Standardized Definitions and Clinical Endpoints in Trials InvestigatingEndovascular Repair of Aortic Dissections

N. Diehm a,*, F. Vermassen b, M.R.H.M. van Sambeek c, on behalf of the DEFINE Investigatorsa Swiss Cardiovascular Center, Division of Clinical and Interventional Angiology, Inselspital, University of Bern, Switzerlandb Department of Vascular Surgery, Ghent University Hospital, Ghent, Belgiumc Department of Vascular Surgery, Catharina Hospital, Eindhoven, The Netherlands

* CoventionFreiburE-ma1078

Surgeryhttp:

WHAT THIS PAPER ADDS

Current studies on endovascular therapy of thoracic aortic pathologies are characterized by a significant het-erogeneity of endpoints. This Trans-Atlantic multidisciplinary manuscript offers uniform reporting standards forendovascular therapy of thoracic aortic pathologies and aims at improving study across outcomes across clinicaltrials in the future.

Objectives: Endovascular therapy is a rapidly expanding option for the treatment of patients with aorticdissection (AD) and various studies have been published. These trials, however, are often difficult to interpret andcompare because they do not utilize uniform clinical endpoint definitions.Methods: The DEFINE Group is a collaborative effort of an ad hoc multidisciplinary team from various specialtiesinvolved in AD therapy in Europe and the United States. DEFINE’s goal was to arrive at a broad based consensusfor baseline and endpoint definitions in trials for endovascular therapy of various vascular pathologies. In thisproject, which started in December 2006, the individual team members reviewed the existing pertinentliterature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upondefinitions. Input was also obtained from regulatory (United States Food and Drug Administration) and industry(device manufacturers with an interest in peripheral endovascular revascularization) stakeholders, respectively.Results: These efforts resulted in the present document containing proposed baseline and endpoint definitionsfor clinical and morphological outcomes. Although the consensus has inevitably included certain arbitraryconsensus choices and compromises, adherence to these proposed standard definitions would provideconsistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of variousendovascular revascularization techniques.Conclusions: This current document is based on a broad based consensus involving relevant stakeholders fromthe medical community, industry and regulatory bodies. It is proposed that the consensus document may havevalue for study design of future clinical trials in endovascular AD therapy as well as for regulatory purposes.� 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.Article history: Received 25 June 2013, Accepted 29 August 2013, Available online 6 September 2013Keywords: Endpoint definitions, Standardization, Reporting standards, Thoracic aortic dissection

INTRODUCTION

Endovascular therapy is a rapidly evolving option for thetreatment of patients with pathologies of the descendingaorta such as intramural hematoma, penetrating aortic ul-cer (PAU), and aortic dissection (AD).1,2 The excitementgenerated by the prospects of new technology has ledendovascular therapists of various specialty backgrounds topursue novel endovascular approaches for this life-threatening vascular pathology.

rresponding author. N. Diehm, Department of Clinical and Inter-al Angiology, Berne University Hospital and University of Berne,gstrasse, 3010 Bern, Switzerland.il address: nicolas.diehm@insel.ch (N. Diehm).-5884/$ e see front matter � 2013 European Society for Vascular. Published by Elsevier Ltd. All rights reserved.//dx.doi.org/10.1016/j.ejvs.2013.08.017

Clinical trials are of utmost importance in the assessmentof new technologies to ascertain clinical efficacy and safety,thereby prompting adoption for clinical use following reg-ulatory approval. Various clinical studies assessing endo-vascular technologies have recently been published.However, substantial variability in endpoint definitions hascreated a significant barrier for comparison of results acrossthese trials.3

In an attempt to remedy these issues, an assembly ofexperts came together on an ad hoc basis to create uniformdefinitions by which future research could be conducted.The DEFINE Group was founded in 2006, consisting of abroad interdisciplinary team (interventional angiologists,cardiologists, and radiologists as well as vascular surgeons,an endovascular neurosurgeon, and non-invasive vascularmedicine specialists) from Europe and the United States.The mission of the DEFINE efforts was to create sets of

646 N. Diehm et al.

definitions aimed at increasing consistency in future endo-vascular therapy trials.4,5 The DEFINE group reviewedscientifically sound, peer-reviewed literature and, afterextensive correspondence and meetings, proposed thedefinitions outlined in the present manuscript. Two meet-ings including all authors of the manuscript, along withrepresentatives of the United States Food and DrugAdministration (FDA) and commercial device manufacturerswere held in New York in November 2011 and in November2012. Several teleconferences were required to continuethe consensus process. Given the multidisciplinary aspectsof the members of the DEFINE writing group, we strived fora non-biased consensus that would be generally acceptedwithin future trials, regardless of specialty or nation.

Key components of this effort included definitions forbaseline clinical and anatomic characteristics,6 clinical out-comes relevant to the patients, morphologic outcomes, andcomplications. Existing standards were modified andupdated, if necessary, to apply specifically to endovascularprocedures and to reflect new insights that have emergedover the last decade.

Given the contribution by the multidisciplinary scientificmembers and by regulatory authorities, we hope that thedefinitions described in the present manuscript will beapplicable for future clinical investigations.

PROPOSED DEFINITIONS FOR ACUTE DESCENDING AORTICPATHOLOGIES

Aortic dissection

Acute aortic dissection is characterized by the rapid devel-opment of an intimal flap separating the true from the falselumen.7e9 In the majority of cases, intimal tears are iden-tified as sites of communication between true and falselumen. The dissection can spread in an antegrade orretrograde fashion, involving side branches and causingcomplications such as malperfusion syndrome by dynamicor static obstruction (from coronary to iliac arteries),rupture, tamponade, or aortic insufficiency. From a patho-physiological point of view, progression of dissection isdifficult to predict once a patient with dissection has sur-vived the initial 2 weeks after inception, although falselumen expansion is likely to develop over time. Severalclinical features may be used to roughly estimate late risk,including evidence of persistent communication, patentfalse channel, and others.6,10

Intramural hematoma

Aortic intramural hematoma is considered a precursor ofclassic dissection, and originates from ruptured vasa vasorumin medial wall layers, eventually provoking a secondarycommunication with the aortic lumen.11e13 This process maybe initiated by ‘aortic wall infarction’. Bloodwithin themedialwall space in the absence of an intimal tear is defined asintramural hematoma (IMH). It should be noted that theinability to detect a small intimal defect (or fenestration) mayallow patients with true dissections to be classified as IMH,

thus the assessment of the lumen, status of the fluid in themedia, and proper imaging are critical. IMH may progressinto dissection if an intimal defect occurs either as a result ofrupture from the media through the intima or vice versa.

Similar to classic dissection, intramural hematoma mayextend along the aorta or progress, regress, or reabsorb.14 Theprevalence of intramural hematomas is 10e30% in patientswith acute aortic diseases and can lead to acute aorticdissection in 21e47% of patients or to regression in about10%.11,13,15,16 Involvement of the ascending aorta is consid-ered an indication for expeditious surgery due to the inherentrisk of rupture, tamponade, or compression of coronary arteryostia. Distal intramural hematoma may warrant watchfulwaiting and, potentially, stent-graft placement in case of localexpansion.13,16e18 Thus, IMHs of the ascending aorta shouldbe reported separately from distal IMHs.

Penetrating aortic ulcer

Ulceration of atherosclerotic aortic plaques can lead toaortic dissection or perforation.14,19e21 Non-invasive imag-ing of aortic ulceration has been improved by tomographicscanning and has shed light on pathophysiology and etiol-ogy. Aortic ulcers occur predominantly in the descendingthoracic and abdominal aorta, penetrate intimal borders,and appear in nipple-like projections with an adjacent he-matoma;22,23 symptomatic ulcers and/or with signs of deeperosion are more likely to rupture than others.

Natural history

Acute aortic dissection of the descending aorta is lessfrequently lethal than that of the ascending aorta. In theabsence of treatment, survival rates are 89% at 1 month,84% at 1 year, and 80% at 5 years.24 However, patients withcomplications such as renal failure, visceral ischemia, orcontained rupture often require urgent repair, with a mor-tality of 20% at day 2 and 25% at 1 month. Advanced age,rupture, shock, and malperfusion are important indepen-dent predictors of early mortality.24

The observation that older age (>55 years) at initial diag-nosis of IMH has a better long-term prognosis may beexplained by more focal microscars along the aortic wallinherently limiting the longitudinal progression of IMH.24

Accordingly, favorable outcomes of IMH are consistently re-ported in patients beyond 65 years.24 Thus, considering bothadvanced aortosclerosis with older age and the lower risk ofprogression, a conservative strategy (with b-blockade andserial imaging) appears to be justified in elderly medically frailpatients and in distal IMH.24 Ulcer-like projections in aorticsegments of IMH identify a subset of patients at high risk.Aortic ulcers are preferentially (>90%) observed in IMH of thedescending aorta, while IMH without PAU is more frequentlypresent in the ascending aorta. Symptomatic PAU incurscomplications such as formation of aneurysm, pseudoaneur-ysm, and dissection, or unpredictable rupture. Careful imagingis vital to identify both diameter and depth of ulcers with IMH,since width>2 cm and depth>1 cmmay herald the need forinterventional or surgical repair to avoid rupture and death.25

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PROPOSED ENDPOINT DEFINITIONS

Endpoint definitions encompass immediate proceduralsuccess, complications, and clinical outcome during follow-up.4,5 All failures occurring within 30 days of the procedure(i.e. absence of procedural success) are considered “acuteprocedural failures”, and are attributed to the procedure. Toevaluate clinical outcomes we propose a minimum follow-up period of 12 months, which is considered short-termfollow-up. Mid-term follow-up refers to follow-up periods ofgreater than 1e3 years and long-term follow-up to begreater than 3 years of post-procedural follow-up. Clinicalfollow-up pertains to any information regarding the clinicalstatus of the patient including mortality.

Mortality

Patient mortality after enrolment in a study must beassessed during follow-up. Aneurysm/dissection-relatedmortality has to be differentiated from all-cause mortality.Causes of death associated with the endovascular proce-dure (procedure-related mortality, i.e. mortality within 30days post procedure or mortality during a hospitalization>30 days due to the procedure) should be reported sepa-rately as well as overall mortality.

Freedom from reintervention

Freedom from open surgical and endovascular reinterven-tion should be reported separately.

Neurological sequelae

� Stroke� Spinal cord ischemia/paresis-paralysis� Vertebral insufficiency

Ischemic symptoms

Visceral ischemia. Symptoms requiring surgical or endo-vascular intervention versus symptoms not requiring inter-vention should be differentiated at baseline and follow-up.

Renal ischemia/renal dysfunction. Symptoms requiringsurgical or endovascular intervention versus symptoms notrequiring intervention should be differentiated at baselineand follow-up. Need for dialysis (temporary vs. chronic)should be reported.

Lower extremity ischemia. Symptoms requiring surgical orendovascular intervention versus symptoms not requiringintervention should be differentiated at baseline and follow-up.

Upper extremity ischemia.

� Intermittent dyspraxia of the left arm at baseline andfollow-up

� Subclavian steal syndrome

Symptoms requiring surgical or endovascular interven-tion versus symptoms not requiring intervention should bedifferentiated at baseline and follow-up.

Morphological outcomes

Contrast-enhanced computed tomography angiography re-mains the gold standard for imaging of thoracic aortic pa-thologies post endovascular treatment.26 The followingparameters should be reported:

Aortic diameters6.

� Maximum transverse aortic diameter measuredperpendicular to the aortic centerline, baseline versusfollow-up

� Minimal diameter of the true lumen and maximaldiameter of the false lumen

� Increase/decrease of maximum transverse diameter>5 mm

� Stable transverse diameter <5 mm change� Increase of diameter to >6 cm� Rupture� Perforation

Membrane rupture. Segmental extent of aortic involve-ment from proximal to distal boundary according toDISSECT definitions.6

Progression of dissection (perioperatively and follow-upvs. baseline):6

� antegrade: progression distally from the primary entrytear

� retrograde: progression distally from the primary entrytear.

Status of false lumen6.

� Patent, defined as evidence of flow or contrastopacification within the false lumen throughout thelength of the dissected aorta

� Partially patent/thrombosed, defined as longitudinalthrombosis of a portion of the aortic false lumen orcircumferential thrombus that partially fills the false lumen

� Thrombosed, defined as absence of flow or contrastopacification within the initially visualized false lumenon contrast-enhanced computed tomography scan

Status of endovascular device

� Type 1 and 3 Endoleak as defined elsewhere27

� Graft migration defined as movement of >10 mmrelative to anatomic landmark with the use of three-dimensional computed tomography reconstruction usinga centerline of flow or any migration leading tosymptoms or requiring intervention27

648 N. Diehm et al.

� Stent fracture defined as visualized on plain radiographyusing a standardized protocol with anteroposterior andlateral projections27

� Graft infolding defined as the lack of apposition of theproximal stent-graft to the aortic wall, with a wedge-shapedgapbetweentheundersurfaceof thestent-graftandthe aorticwall along the lesser curvatureof the aortic arch28

� Graft collapse defined as aortic occlusion resulting fromgraft infolding

Procedural success

Technical or device success is defined as successful introduc-tion and deployment of the device at the intended segmentwith successful coverage of the primary tear site defined asthe proximal margin of the origin of the dissection.6

Procedural success is defined as the composite of tech-nical success, absence of the need for conversion to opensurgery or immediate endovascular reintervention, absenceof aortic death, absence of graft thrombosis, obstruction,twisting or kinking or graft migration >10 mm proximally ordistally, absence of failure of graft integrity, absence ofaneurysm rupture and absence of increase in aortic diam-eter >5 cm within 30 days of the baseline procedure.

Hemodynamic outcome

Hemodynamic stabilization defined as absence of need formechanical or drug support to maintain circulation.

Complications

Complications should be reported according to the generalclinical research guidelines and the applicable (local) laws.For the purpose of this guidance document on definitionsfor complications, reference is made to the InternationalSociety for Standardization (ISO) 14155, the InternationalConference on HarmonisationeGood Clinical Practice (ICH-GCP) guidelines and the Food and Drug Administration(FDA) 21 Code of Federal Regulations (CFR) chapter x812.3.

The primary mode of action of the investigational prod-uct as well as the region where the trial is performed willdetermine which regulations must be used. Additionally,combined products or non-medical devices may requireusing a combination of these guidelines.

Any untoward occurrence in a subject should be differ-entiated as follows:

� Adverse events (AE)� Serious adverse events (SAE)� Adverse device effect� (Serious) Adverse device effect (SADE)� Unanticipated adverse device effect (UADE)� Major adverse event (MAE)

In case the investigational product is classified differentthan a medical device, other general definitions may beapplicable (e.g. Suspected Unexpected Serious AdverseReaction [SUSAR]).

Adverse events (AE) e ISO 14155 (3.2)

Any untoward medical occurrence, unintended disease orinjury, or untoward clinical signs (including abnormal labo-ratory findings) in subjects, users or other persons, whetheror not related to the investigational medical device.

NOTE 1: This definition includes events related to theinvestigational medical device or the comparator.NOTE 2: This definition includes events related to theprocedures involved.NOTE 3: For users or other persons, this definition isrestricted to events related to investigational medicaldevices.

Serious adverse event (SAE) e ISO 14155 (3.37)

A SAE is an AE that

� led to a death� led to a serious deterioration in the health of the subjectthat resulted ine a life-threatening illness or injurye permanent impairment of a body structure or a body

functione inpatient hospitalization or prolongation of existing

hospitalizatione medical or surgical intervention to prevent permanent

impairment to body structure or a body function

� led to fetal distress, fetal death or a congenitalabnormality or birth defect.

NOTE: Planned hospitalization for a pre-existingcondition, or a procedure required by the CIP, withoutserious deterioration in health, is not considered aserious adverse event.

All AEs, whether serious or not, must be rated “related orunrelated” to the investigational product.

Adverse device effect e ISO 14155 (3.1)

An adverse device defect is defined as any untoward andunintended response to a medical device.

NOTE 1: This definition includes adverse eventsresulting from insufficient or inadequate instructionsfor use, deployment, implantation, installation, oroperation, or any malfunction of the investigationalmedical device.NOTE 2: This definition includes any event resultingfrom use error or from intentional misuse of theinvestigational medical device.

Serious adverse device effect e ISO 14155 (3.36)

An adverse device effect that has resulted in any of theconsequences characteristic of a serious adverse event.

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Unanticipated adverse device effecte FDA 21 CRF x812.3 (s)Any serious adverse effect on health or safety or any life-threatening problem or any life-threatening problem ordeath caused by, or associated with, a device if that effect,problem, or death was not previously identified in nature,severity, or degree of incidence in the investigational plan orapplication (including a supplementary plan or application),or any other unanticipated serious problem associated with adevice that relates to the rights, safety or welfare of subjectsis defined as an unanticipated adverse device effect.

Major adverse event

The MAE definition is different for each protocol and mustbe defined in the protocol.

It is recommended to use an independent committee(Clinical Event or Data Safety and Monitoring Committee)for the adjudication of the SAEs to determine if an event is aMAE or not. The CEC may define, prior to the start of thestudy, the type of events that will be reviewed andadjudicated.

All AEs and SAEs must appear in the final report. Infor-mation related to the adjudication of the events may beadded. Reporting by the manufacturer/sponsor to the reg-ulatory bodies must be performed according the specifiednational regulations.

Additionally, the following occurrences should appear inthe related publication or at a minimum in the final trialreport:

� procedural-related serious adverse events� investigational product related serious adverse events� device failure or malfunction.

Next to the MAE, the reported (serious) adverse eventsshould be classified and reported according to the followingfour complication categories: access site complications,vessel specific complications (treatment site includingproximal and distal to the site), organ-specific complica-tions, systemic complications.

CONCLUSIONS

Endovascular treatment of descending aortic dissection is arapidly growing field that has resulted in a number ofclinical trials. These differ across a heterogeneous com-posite of definitions thereby resulting in reporting in-consistencies and a lack of comparability across varioustrials.

The present manuscript aimed to establish definitions asa point of reference for future clinical trials.4,5 Use of thelatter will improve comparability of studies dealing withendovascular therapy of AD to further elucidate and provelong-term credibility of this method. Thus, adherence tothese definitions is recommended for future publications.

ACKNOWLEDGEMENTS

We gratefully acknowledge and appreciate the support andcontributions to this manuscript by the DEFINE group and

its members focused on aortic diseases as part of theoverall DEFINE project. These individuals include: DorothyAbel, Giancarlo Biamino, Michael D. Dake, Christopher JFrancois, Michael R. Jaff, Jon Matsumura, Jose Pablo Mo-rales, D. Craig Miller, Christoph Nienaber, Eric Roselli, andMatt Thompson. Furthermore, we kindly acknowledgeAntonie Jager, CongO Congress Organization and Aly Talen,genae associates, for their help in manuscript preparation,organization of the DEFINE group meetings and overallmanagement of the DEFINE project.

CONFLICT OF INTEREST

None.

FUNDING

None.

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