

91 C4 – C6 (chronic venous insufficiency)

1.1 – 2.5

Conclusions

0.016

27/91 (29.7)

In men with primary CVD clinical classes C0 to C6 older age (over 50 years), smoking and a positive family history of VTE were relevant SVT risk factors. In women with primary CVD clinical classes C0 to C6 , risk factors were older age (over 50 years), increased BMI (≥25 kg/m2) and a positive family history of VTE. Compared with CVD C0-C3 clinical classes, chronic venous insufficiency significantly increases the risk of SVT.

OR = odds ratio, CI = confidence interval

age older than 60 years and cigarette smoking [4]. In our group of 641 outpatients, the risk of SVT increased significantly in overweight people and very significantly in obese patients. Overweight and obesity were revealed as a very significant risk factor only in women, not in men. Smoking plus BMI ≥ 2 5 kg/m2 almost doubled the risk of SVT. High-oestrogen oral contraceptives may increase the risk of thrombosis by a factor of 3 – 12 times, although the absolute risk remains low. Newer, low-dose oral contraceptives are associated with a much lower risk of thrombophlebitis, although the absolute risk has not been well quantified [4, 12]. Surprisingly in our group of outpatients, oestrogen hormone therapy had no influence on the prevalence of SVT. Patients with CVD and a family history of VTE, had a very significantly increased risk of SVT compared to patients without a VTE family history (p = 0.004). To the best of our knowledge, family history as an SVT risk factor has not been published to date. Third, we examined age, BMI and smoking habit as risk factors according to gender. Older age was confirmed as an important risk factor in men and also in women. BMI was very significantly increased in all SVT-positive patients but as a risk factor it was only found in women, not in men. The risk of SVT associated with older age and BMI ≥ 2 5 kg/m2 was independent of smoking habit. In male smokers, the risk of SVT was significantly associated with older age. In women, smoking did not increase the risk of SVT even in older age and with a BMI ≥ 2 5 kg/m2 (Tab. IV). Fourthly, we evaluated and compared the risk of SVT in patients with CVD C0-C3 clinical classes and chronic venous insufficiency. Higher clinical classes of CVD in the lower limbs (C4-6) were associated with a higher risk of SVT. In chronic venous insufficiency, the risk of SVT was 1.7 times higher than varicose veins (Tab. V). This study revealed that the risk of SVT in primary CVD was associated with female gender and in both genders to the same extent, age-related. In all CVD clinical classes (C0 to C6, CEAP) in men the risk increased with age and smoking independently of BMI and in women with age and higher BMI (≥ 2 5 kg/m2) independently of cigarette smoking habit. Oestrogen hormone therapy did not increase the risk of SVT in women regardless of smoking status. A positive family history of VTE was revealed as a very important risk factor in both genders. © 2016 Hogrefe

References 1. Marchiori A, Mosena L, Prandoni P. Superficial vein thrombosis: risk factors, diagnosis and treatment. Semin Thromb Hemost 2006; 32: 737 – 743. 2. Decousus H, Prandoni P, Mismetti P, Calisto Study Group: Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Eng J Med 2010; 363: 1222 – 1232. 3. Bagge VJ, Chung K, Koole K, et al. Association of varicosities and concomitant deep venous thrombosis in patients with superficial venous thrombosis, a systematic review. Eur J Gen Pract. 2014 Jun 9: 1 – 7. [Epub ahead of print] 4. Rosch AJ, Khait L. Superficial thrombophlebitis. Medscape, Apr. 21, 2014. 5. Bergan JJ, Schmid-Schönbein GW, Smith PD, et al.: Chronic venous disease. N Engl J Med 2006; 355: 488 – 498. 6. Eklof B., Rutherford RB., Bergan JJ, et al. Revision of the CEAP classification of chronic venous disorders. Consensus statement. J Vasc Surg 2004; 40: s. 1248 – 1252. 7. Chiesa R., Marone EM., Limoni C., et al.: Chronic venous insufficiency in Italy: the 24-Cities-Cohort Study. Eur J Vasc Endovasc Surg 2005; 30: 422 – 429. 8. Karathanos C, Exarchou M, Tsezou A, et al. Factors associated with the development of superficial vein thrombosis in patients with varicose veins. Thromb Res 2013; 132: 47 – 50. 9. Karathanos Ch, Sfyroeras G, Drakou A, et al. Superficial vein thrombosis in patients with varicose veins: role of thrombophilia factors, age and body mass. Eur J Vasc Endovasc Surg 2012; 43: 355 – 358. 10. WHO experts consultation: Appropriate body-mass index for Asian population and its implications for policy and intervention strategies. Lancet 2004; 363: 1077. 11. Heit JA, O’Fallon WM, Petterson TM, et al. Relative impact of risk factors for deep vein thrombosis and pulmonary embolism. A Population-based study, Arch Intern Med 2002; 162: 1245 – 1248. 12. Rosendaal FR, Helmerhorst FM, Vandenbroucke JP. Oral contraceptives, hormone replacement therapy and thrombosis. Thromb Haemost 2001; 86: 112 – 23. Submitted: 11.05.2015 Accepted after revision: 07.07.2015 There are no conflicts of interest existing Correspondence address Dalibor Musil, MD, PhD Vascular Department Department of Internal Medicine I – Cardiology, Teaching Hospital I.P.Pavlova 6 77900 Olomouc Czech Republic musil.dalibor@quick.cz

Vasa (2016), 45 (1), 63 – 66

Case report

Coil embolization of a posterior circumflex humeral aneurysm in a volleyball player Mary Tao1, Naomi Eisenberg1, Jeff Jaskolka2, and Graham Roche-Nagle1 1 2

Department of Vascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Canada Department of Interventional Radiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Canada

Key message: Vascular injuries to the posterior circumflex humeral artery are a rare clinical entity but may result in digital ischemia due to embolic dislodgement following repetitive and exaggerated overhead motions in active sportspeople.

Introduction Upper extremity ischemia secondary to peripheral arterial emboli often results from an underlying atherosclerotic or cardiogenic aetiology. However, high-performance athletes who engage in repetitive, vigorous overhead motions are susceptible to upper extremity ischemia secondary to vascular injuries, specifically distal thrombotic occlusion from a proximal source. This report describes the diagnosis and management of digital ischemia with endovascular coil embolisation in an elite volleyball player with a thrombosed posterior circumflex humeral artery (PCHA).

strated thrombosis within the PCHA, approximately 1 cm from the origin, with distal embolic occlusions along the entirety of the ulnar artery, and at the deep branch of the radial artery and the distal third of the anterior interosseous artery (Fig. 2). There was minimal reconstitution of the ulnar artery at the palmar arch. The remainder of the clinical and radiographic studies was unremarkable. The patient was commenced on anticoagulation and underwent coil embolisation of the right PCHA. Via right groin access a 5-Fr DAV catheter was used to select the brachiocephalic, right subclavian artery and right PCHA. A 2.4Fr Progreat microcather (Terumo, Japan) was advanced distally. Subsequently, a 6 × 20 mm, followed by a 4 mm × 2 cm long, Tornado microcoil was placed in the proximal portion of the PCHA. Completion arteriogram

Case report A 20-year-old female, right-handed professional volleyball player was referred to the vascular surgery clinic with a two week history of sudden coolness and numbness in her dominant hand which worsened with exposure to cold and with activity. She noted pale discoloration of the lateral three fingers on her right hand. Examination revealed absent right ulnar pulses and slow capillary refill when compared to the left side. There were equal blood pressures on both arms. Duplex ultrasound confirmed an ulnar artery occlusion and dampened finger waveforms in her right 3rd-5th fingers. However, there was no documented compression of the left subclavian artery or a subclavian aneurysm as a source of the emboli. There were no signs for cardiac arrhythmia in the ECG. Magnetic resonance angiography (Fig. 1) demonVasa (2016), 45 (1), 67 – 70 DOI 10.1024/0301-1526/a000498

Figure 1. Coronal high resolution venous phase image from gadolinium enhanced MRA showing filling defect and evidence of distal thrombosis within the posterior circumflex humeral artery approximately 1 cm from the origin (white arrow).

M. Tao et al.: Posterior circumflex humeral aneurysm

Discussion

Figure 2. Coronal maximum intensity projection imaging from single phase of dynamic MRA of forearm shows abrupt occlusion of deep palmar arch in hand (white arrow), segmental occlusion of anterior interosseous artery (pink arrow) and poor filling of ulnar artery (green arrow) in keeping with emboli from proximal source.

showed satisfactory position of the coils (Fig. 3). Anticoagulation was discontinued after 3 months. Follow-up MRI demonstrated successful occlusion of the right PCHA (Fig. 4). At six months follow-up she was asymptomatic with no complaints and returned to playing volleyball.

Vascular injuries to the posterior circumflex humeral artery (PCHA) are a rare but significant problem in highperformance athletes who engage in overhead throwing activities. It has been reported in baseball pitchers [1] and several studies amongst elite volleyball players have documented aneurysm formation of the PCHA [2 – 6]. A recent survey revealed that a high percentage of volleyball players in the Netherlands, with a mean age of 24, self-reported symptoms of digital ischemia. The prevalence of cold digits during practice and competition was 27 %. The study was prompted by increased numbers of volleyball players presenting with ischemic digits of the dominant hand associated with vascular injuries to the PCHA and resulting distal emboli [2]. Other literature has demonstrated that a volleyball career longer than 17 years is associated with a 6.7-fold increase in the risk of ischemia-related complaints in the dominant hand [7]. In volleyball, the overhead spiking and serving motion involves excessive external rotation and hyper-abduction of the shoulder [8]. During this manoeuvre, the relatively fixed circumflex arteries are potentially subjected to compression by the humeral head. Cadaver dissections have shown that as the arm is moved into an overhead position, the axillary artery becomes compressed by the humeral head, which acts like a fulcrum [9]. Furthermore, sonographic investigations revealed that the glenohumeral joint is anteriorly translated during the overhead motion and that there is a correlation between such displacement and the degree of axillary artery compression and more distal flow-mediated vasodilation [10, 11]. Positional compression of the distal axillary artery and its branches may

Figure 3. Arteriogram shows chronic-appearing occlusion (black arrow) of the right posterior circumflex humeral artery with approximately 1.5 cm of patent lumen at the origin. A 6 x 20 mm and 4 x 20mm Tornado microcoil were placed in the proximal portion of the circumflex humeral artery. Completion arteriogram showed satisfactory positioning of the coils (black arrow) and no further filling of the posterior circumflex humeral artery or its branches.

Vasa (2016), 45 (1), 67 – 70

M. Tao et al.: Posterior circumflex humeral aneurysm

cause chronic irritation leading to aneurysmal degeneration [12]. Turbulent flow in these aneurysms readily produces mural thrombus which is susceptible to distal embolisation during hyperextension as the humeral head acts to compress the aneurysm, thus pushing the thrombus into the distal arterial stream [12 – 14]. The thromboembolic complications of the affected extremity will result in manifestations of digital ischemia, as seen in our patient. Embolic occlusions of the distal arteries in the hand may result in disabling pain, numbness, coldness, discoloration and occasional ulcerations. Clinical presentations of thromboembolic complications, however, can be subtle and often remain undetected for a long time due to the rich collateral network around the shoulder [2]. Importantly, vascular injuries are often mistaken for musculoskeletal injuries and fatigue partly because symptoms resembling arm claudication, digital numbness and circulatory changes are not uncommon in elite athletes [12]. A thorough history and detailed upper extremity peripheral vascular physical examination is needed and should include a pulse examination and careful inspection of any changes in colour and temperature at the affected and contralateral limb. A focused neurological evaluation should be performed and the presence of thoracic outlet syndrome should be excluded with provocation tests. A DASH (Disabilities of the Arm, Shoulder and Hand) outcome measure questionnaire may be used to evaluate physical function, symptoms and disability [15]. Subsequent radiographic investigations are necessary to allow for a definitive diagnosis of PCHA pathologies. Available imaging modalities include Doppler ultrasonography, digital subtracted angiography, computed tomographic angiography and magnetic resonance angiography [14]. Doppler ultrasonography can detect dampened digital waveforms and direct evidence of thromboembolism in the distal arteries and although Doppler ultrasonography have been shown to be effective in visualising the PCHA [16], MR angiography remains the most definitive diagnostic investigation for confirmation of dynamic circulatory compromises. It provides excellent resolution and is useful for gathering clinically important information that cannot be obtained using other modalities [17]. The choice of treatment depends on the extent of injury, patient preference and anatomical location of the aneurysmal dilatation. Although non-operative therapy has been shown to be successful in one case of positional compression of axillary artery [18], many examples of failed nonoperative management resulting in the progression of disease and significant disability from thromboembolic sequelae have been described [19, 20]. Thrombolytic therapy may be used initially to dissolve newly formed distal emboli, though recurrences may occur upon return to activity if the underlying embolic source is not addressed. Successful outcomes of surgical and endovascular approaches for PCHA aneurysms have been previously described in the literature [3, 4, 12, 14, 15]. The current literature suggest that the favoured approached depends on the proximity of the aneurysm origin to the axillary artery [15]. Vasa (2016), 45 (1), 67 – 70

Figure 4. Follow up gadolinium enhanced MRA at 6 months post embolisation demonstrating occlusion of right posterior circumflex humeral artery (white arrow) with almost no further patent vessel beyond its origin.

Successful coiled embolisation is achievable provided that the aneurysmal dilatation contains no thrombi and is relatively long and if the origin of the PCHA is unaffected [15]. The benefits to the endovascular approach include its ease in delivery, safety and shortened recovery time compared to surgical approaches since it can be performed under local anaesthetic. It is important to note the complications of coiling, which include the potential for obstruction of crucial axillary branches, further embolisation and dislocation of the coil during forceful overhead actions [12, 15]. The endovascular approach is only appropriate given the appropriate above described circumstances; the authors do not endorse this approach for more complex injuries. Anticoagulation is the cornerstone of therapy although the duration is less clearly defined in these rare cases.

Conclusions Athletes who engage in overhead movements are vulnerable to upper limb arterial damage including aneurysm formation and thromboembolism due to repetitive microtrauma resulting from compression of the artery with the humeral head. Given the potential catastrophic ischemic complications of arterial thrombosis, early recognition and prompt treatment is of vital importance. Based on our experience and previous reports, we recommend that those predisposed individuals who demonstrate signs and symptoms of upper extremity ischemia should be promptly evaluated clinically and undergo a Doppler investigation and MR angiography, as indicated. Endovascular intervention with coiled embolisation can be a successful method © 2016 Hogrefe

of treatment for PCHA aneurysms and may allow athletes to return to their previous level of competition faster than more conventional surgical approaches.

Key words Posterior circumflex humeral artery, digital ischemia, embolisation, volleyball, vascular injuries

References 1. Reutter D1, Hunziker R, Husmann M. Computed angiogram of the upper extremities for diagnosing a rare cause of brachial arterial embolism: the ‘Pitcher Syndrome’. Eur Heart J 2010 Nov; 31 (22): 2782. 2. van de Pol D, Kuijer PP, Langenhorst T, et al. High prevalence of self-reported symptoms of digital ischemia in elite male volleyball players in the Netherlands: A cross-sectional national survey. Am J Sports Med 2012; 40 (10): 2296 – 2302. 3. Reekers JA, den Hartog BM, Kuyper CF, et al. Traumatic aneurysm of the posterior circumflex humeral artery: A volleyball player’s disease? J Vasc Interv Radiol 1993; 4 (3): 405 – 408. 4. Vlychou M, Spanomichos G, Chatziioannou A, et al. Embolisation of a traumatic aneurysm of the posterior circumflex humeral artery in a volleyball player. Br J Sports Med 2001; 35 (2): 136 – 137. 5. Stanz K, Wedler V, Kopfli P, et al. [Compression syndrome of the arteria circumflexa humeri posterior in a volleyball player]. Vasa 2001; 30 (3): 229 – 232. 6. Arko FR, Harris EJ, Zarins CK, et al. 4th. Vascular complications in high-performance athletes. J Vasc Surg 2001; 33 (5): 935 – 942. 7. van de Pol D, Kuijer PP, Langenhorst T, et al. Risk factors associated with self-reported symptoms of digital ischemia in elite male volleyball players in the netherlands. Scand J Med Sci Sports 2013. 8. Reeser JC, Fleisig GS, Bolt B, et al. Upper limb biomechanics during the volleyball serve and spike. Sports Health 2010; 2 (5): 368 – 374. 9. Rohrer MJ, Cardullo PA, Pappas AM, et al. Axillary artery compression and thrombosis in throwing athletes. J Vasc Surg 1990; 11 (6): 761-8; discussion 768 – 9.

M. Tao et al.: Posterior circumflex humeral aneurysm

10. Stapleton CH, Herrington L, George K. Anterior translation at the glenohumeral joint: A cause of axillary artery compression? Am J Sports Med 2008; 36 (3): 539 – 544. 11. Stapleton CH, Green DJ, Cable NT, et al. Flow-mediated dilation and intima-media thickness of the brachial and axillary arteries in individuals with and without inducible axillary artery compression. Ultrasound Med Biol 2009; 35 (9): 1443 – 1451. 12. Duwayri YM, Emery VB, Driskill MR, et al. Positional compression of the axillary artery causing upper extremity thrombosis and embolism in the elite overhead throwing athlete. J Vasc Surg 2011; 53 (5): 1329 – 1340. 13. Jackson MR. Upper extremity arterial injuries in athletes. Semin Vasc Surg. 2003; 16 (3): 232 – 239. 14. Demondion X, Herbinet P, Van Sint Jan S, et al. Imaging assessment of thoracic outlet syndrome. Radiographics 2006; 26 (6): 1735 – 1750. 15. Atema JJ, Unlu C, Reekers JA, et al. Posterior circumflex humeral artery injury with distal embolisation in professional volleyball players: A discussion of three cases. Eur J Vasc Endovasc Surg 2012; 44 (2): 195 – 198. 16. Robinson DJ, Marks P, Schneider-Kolsky ME. Ultrasound of the posterior circumflex humeral artery. J Med Imag Rad Oncol 2010; 54 (3): 219 – 223. 17. Reeser JC. Diagnosis and management of vascular injuries in the shoulder girdle of the overhead athlete. Curr Sports Med Rep 2007; 6 (5): 322 – 327. 18. Ligh CA, Schulman BL, Safran MR. Case reports: Unusual cause of shoulder pain in a collegiate baseball player. Clin Orthop Rel Res 2009; 467 (10): 2744 – 2748. 19. Todd GJ, Benvenisty AI, Hershon S, et al. Aneurysms of the mid axillary artery in major league baseball pitchers--a report of two cases. J Vasc Surg 1998; 28 (4): 702 – 707. 20. Fields WS, Lemak NA, Ben-Menachem Y. Thoracic outlet syndrome: Review and reference to stroke in a major league pitcher. AJR Am J Roentgenol 1986; 146 (4): 809 – 814. Submitted: 21.07.2015 Accepted after revision: 26.07.2015 There are no conflicts of interest existing. Correspondence address Dr. Graham Roche-Nagle, MD Department of Vascular Surgery Toronto General Hospital 200 Elizabeth Street M5G 2C4 Toronto Canada graham.roche-nagle@uhn.ca

Vasa (2016), 45 (1), 67 – 70

Gesundheit, Krankheit und das Gesundheitssystem verstehen

David Klemperer

Sozialmedizin – Public Health Gesundheitswissenschaften Lehrbuch für Gesundheits- und Sozialberufe 3., überarb. Auﬂ. 2015. 384 S., 153 Abb., Kt € 29.95 / CHF 39.90 ISBN 978-3-456-85550-9 AUCH ALS E-BOOK

Dieses Lehrbuch will die Gesundheits- und Sozialberufe darin unterstützen, ihre beruﬂiche Praxis weiterzuentwickeln. Dafür ist eine breite Wissensbasis hilfreich, die dieses Buch praxisnah vermittelt. Dazu zählt das Wissen über • Individualmedizin und Bevölkerungsgesundheit (Public Health) • Modelle von Gesundheit und Krankheit • Epidemiologie und Forschungsmethoden • Prinzipien einer evidenzbasierten beruﬂichen Praxis

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• Theorie und Praxis von Gesundheitsförderung und Krankheitsprävention • soziale Ungleichheiten der Gesundheit. Das Buch richtet sich sowohl an Studierende als auch an bereits Berufstätige. Angesprochen sind ebenfalls Patientenvertreter in der Selbstverwaltung, Krankenkassenmitarbeiter, Mitglieder und Mitarbeiter der gesundheitsbezogenen Selbsthilfe, Journalisten und an Gesundheitspolitik Interessierte.

Mit ZRM in den Diabetes-Alltag

Giovanna Eilers / Maja Storch

Dolce Vita mit Diabetes Ein genussvoller Leitfaden für den Umgang mit Diabetes 2016. 336 S., Gb € 24.95 / CHF 32.50 ISBN 978-3-456-85543-1 AUCH ALS E-BOOK

Diabetes zu haben ist eine Herausforderung: Tagtäglich soll man sich damit beschäftigen und sein Leben darauf einrichten. Dinge müssen erfüllt werden, die wahrlich nicht immer Spaß machen. Um einen herum haben viele gutgemeinte Ratschläge auf Lager, wie man es besser packen könnte – vor allem die behandelnden Ärzte. Nur: Erledigen muss man die Aufgaben leider selbst (etwa mehrmals am Tag den Blutzucker messen oder ans Insulinspritzen denken). Wie kann man diese oft lästigen Diabetes-Vorsätze umsetzen und das auf eine Art und Weise, die nicht so anstrengend und doch erfolgreich ist? Das fragen sich die Helden dieses Buches, alles Menschen mit Diabetes, – und erhalten Antworten:

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In einem abwechslungsreichen Dolce Vita-Diabetes-Kurs lernen die Hauptpersonen und der Leser, wie man mit Hilfe des Zürcher Ressourcen Modells (ZRM) eigene Stärken entdecken und diese für die ganz persönlichen Diabetes-Lösungen einsetzen kann.Weil ein wichtiger Aspekt im Umgang mit dem Diabetes die vielen «mulititask»-Situationen im Alltag sind, ist ein Schwerpunkt die Selbstcoaching-Phase, in der sich die Diabetes-Helden selbstständig machen und als ihre Experten eine eigene Strategie für das Meistern tagtäglicher Fallstricke entwickeln.

Journal Club

Pushing the limits of endovascular intervention: favourable results of recent intracranial trials While the incidence of acute myocardial infarction is fortunately falling, that of acute ischemic stroke is continuously rising, affecting more than 200,000 patients in Germany each year. Regarding the benefits of emergency catheter-based interventions in acute myocardial infarction, it was only one step further to transfer this approach to acute ischemic stroke. Unexpectedly, a number of recent trials have failed to show any benefit of intracranial interventions compared to a standard therapy with i.v. thrombolysis [1 – 3]. However, these trials suffered from numerous limitations, the major ones being the broad spectrum of different endovascular techniques employed and the low number of patients included per participating centre. Now, a series of randomised controlled trials using contemporary intracranial devices were published and cast a completely different light on this field [4 – 8].

MR CLEAN and “companions” The breaking point came in December 2014, when the Dutch MR CLEAN trial with 500 randomised patients was published [4], followed in February 2015 by ESCAPE (n = 316) [5] and EXTEND-IA (n = 70) [6], and finally in April 2015 by SWIFT PRIME (n = 196) [7] and REVASCAT (n = 206) [8]. The last 3 studies had to be stopped early due to superiority of the endovascular arm [6 – 8]. The endpoint in all of these trials was the proportion of patients with a good functional independency at 90 days, as indicated by a score of 0 to 2 on the modified Rankin scale. The results and distinct devices which were compared to

standard therapy are summarised in Figure 1. Throughout all these trials, there was a consistent and significant benefit of endovascular compared to standard treatment. This advantage persisted even during a relatively long time window up to 12 h after onset of symptoms. Overall mortality in ESCAPE was significantly lower after endovascular treatment [5], while it was similar after both therapies in the other trials [5, 7, 8]. Complication rates, especially peripheral and intracranial bleedings, were also not different [5 – 8].

Open issues These trials, together with others, represent a breakthrough in the treatment of acute ischemic stroke. From the opinion of the investigators and editorialists, this was mainly achieved by the use of new stent retrievers which were able to remove thrombi more efficiently and safely. Nevertheless, a number of open issues need to be addressed, as discussed in the accompanying editorials and comments. First, only a small amount of the screened eligible patients was included, thereby representing a possible selection bias. Second, is has to be questioned whether the good results from these experienced centres can be transferred to all others offering this therapy. Third, under the aspect that revascularisation might still be beneficial even in a time window as long as 12 h, it has to assessed in which case and to what extent patients might benefit from being transferred to secondary centres with the required infrastructure for a 24/7 catheter intervention. This will lead to the question whether, from a public health point of view, invasive stroke therapy will have to be made available through a dense network of neuro-interventional sites or, rather, may have to be focused in few specialised centres.

References

Figure 1. The results of 8 trials are shown (reference numbers on the left), comparing endovascular (black bars) to standard therapy (grey bars) in acute ischemic stroke. The endpoint was the proportion of patients with a score of 0– 2 on the modified Rankin Scale after 90 days (significance levels given at the base of the bars; “n.s.” indicates not significant). The distinct endovascular devices and the time period from onset of symptoms to treatment are shown on the right.

Vasa (2016), 45 (1), 71 DOI 10.1024/0301-1526/a000499

1. Kidwell CS, et al. N Engl J Med 2013; 368:914 – 23. 2. Ciccone A, et al. N Engl J Med 2013; 368:904 – 13. 3. Broderick JP, et al. N Engl J Med 2013; 368:893 – 903. 4. Berkhemer OA, et al. N Engl J Med 2015; 372:11 – 20. 5. Goyal M, et al. N Engl J Med 2015; 372: 1019 – 30. 6. Campbell BCV, et al. N Engl J Med 2015; 372:1009 – 18. 7. Saver JL, et al. N Engl J Med 2015; 372: 2285 – 95. 8. Jovien TG, et al. N Engl J Med 2015; 372: 2296 – 306.

Correspondence adress Karsten Papke, Bonifatius Hospital Lingen & Holger Reinecke, University Hospital Münster. holger.reinecke@ukmuenster.de

Die Gesundheit beider Geschlechter

Petra Kolip / Klaus Hurrelmann (Hrsg.)

Handbuch Geschlecht und Gesundheit Männer und Frauen im Vergleich 2., vollst. überarb. und erw. Auﬂ. 2015. 448 S., 47 Abb., 30 Tab., Gb € 79.95 / CHF 99.00 ISBN 978-3-456-85466-3 AUCH ALS E-BOOK

In der bisherigen wissenschaftlichen Diskussion laufen die theoretischen und methodischen Forschungen zur Frauengesundheit und Männergesundheit noch weitgehend nebeneinander her. In diesem Handbuch, das hier in völlig überarbeiteter und erweiterter zweiter Auﬂage vorliegt, werden sie aufeinander bezogen und in eine vergleichende Darstellung eingebracht. Die über 30 Beiträge nehmen eine systematisch vergleichende Perspektive in der geschlechterbezogenen Gesundheitsforschung ein und führen damit die Frauengesundheitsforschung und die Männergesundheitsforschung zusammen, ohne die Besonderheiten der beiden Gebiete zu vernachlässigen.

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Im ersten Teil des Buches werden Theorien und Methoden der geschlechtervergleichenden Forschung vorgestellt, gefolgt von einer Erörterung sozialer und umweltbedingter Einﬂussfaktoren. Der dritte Teil liefert eine ausführliche Darstellung der Geschlechterunterschiede bei Entstehung und Verbreitung von unterschiedlichen Krankheitsbildern und gesundheitlichen Problemlagen. Im vierten Teil stehen Beiträge zu Geschlechteraspekten des Versorgungssystems im Zentrum. Im abschließenden Teil werden Bevölkerungsgruppen mit besonderem Bedarf ins Zentrum gerückt.

From the societies

EMIL-Award für Dr. Nasser Malyar

DGA würdigt Gefäßmediziner Im Rahmen der 44. Jahrestagung der DGA ehrte die Fachgesellschaft Wissenschaftler für ihre herausragenden Arbeiten auf dem Gebiet der Angiologie. Prof. Dr. Ulrich Hoffmann, Präsident der DGA, überreichte am 27. September 2015 den Promotionspreis, den EMIL-Award und den CLI-Preis. Mit dem Young Investigator Award wurde am 29. September die beste Abstracteinreichung eines Nachwuchswissenschaftlers gewürdigt.

Promotionspreis geht an Dr. Thomas Wehrum Dr. Wehrum ist seit 2014 in der Neurologischen Universitätsklinik Freiburg tätig. Der Preis ist mit 2.500 Euro dotiert und würdigt die wissenschaftliche Arbeit: „Detektion retrograder Embolisation in der Aorta bei Schlaganfallpatienten und Kontrollen mittels analysebeschleunigter 4D Phasenkontrast MRT“. Komplexe atherosklerotische Plaques (Durchmesser ≥ 4mm, ulzeriert, mit anhaftendem Thrombus) der aufsteigenden Aorta und des Aortenbogens sind seit den 1990er Jahren eine anerkannte Schlaganfallursache. Eine mögliche retrograde Embolisierung in das Gehirn ausgehend von Plaques im distalen Aortenbogen (bzw. proximale absteigende Aorta) wurde bislang nur bei Patienten mit ausgeprägter Aortenklappeninsuffizienz beschrieben. Das Ziel dieser Arbeit war die Erfassung der Häufigkeit potentieller retrograder Embolisierung bei unselektierten Schlaganfallpatienten (n = 67) und bei Kontrollen (n = 2 2) mithilfe der flusssensitiven 4D Magnet-Resonanz-Tomographie. Dieses Verfahren erlaubt eine zeitaufgelöste und dreidimensionale Darstellung des Blutflusses in-vivo. Interessanterweise konnte bei allen Schlaganfallpatienten und Kontrollen ein deutlicher Rückfluss aus der absteigenden Aorta in den Aortenbogen nachgewiesen werden. Es wurde gezeigt, dass bei vielen Patienten embolisches Material von einer Plaque bis zum Abgang eines hirnversorgenden Gefäßes zurücktransportiert werden könnte. Für Patienten mit einer im betroffenen Abschnitt lokalisierten komplexen Plaque und bildmorphologisch embolischem Schlaganfall konnte so eine potentielle Schlaganfallursache nachgewiesen werden. Die erstaunliche Häufigkeit dieses Phänomens (unabhängig vom Vorliegen einer Aortenklappeninsuffizienz) lässt vermuten, dass bei vielen Patienten mit ungeklärter Schlaganfallursache eine retrograde Embolisierung als Schlaganfallmechanismus vorliegen könnte.

Dr. Malyar ist Oberarzt in der Angiologie im Department für Kardiologie und Angiologie am Universitätsklinikum Münster. Der EMIL-Award ist mit 2.500 Euro dotiert und als Anschubfinanzierung für ein hervorragendes Versorgungsforschungsprojekt ausgelobt. Der Preis würdigt eine Projektskizze mit dem Titel „Peripheral arterial disease and critical limb ischemia: still poor outcomes and lack of guideline adherence“. Die periphere arterielle Verschlusskrankheit (pAVK) wird zunehmend zu einer globalen medizinischen und gesundheitsökonomischen Herausforderung. Die Prävalenz der pAVK unter allen stationär behandelten Patienten in Deutschland im Jahre 2009 betrug 3,0 %, darunter beträgt der Anteil derjenigen mit einer kritischen Extremitätenischämie 43 %. Das Ziel der Studie war es, den aktuellen Status quo der pAVK-Patienten hinsichtlich Prävalenz des Schweregrades (gemäß Rutherford R1-R6), Konstellation der Risikofaktoren, der chirurgischen und endovaskulären Revaskularisationsmaßnahmen sowie der Prognose bezüg lich Beinamputation und Mortalität zu ermitteln. Hierfür wurden Daten von insgesamt 41.882 pAVK-Patienten der Barmer GEK (BEK) aus den Jahren 2009 bis 2013 analysiert. Der Schweregrad der pAVK war signifikant assoziiert mit der Rate an Amputationen, der ischämischen Schlaganfälle, der Herzinfarkte sowie der Gesamtmortalität (P < 0.001). So stieg die nach der Kaplan-Meier-Analyse projizierte 4-Jahres-Amputationsrate von 4,6 % in R1-3 auf 67,3 % in R6. Die Mortalitätsrate betrug 19 % für R1-3 und 63,5 % für R6. Den kombinierten Endpunkt Amputation oder Mortalität erreichten sogar 21,4 % in R1-3 und 85,7 % in R6. Die Prognose der Patienten mit pAVK – insbesondere derjenigen mit einer kritischen Extremitätenischämie – ist trotz der Fortschritte in der konservativen und interventionellen Therapie weiterhin sehr schlecht. Diese Daten verdeutlichen die weiterhin inadäquate Adhärenz evidenzbasierter Therapieempfehlungen und Leitlinien bei pAVKPatienten.

CLI-Preis geht an PD Dr. Jörg Herold PD Dr. Herold ist leitender Oberarzt der Angiologie in der Klinik für Kardiologie, Angiologie und Pneumologie der Otto-von-Guericke-Universität Magdeburg. Der Preis ist mit 5.000 Euro dotiert und wird für die Arbeit verliehen: „Tetanus toxoid-pulsed monocyte vaccination for augmentation of collateral vessel growth“. Das Kollateralenwachstum (Arteriogenese) wird durch lokale Entzündungsprozesse angetrieben. Pathogenetisch kommt es aufgrund erhöhter mechanischer Beanspruchung (Shear-Stress) in prä-existierenden arteriolären Umgehungskreisläufen, welche die Stenose überbrücken, zu gesteigerter endothelialer Aktivierung und damit zu einer Monozytenrekrutierung. Die Arbeitsgruppe konnte zeigen, dass das Homing-Verhalten der Monozyten für eiVasa (2016), 45 (1), 73 – 77 DOI 10.1024/0301-1526/a000500

nen therapeutischen Ansatz ausgenutzt werden kann. Während die Transplantation von allogenen Monozyten die Arteriogenese stark förderte, hatten autologe Monozyten einen nur geringen Einfluss auf die Verbesserung des Kollateralenwachstums. Es wurde jetzt die Hypothese aufgestellt, dass eine Immunisierung mittels Tetanustoxin (TT) und eine Modifikation der autologen Monozyten in der Lage ist, die Arteriogenese mit demselben Potential wie eine allogene Transplantation zu fördern. Versuchsaufbau: BALB/c-Mäusen wurden mit TT an Tag 0 und nach 3 Wochen immunisiert. Es erfolgte dann die Analyse des TT-Antikörper-Titer sowie der Zytokinexpression und der Monozyten / T-Zell-Interaktion mittels ELISA, Proliferationsassays und ELISPOT-Technik. In dieser Studie wurden syngene Monozyten (= autolog im selben Mausstamm) ex vivo mit Tetanustoxoid (TT) modifiziert und anschließend in TT prä-immunisierten Mäuse, deren Hinterbeine ligiert transplantiert worden waren, systemisch injiziert. Die Transplantation wurde 24 Stunden nach der Ligatur der rechten Femoralarterie von immunisierten Mäusen durchgeführt und ein Perfusionsindex (PI = Verhältnis des unligierten zum ligierten Bein) mittels LaserDoppler-Perfusions-Bildgebung nach 1, 2 und 3 Wochen berechnet. Die Transplantation von 2.5 mio synMo führte zu keiner Verbesserung der Reperfusion (PI 0,56 ± 0,07 vs. Kontrolle PI = 0,48 ± 0,09), wohingegen die Transplantation von 2.5 mio TT-synMo in der Lage war, die Arteriogenese zu triggern und den PI um 80 % zu steigern (0,82 ± 0,08, P < 0.001)). Um einen möglichen Mechanismus zu analysieren, wurde untersucht, ob eine mögliche CD-4 T-Zell vermittelte Immunantwort für diese Förderung und Interaktion zu lokalen Entzündungszellen verantwortlich war. Diese gelang durch eine CD-4 T-Zell Depletion. Nach dieser war der enorme arteriogene Effekt der TT-modifizierten syngenen Monozyten vollständig blockiert (PI nach der Transplantation von modifizierten Monozyten 0,50 ± 0,08 vs. Kontrolle 0,49 ± 0,9 (p < 0,001)). Die histologische Aufarbeitung der Hinterläufe zeigte nach der Ligatur und Transplantation von nicht modifizierten Monozyten einen 2 – 2 ,5 fachen Anstieg der Kapillardichte in der Wadenmuskulatur (22 – 50 ± 5 Gefäße/mm vs. 21 ± 3 Gefäße/mm, p < 0,001) nach Transplantation von TT-modifizierten Monozyten. Dies resultierte aus der schlechteren Kollateralenentwicklung im Oberschenkel und vorherrschenden Ischämie im Unterschenkel nach Transplantation von nicht modifizierten Monozyten. Diese Daten implizieren, dass die Transplantation von TT-modifizierten autologen Monozyten eine innovative und klinisch anwendbare Methode zur therapeutischen Augmentation der Arteriogenese anbietet.

From the societies

für ihre Arbeit mit dem Titel „Atrial fibrillation is a risk marker for worse in-hospital and long-term outcome in patiens with peripheral artery disease“. Mit dem YIA wird die beste Abstracteinreichung eines jungen Wissenschaftlers unter 35 Jahren ausgezeichnet. Periphere arterielle Verschlusskrankeit (pAVK) und Vorhofflimmern (VHF) treten zunehmend gemeinsam auf. Um die Auswirkungen von VHF auf Patienten mit pAVK zu untersuchen, analysierte die Münsteraner Forschungsgruppe 41.882 stationär im Krankenhaus versorgte pAVK-Patienten im Zeitraum von 2009 – 2011 (follow-up bis Dezember 2012). VHF wurde bei 5.622 pAVK-Patienten nachgewiesen (13,4 %) und war assoziiert mit erhöhtem Patientenalter (78 ± 9 vs. 70 ± 11 Jahre, p < 0,001) sowie vermehrt mit Diabetes (40,8 vs. 31,1 %), chronischer Niereninsuffizienz (40,1 vs. 19,0 %), koronarer Herzkrankheit (38,0 vs. 23,0 %) und Herzinsuffizienz (26,9 vs. 7,2 %; jeweils p < 0,001). PAVK Patienten mit VHF wurden trotz höherer pAVK-Stadien (71,4 % CLI vs. 46,0 %) seltener revaskularisiert (67,0 % vs 56,1 %, p < 0,001). Mittels Cox-Regressionsanalyse wurde VHF als unabhängiger Prädiktor für die Langzeit-Endpunkte Tod (HRR 1,46; 95 % CI 1,39 – 1,52), Schlaganfall (HRR 1,63; 95 % CI 1,44 – 1,85) und Amputation (HRR 1,14; 95 % CI 1,07 – 1,21; jeweils p < 0,001) ermittelt und schränkt demnach nicht nur in der Inhospital-Phase, sondern auch langfristig die Prognose von pAVK-Patienten ein.

Deutsche Gesellschaft für Angiologie vergibt erstmals DGA-Journalistenpreis Die Deutsche Gesellschaft für Angiologie – Gesellschaft für Gefäßmedizin e.V. hat anlässlich der 44. Jahrestagung in Freiburg erstmalig den DGA-Journalistenpreis vergeben. Ausgezeichnet wurden Beiträge, die anschaulich und kompetent formuliert über Gefäßerkrankungen, deren Prävention, Verbreitung, Behandlung, Nachsorge und Folgen berichten. In den beiden Kategorien Print/Online sowie Hörfunk/TV wurden jeweils zwei Beiträge von der Jury als auszeichnungswürdig eingestuft und der Preis somit an vier Journalisten verliehen. Andrea Neuen-Biesold, freiberufliche Journalistin u. a. für Versichertenmagazine der Krankenkassen und Apotheken-Kundenzeitschriften, wurde für ihren im AOK-Magazin veröffentlichten Beitrag „Wenn es eng wird“ ausgezeichnet. Darin berichtet sie über die Symptome, Risikofaktoren und Vorsorge von Arteriosklerose. Frieder Piazena, freier Journalist im Ressort Gesundheit des Tagesspiegels, erhielt die Ehrung für seine Artikelserie im Tagesspiegel-Magazin GESUND zum Themenschwerpunkt Herz, Kreislauf und Gefäße. In seiner Reportage „100 Meter Schmerzen“ schreibt er über die periphere arterielle Verschlusskrankheit, Therapieoptionen sowie neue Entwicklungen und stellt die Erkrankung aus Sicht eines Patienten dar. In weiteren Artikeln informiert er über die Themen Thrombose („Zeitbombe im Blut“) sowie über Krampfadern und Besenreiser („Drachen in der Haut“). Vasa (2016), 45 (1), 73–77

From the societies

Der Beitrag „Was die Blutgefäße gesund hält – Der Arteriosklerose keine Chance“ von Ingeborg Hain, freie Hörfunkjournalistin u. a. für ARD/Bayerischen Rundfunk, wurde in der Kategorie Hörfunk prämiert. Der Fokus liegt dabei neben der Darstellung der Erkrankung auf der Vorbeugung der Arterienverkalkung.

Über „Erschreckende Zahlen – zu viele Amputationen bei Durchblutungsstörungen“ berichtete Dr. Sigrun Damas, freiberufliche Medizinjournalistin, in ihrem Fernseh-Beitrag für die Sendung NDR-Visite für den sie mit dem Journalistenpreis ausgezeichnet wurde. Die Preise wurden im Rahmen der Eröffnungsveranstaltung verliehen und sind mit jeweils 1.000 Euro dotiert.

Auch 2015 haben die korporativen Mitglieder der DGA auf der Jahrestagung in Freiburg wieder ein Symposium abgehalten, diesmal mit dem Thema „Studieninterpretation leicht gemacht“. Es fand bei den Kongressteilnehmern ein überaus großes Interesse. Hier die Zusammenfassungen der drei Vorträge:

Verschiedene Studientypen – und worauf der Klinker achten muss Prof. Konstantinides erinnerte zunächst die Teilnehmer an die „Basics“ der Biostatistik, nämlich die Vorab-Formulierung im Studienprüfplan der sog. „0-Hypothese“ (H0, d.h. keine Unterschiede, z.B. kein Effekt der neuen Therapie im Vergleich zum bisherigen Medikament) und der alternativen Hypothese (H1, z.B. die neue Therapie verbessert signifikant die Prognose der Patienten) beim primären Endpunkt klinischer Studien. Mittels eines einfachen tTests wird am Ende der Studie die Frequenz des Endpunktes in beiden Patientengruppen (Interventions- und Kontrollgruppe) verglichen: Ein p-Wert von <0,05 führt dazu, die H0 abzulehnen. Das Signifikanzniveau sagt allerdings nichts über das Ausmaß der Unterschiede bzw. des Interventionseffektes aus. Dies wird vielmehr in den 95 %-igen Konfidenzintervallen und deren Abstand abgebildet. Bei einer Studie ist es ferner wichtig zu errechnen, welches die Chancen der Interventionsgruppe – im Vergleich zu der Kontrollgruppe – sind, den klinischen Endpunkt zu erreichen. Hierbei wird in prospektiven randomisierten Studien das relative Risiko (RR) kalkuliert, d.h. die Ratio „Frequenz des Endpunktes in der Interventionsgruppe durch Wahrscheinlichkeit des Endpunktes in der Kontrollgruppe“. Sind beispielsweise in der Interventionsgruppe 5% der Patienten während der gesamten Studiendauer gestorben, während es in der Kontrollgruppe 10% der Patienten waren, beträgt das RR 50 %. In nicht-kontrollierten Kohortenstudien wird dagegen die Odds Ratio (OR) kalkuliert. So haben wir beispielsweise in folgender 2 × 2 Tabelle: Herzinfarkt

Kein Herzinfarkt

Gesamt

Raucher

a = 24

b = 33

a + b = 57

Nicht-Raucher

c = 15

d = 44

c + d = 59

Gesamt

116

Die OR ist [(a/b) dividiert durch (c/d)], d.h. 24/33 / 15/44 = 2,13. Die Chancen („odds“) eines Herzinfarktes sind bei Rauchern 2,13-mal höher als bei Nicht Rauchern im Studienzeitraum. Die Odds Ratio, z.B. der Raucher gegenüber © 2016 Hogrefe

den Nicht-Rauchern, kann auch für weitere Variablen („confounding variables“) adjustiert werden. Das relative Risiko wäre dagegen [a/(a+b) dividiert durch c/(c+d)], in diesem Fall 24/57/15/59 = 1,66 gewesen. Letzteres darf aber, wie bereits erwähnt, bei einer unkontrollierten Kohortenstudie nicht verwendet werden. Wenn wir bei einem längeren Beobachtungszeitraum am zeitlichen Verlauf des Erreichens der Endpunkte interessiert sind, dann werden die Kaplan-Meier-Kurven beider Gruppen (Wahrscheinlichkeit des ereignisfreien Überlebens über die Zeit) erstellt und mittels des log-rank-Tests verglichen. Es wird dann die Hazard Ratio (HR) kalkuliert. Bei unkontrollierten Studien wird eine adjustierte Cox Regression durchgeführt, um den Effekt der Intervention von jenem anderer Basisvariablen zu bereinigen. Was ist „Intention to Treat“ (ITT)-Population und was „Per Protokoll“ (PP)-Population? In einer idealen Studie würde jeder Patient: • Alle Einschlusskriterien und kein Ausschlusskriterium erfüllen • Exakt wie im Prüfplan vorgesehen behandelt werden • Die vorgesehene Behandlung 100 % einhalten • Bis zum Ende der Studie komplette Daten generieren. Die trifft aber in der Realität auch bei den am sorgfältigsten durchgeführten Studien nicht zu. Die ITT-Analyse, d.h. der Vergleich beider Gruppen so wie sie bei der Randomisierung definiert wurden und ungeachtet dessen, wer schließlich während der Studie welche Therapie erhielt und für wie lang, berücksichtigt alle Fehler und Unperfektheiten, die in der „echten Welt“ passieren können. In der ITT-Analyse wird der Unterschied, d.h. der Effekt der neuen Therapie, durch etwaige Abweichungen vom Prüfplan „verdünnt“ und minimiert. Sie ist daher die strengste Form einer statistischen Analyse und wird verwendet um zu prüfen, ob eine neue Therapie unter den „widrigsten Bedingungen“ der bisherigen überlegen ist. Wenn das neue Medikament den ITT-Test „bestanden“ hat, muss sein Effekt tatsächlich deutlich und signifikant sein. Um für Nicht-Unterlegenheit zu testen, ist es dagegen aussreichend, die PP-Populationen miteinander zu vergleichen, d.h. aus jeder durch die Randomisierung definierten Gruppe nur diejenigen Patienten in der Analyse zu berücksichtigen, welche die Studie ohne schwerwiegende Abweichungen vom Prüfplan abgeschlosssen haben. Damit haVasa (2016), 45 (1), 73 – 77 DOI 10.1024/0301-1526/a000500

From the societies

ben tatsächlich alle Patienten der Interventionsgruppe das neue Medikament und alle in der Kontrollgruppe das Standardmedikament erhalten. Hier wird aber nicht be rücksichtigt, ob das neue Medikament z.B. sehr wirksam war aber schlecht toleriert wurde und daher bei vielen Patienten abgesetzt werden musste. Eines ist klar: Je geringer die PP-Population im Vergleich zu der ITT-Populati-

on, desto schlechter die Qualität der Studie (oder des Prüfmedikamentes), da der Prüfplan anscheinend bei vielen Patienten nicht eingehalten wurde.

Biometrische Aspekte bei der Interpretation von Studienergebnissen im Rahmen von Nutzenbewertungen des IQWiG

Vergleichen. Es wurde dargelegt, dass der IQWiG-Ansatz zum Ausmaß des Zusatznutzens pragmatisch und praktikabel ist, aber zukünftig noch Erweiterungen notwendig sind, z. B. zur Bewertung stetiger Endpunkte. Die Interpretation von Subgruppenanalysen kann in der Praxis problematisch sein, dennoch sind aufgrund der gesetzlichen Vorgaben und der wissenschaftlichen Notwendigkeit Subgruppenanalysen notwendig. Die Anwendung indirekte Vergleiche ist bei der Bewertung des Zusatznutzens möglich, z. B. falls für die zu vergleichenden Interventionen keine direkten Head-to-Head-Studien verfügbar sind. Allerdings ist mithilfe indirekter Vergleiche aufgrund der damit verbundenen methodischen Probleme in der Regel kein Beleg des Zusatznutzens eines neuen Arzneimittels ableitbar.

In seinem Vortrag gab Ralf Bender „Biometrische Aspekte bei der Interpretation von Studienergebnissen im Rahmen von Nutzenbewertungen des IQWiG“ eine Einführung in die Arbeit des IQWiG im Rahmen des Arzneimittelmarktneuordnungsgesetzes (AMNOG). Es wurden die wesentlichen Kriterien des IQWiG bei der Bewertung des Zusatznutzens von Arzneimitteln erläutert mit besonderem Augenmerk auf die Bewertung des Ausmaßes eines Zusatznutzens gemäß der gesetzlichen Vorgaben. Zwei weitere Schwerpunkte waren die Interpretation von Subgruppenanalysen und methodische Aspekte bei indirekten

Kontroversen bei der Evidenz beurteilung medizinischer Forschung Der Vortrag stellte aktuelle Diskussionen zu Interpretationen von Studienergebnissen am Beispiel von a) Subgruppenanalysen und b) kardiovaskulären Outcome-Studien vor. Prospektiv geplante klinische Studien haben in der Regel eine primäre Zielstellung, sodass das Design und die Hypothesen der Studie auf dieses Ziel ausgerichtet werden können. Bei der Auswertung dieser Studien erscheinen im Nachhinein oft weitere (explorative) Ergebnisse von Interesse. Ein Beispiel dafür sind differentielle Effekte des primären Endpunktes in verschiedenen Subgruppen, wie das Geschlecht, Alter, Komorbiditäten oder weiteren demographischen und medizinischen Variablen. Beispielsweise wurde in einer Studie zwischen Aspirin und Sulfinpyrazonen 1978 festgestellt, dass Aspirin das Risiko von kardiovaskulären Ereignissen signifikant senkt. Allerdings war dieser Effekt bei Männern wesentlich ausgeprägter, sodass die Studienautoren den Effekt in Frauen als „nicht signifikant“ beschrieben. In der Folge war dieses Ergebnis für Jahrzehnte in Therapie-Richtlinien umgesetzt worden. Erst eine Meta-Analysen wie die 2009 erschienene konnten nachweisen, dass kein differentieller © 2016 Hogrefe

Prof. Dr. S. Konstantinides Centrum für Thrombose und Hämostase, Universitätsmedizin Mainz

Prof. Ralf Bender Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, Köln

Subgruppeneffekt vorliegt, sondern das Ergebnis durch Zufälligkeit erklärt werden konnte. Andererseits wurden in den vergangenen Jahren auch eine Reihe genetischer Faktoren bestätigt, deren Auftreten unterschiedliche Therapieeffekte erklären kann. Beispielsweise spricht der wild-type K-ras auf Cetuximab an, während Cetuximab keinen Vorteil bei mutiertem K-ras besitzt. Beim Vergleich von Gefitinib mit Carboplatin-Paclitaxel ist sogar ein entgegengesetzter Therapieerfolg zu erkennen, je nachdem ob eine positive oder negative EGFR Mutation vorliegt. Werden differentielle Subgruppeneffekte nur in einer Studie gefunden und nicht in Folgestudien untersucht, ist ihre Beurteilung problematisch, wie man am Beispiel der CAPRIE Studie für Clopidogrel sehen kann, bei dem unterschiedliche Effekte in drei medizinischen Subgruppen auftraten. Während das englische NICE das positive Gesamt-Studienergebnis hervorhob, hatte das deutsche IQWiG die Kostenerstattung nur in der Subgruppe empfohlen, in denen ein eigenständiger signifikanter Effekt vorlag. Als weitere Kontroverse wurde die Beurteilung der kardiovaskulären Sicherheit des Diabetesmedikamentes Rosiglitazone vorgestellt. In einer ersten Meta-Analyse mehrerer klinischer Studien ergab sich ein Hinweis auf ein erhöhtes Risiko für Herzinfarkte. In der Folge wurde in einer gerade laufenden Studie eine Zwischenanalyse durchVasa (2016), 45 (1), 73–77

From the societies

geführt, die diesen Hinweis nicht bestätigen konnte, dafür aber Herzinsuffizienz als Nebenwirkung zeigte. Weitere in der Folge durchgeführte Analysen ergaben unterschiedliche Ergebnisse, die von den Zulassungsbehörden verschieden bewertet wurden. So wurde die Indikation für das Medikament in den USA frühzeitig erheblich einschränkt, während es in Europa mit nur wenigen Einschränkungen weiter zur Verfügung stand. Im Dezember 2008 wurde allen neuen Diabetesmedikamenten zur Auflage gemacht, ihr kardiovaskuläres Risiko gegenüber Plazebo zu untersuchen. Da in einer typischen Patientenpopulation bei etwa 5 % der Patienten mit

einem entsprechenden Ereignis gerechnet werden kann, bewegen sich die Fallzahlen dieser Studien im Bereich von 5.000 bis 15.000. Einige Studien wurden 2015 abgeschlossen – in allen Fällen konnte die Vergleichbarkeit des kardiovaskulären Risikos nachgewiesen werden. Dabei wurde teilweise kritisch hinterfragt, ob allein das Senken des Blutzuckerspiegels ein therapeutisches Ziel sein kann, oder ob über die Vergleichbarkeit hinaus auch eine Überlegenheit gezeigt werden sollte. Bis heute konnte dies nur ein Diabetesmedikament zeigen. Prof. Dr. A. Ring Leiter Biometrie und statistische Programmierung, medac AG, Wedel

Vasa (2016), 45 (1), 73 – 77 DOI 10.1024/0301-1526/a000500

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Oberflächliche Venenthrombose Indikation für eine effektive antithrombotische Therapie mit Fondaparinux Die oberflächliche Venenthrombose (OVT) der unteren Extremitäten erfordert als ernstzunehmende klinische Entität mit potentiell schweren akuten und langfristigen Folgeschäden eine konsequente Therapie. Darauf wies PD Dr. Florian Langer, Hamburg, auf einem Expertengespräch hin. Die einzige placebokontrollierte Studie mit klinischen Endpunkten liegt für den selektiven Faktor Xa-Antagonisten Fondaparinux (Arixtra®) vor. In der CALISTO-Studie (n = 3002) reduzierte Fondaparinux 2,5 mg das Risiko symptomatischer thromboembolischer Komplikationen um 85 % (p < 0,001 vs. Placebo). Die Inzidenz schwerer Blutungen lag auf Placeboniveau. Patienten mit einer OVT müssen neben Akutkomplikationen – tiefe Venenthrombose (TVT) oder Lungenarterienembolie (LAE) – auch mit Spätfolgen wie venösen Durchblutungsstörungen und Ulzerationen rechnen, warnte Langer. In der STEPH- und in der POST-Studie wurden nahezu bei jedem vierten Patienten eine TVT nachgewiesen, knapp 5 % hatten eine symptomatische LAE (1, 2). Diese Zahlen machen deutlich, dass die OVT nicht selten nur die Spitze eines Eisberges ist, hinter der sich schwere thromboembolische Störungen verbergen. Die Risikofaktoren der OVT sind mit denen der TVT/ LAE vergleichbar, wobei OVT-Patienten häufiger (> 80 %) eine Varikosis bei chronisch-venöser Insuffizienz aufweisen (1). Duplexsonografie als Diagnostik der Wahl Mit der klinischen Untersuchung kann die Ausdehnung der OVT nach proximal sowie hinsichtlich einer Beteiligung der tiefen Venen im Sinne einer aszendierenden Thrombose nicht sicher objektiviert werden. Diagnostik der Wahl ist die duplexsonografische Abklärung mit der Frage nach der Ausdehnung und begleitender TVT. Darüber hinaus sollte der Patient nach Symptomen einer LAE befragt und im Verdachtsfall umgehend eine weiterführende Diagnostik eingeleitet werden. Im Mittelpunkt der Behandlung steht neben symptomatischen Maßnahmen wie Mobilisation, Kühlung sowie lokaler Entzündungshemmung und Schmerztherapie vor allem die Prävention venöser Thromboembolien. Die bisher vorliegende Evidenz zur Therapie der isolierten OVT war lange Jahre schwach,

und die methodische Qualität der Studien unzureichend (3). Die Behandlung mit niedermolekularen Heparinen (NMH) zeigte in randomisierten, klinischen Studien keinen nachhaltigen Nutzen. Nach Behandlungsende kam es regelmäßig zu einem sog. „Catch-up-Effekt“. Dabei schloss die Verum-Gruppe in der Anzahl der Endpunkt-relevanten Ereignisse rasch zur Placebo-Vergleichsgruppe auf (3 – 5). Beste Evidenz für Fondaparinux Die einzige randomisierte, doppelblinde, placebokontrollierte Studie mit klinischen Endpunkten liegt für den selektiven Faktor X-Antagonisten Fondaparinux vor, der auch als einziges Antithrombotikum zur Therapie der OVT zugelassen ist. In der CALISTO-Studie erhielten 3002 Patienten mit akuter, symptomatischer OVT der unteren Extremitäten mit einer Mindestlänge von ≥ 5 cm und > 3 cm von der Einmündung der V. saphena in die V. femoralis entfernt täglich Fondaparinux 2,5 mg subkutan oder Placebo. Der primäre Wirksamkeitsendpunkt war eine Kombination aus symptomatischer TVT oder LAE, OVT-Ausdehnung, OVT-Rezidiv oder Todesfälle jeglicher Ursache bis Tag 47. Der primäre Sicherheitsendpunkt waren schwere Blutungen bis Tag 47 (6). Bis zum Studienende reduzierte Fondaparinux gegenüber Placebo signifikant das relative Risiko des kombinierten Wirksamkeitsendpunkts um 85 % (0,9 % vs. 5,9%; p < 0,001) (Abb. 1). Die Risikoreduktion einer TVT und LAE betrug ebenfalls 85 % (p < 0,001). Der Behandlungserfolg blieb bis zur Nachbeobachtung an Tag 77 erhalten, und war konsistent über alle Patienten-Subgruppen hinweg. Langer wies darauf hin, dass unter Fondaparinux kein Risiko heparininduzierter Thrombozytopenien (HIT-II) besteht. Damit entfallen regelmäßige Thrombozytenkontrollen. Darüber hinaus besitzt Fondaparinux keine Wechselwirkungen mit anderen Medikamenten, die dessen Wirkspiegel beeinflussen könnten (7).

Dr. Alexander Kretzschmar Eine Information von: Aspen Germany GmbH Montgelasstraße 14 81679 München www. aspenpharma.com Quellen Expertengespräch „Paradigmenwechsel in der Therapie der oberflächlichen Venenthrombose – Fondaparinux(Arixtra® – setzt Standards“, Freiburg 28. September 2015. Veranstalter: Aspen Germany GmbH, München.

Literatur

Abb. 1: Die Wirksamkeit von Fondaparinux 2,5 mg bezüglich des primären Wirksamkeitsendpunktes blieb auch 30 Tage über das Therapieende hinaus erhalten.

1. 2. 3. 4. 5. 6. 7.

Frappé P et al. J ThrombHaemost 2014;12: 831 – 8. Decousus H et al. Ann Intern Med 2010;152; 218 – 24. DiNisio M et al. The Cochrane Library 2008,2: 93S. Decousus H et al. Arch Intern Med 2003; 163: 1657 – 1663. Prandoni P et al. J ThrombHaemost 2005;3: 1152 – 1157. Decousus H et al. N Engl J Med 2010;363: 1222 – 32. Fachinformationen Arixtra® 2,5 mg und 1,5 mg, Stand 8/2014.

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