Clinical Endpoints in Peripheral Endovascular Revascularization Trials: a Case for Standardized Definitions

Article Outline

• Abstract
• Introduction
• Proposed Baseline and Endpoint Definitions
  • Patient clinical and anatomical baseline characteristics
  • Clinical evaluation
    • Functional status at baseline
    • Quality of life at baseline
    • Hemodynamic evaluation at baseline
  • Risk factors and comorbidities
  • Medication usage
  • Baseline anatomic characteristics
    • Anatomic levels
    • Arterial segments
    • Arterial inflow and outflow
    • Involvement of arterial origin/ostium
    • Lesion length
    • Degree of obstruction
    • Calcification
• Endpoint Definitions: Clinical Outcomes and Complications
  • Procedural success
  • Clinical outcomes for treatment of IC
    • Change in functional status in patients treated for IC
    • Change in disease severity in patients treated for IC
  • Clinical outcomes for treatment of critical limb ischemia (CLI)
    • Change in functional status in patients treated for CLI
  • Change in disease severity in patients treated for CLI
  • Hemodynamic outcome
  • Mortality
  • Amputation
  • Complications
    • Adverse events (AE) - ISO 14155-1 (3.2)
    • Serious adverse event (SAE) - ISO 14155-1 (3.19)
    • Adverse device effect - ISO 14155-1 (3.1)
    • Serious adverse device effect - ISO 14155-1 (3.19)
    • Unanticipated adverse device effect - FDA 21 CRF § 812.3 (s)
    • Major Adverse Event (MAE)
• Morphologic Outcome
• Statistical Analysis
• Conclusions
• Acknowledgement
• Disclosures
• Sources of funding
• Author contributions
• Appendix. Clinical categories of chronic limb ischemia according to Rutherford 3
• References
• Copyright

Abstract 

Background

Endovascular therapy is a rapidly expanding option for the treatment of patients with peripheral arterial disease (PAD), leading to a myriad of published studies reporting on various revascularization strategies. However, these reports are often difficult to interpret and compare because they do not utilize uniform clinical endpoint definitions. Moreover, few of these studies describe clinical outcomes from a patients' perspective.

Methods and results

The DEFINE Group is a collaborative effort of an ad-hoc multidisciplinary team from various specialties involved in peripheral arterial disease therapy in Europe and the United States. DEFINE's goal was to arrive at a broad based consensus for baseline and endpoint definitions in peripheral endovascular revascularization trials for chronic lower limb ischemia. In this project, which started in 2006, the individual team members reviewed the existing pertinent literature. Following this, a series of telephone conferences and face-to-face meetings were held to agree upon definitions. 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. The efforts resulted in the current document containing proposed baseline and endpoint definitions in chronic lower limb PAD. Although the consensus has inevitably included certain arbitrary choices and compromises, adherence to these proposed standard definitions would provide consistency across future trials, thereby facilitating evaluation of clinical effectiveness and safety of various endovascular revascularization techniques.

Conclusion

This current document is based on a broad based consensus involving relevant stakeholders from the medical community, industry and regulatory bodies. It is proposed that the consensus document may have value for study design of future clinical trials in chronic lower limb ischemia as well as for regulatory purposes.

Keywords: Reporting standards, Outcome analysis, Clinical improvement, Angiography

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Introduction 

Endovascular therapy is a rapidly evolving option for the treatment of patients with peripheral arterial disease (PAD).¹ The excitement generated by the prospects of new technology has led endovascular therapists of various specialty backgrounds to pursue innovative approaches utilizing minimally invasive arterial revascularization.

Clinical trials are of utmost importance in the assessment of new technologies to ascertain clinical efficacy and safety, thereby prompting adoption for clinical use following regulatory approval. A number of clinical studies assessing technologies in endovascular lower limb arterial revascularization have recently been published. However, substantial variability in endpoint definitions has created a significant barrier for comparison of results across these trials.² Moreover, previous studies on lower limb peripheral arterial revascularization have rarely described clinical outcomes from a patients' perspective.²

The DEFINE Group was founded in 2006, consisting of a broad interdisciplinary team (interventional angiologists, cardiologists and radiologists as well as vascular surgeons, an endovascular neurosurgeon and non-invasive vascular medicine specialists) from Europe and the United States. The mission of this first DEFINE effort was to create a set of definitions which would increase consistency in future peripheral endovascular revascularization trials. The DEFINE Group reviewed the present literature and, after extensive correspondence and meetings, proposed the definitions outlined in the present manuscript. Two meetings including all authors of the manuscript, along with representatives of the United States Food and Drug Administration (FDA) and commercial device manufacturers were held in Washington, DC, in July 2007 and in New York, NY, in November 2007. Several teleconferences were also required to continue the process.

Key components of this effort included definitions for baseline clinical and anatomic characteristics, clinical outcomes relevant to the patients, morphologic outcomes, and complications. Existing standards for reporting lower extremity ischemia were modified and updated, if necessary, to apply specifically to peripheral endovascular procedures and to reflect new insights that have emerged over the last decade.², ³, ⁴, ⁵ Given the contribution by the multidisciplinary scientific members and the regulatory authorities, we hope that the definitions described in the present manuscript will be applicable for future clinical investigations.

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Proposed Baseline and Endpoint Definitions 

Patient clinical and anatomical baseline characteristics 

Baseline definitions include descriptions of clinical patient characteristics and of the characteristics of the vascular lesion(s) that are to be treated with the endovascular therapy under investigation.

Pre-treatment evaluation should include objective and quantitative measures of disease severity, measurement of functional status and a description of known atherosclerotic risk factors which may have an impact on procedural and clinical outcomes (Table 1).

Table 1. Patient clinical and anatomical baseline characteristics

•Separate outcome reporting for patients with claudication and critical limb ischemia. •Rutherford stages at baseline. •In claudicants: standardized treadmill testing (2 miles per hour [3.2km/h] at a 12% grade or 2 miles per hour [3.2km/h] with 2% increase in grade every 2 minutes); claudication onset time (COT) and absolute claudication time (ACT). •Quality of life at baseline: EuroQOL 5 Dimension. •Walking ability: walking impairment questionnaire. •In claudicants: ankle-brachial index (ABI) at rest and after exercise. •In patients with critical limb ischemia: systolic ankle pressure and ABI. •Oscillographic reading or toe pressure measurement if ABI cannot be appropriately measured. •Risk factors and comorbidities: Age, gender, race, hypertension, hyperlipidemia, diabetes mellitus, smoking, ischemic heart disease, congestive heart failure, renal insufficiency, cerebrovascular disease. •Medication:,Anticoagulants, antithrombotic agents, statins, beta-blockers, angiotensin converting enzyme inhibitors, angiotensin-II receptor antagonists. •Anatomic levels, arterial segments, arterial in- and outflow, involvement of arterial origin/ostium, lesion length, degree of obstruction (as determined by intra-arterial pressure measurement, intravascular ultrasound, angiography, magnetic resonance or computed tomography angiography or by duplex ultrasound, calcification (none, moderate, heavy).

Clinical evaluation 

Patients with intermittent claudication (IC) and those with critical limb ischemia (CLI) should be evaluated separately in outcomes analyses. Baseline clinical evaluations should include anatomic descriptions and functional status, as well as quality of life.

Disease severity in patients with chronic lower limb ischemia should be objectively described according to criteria proposed by Rutherford (Appendix).³

Functional status must be quantified by standardized treadmill testing using a graded exercise treadmill protocol (speed constant at 2 miles per hour [3.2km/h], 2% increase in grade every 2 minutes) in all patients studied for IC.⁶ This treadmill test should be performed until claudication pain occurs or to a maximum of 5 minutes. Changes in claudication onset time (COT: time after initiation of exercise when the patient first experienced symptoms of claudication) and absolute claudication time (ACT: time after initiation of exercise until he/she can not walk further due to severe claudication pain) are to be reported in minutes and seconds. Patients who are not able or willing to undergo standardized treadmill testing should be excluded from IC trials.

The EuroQol 5 Dimensions (EQ5D) is recommended to be used to measure quality of life,⁷ whereas the walking impairment questionnaire is recommended to assess walking distance and speed of patients with IC.⁷, ⁸

In patients with IC, ankle brachial index (ABI) measurements at rest and after treadmill exercise (after reaching the absolute claudication distance, ACD) should be performed according to the AHA recommendations.⁵, ⁹ In patients with CLI, only systolic ankle pressure, ABI and digital pressures or photoplethysmographic waveforms at rest are required.

In scenarios in which the ABI cannot be measured, such as in case of medial arterial calcification (e.g. diabetes mellitus or renal insufficiency), photoplethysmographic or oscillometric reading or toe pressure measurement and determination of the toe brachial index should be used.³, ⁵, ¹⁰

Risk factors and comorbidities 

The following risk factors and comorbidities should be recorded:

•Hypertension, as defined by the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure¹¹ or if the patient is on antihypertensive therapy for the indication of hypertension:

■Normal blood pressure: systolic<120mmHg and diastolic<80mmHg

■Prehypertension: systolic 120–139mmHg or diastolic 80–89mmHg

■Stage 1 hypertension: systolic 140–159mmHg or diastolic 90–99mmHg

■Stage 2 hypertension: systolic≥160mmHg or diastolic≥100mmHg

•Diabetes mellitus: HbA1c>7% or if or if patient consumes oral hypoglycaemic agents¹³

•Renal insufficiency: glomerular filtration rate<60ml/min (calculated according to Cockcroft formula¹⁵)

Medication usage 

Pre-, peri-, and post-procedural medications should be specified as follows (including generic name, dose, frequency, and (if possible) duration of use):

Baseline anatomic characteristics 

Baseline anatomic characteristics should be reported for all enrolled patients: anatomic levels, arterial segments, inflow, outflow, involvement of ostium, along with specific location of lesion within the named vessel(s), lesion length, stenosis or occlusion; degree of thrombus and calcification. The TASC lesion classification,¹⁰, ¹⁶ although commonly utilized, may not be the ideal schema,¹⁷ and we suggest a more complete description of the arterial lesion.

Multilevel disease is defined as presence of significant obstructive lesions at more than one level. The right and left leg are considered separately. Thus, the combination of a lesion in the left common iliac combined with a lesion in the left popliteal artery equals multilevel disease, whereas presence of a lesion in the left common iliac combined with a lesion in the right popliteal artery is considered bilateral single level disease.

Segments refer to specific locations in which patient outcomes of endovascular therapy may differ. The following segments should be differentiated:

Arterial inflow is defined with regard to the above-defined anatomic levels (2.5.1). The inflow to a vascular lesion at a certain level refers to the combined levels proximal to the lesion. Thus, for a lesion in the superficial femoral artery (i.e. femoropopliteal level), arterial inflow refers to the common femoral artery and the aortoiliac level. For a lesion in the anterior tibial artery (i.e. crural level), inflow refers to both the aortoiliac and femoropopliteal levels. Good inflow implies straightline vessels proximal to a site that are free of hemodynamically significant obstruction (i.e. ≥50% stenosis) of the inflow arteries.

Impaired inflow means that the vessels proximal to the site contain hemodynamically significant lesions (i.e. ≥50%), whereas impaired inflow represents the presence of such lesions. Arterial outflow is defined accordingly, with the outflow of a vascular lesion being defined as the combined levels distal to a lesion. The superficial and deep femoral arteries are the runoff vessels for iliac artery procedures, and the tibial arteries are the runoff vessels for femoropopliteal procedures.

For further definition of below-the-knee outflow, the number of patent arteries with patency directly to the foot arteries should be specified. Thus, for a lesion in the superficial femoral artery (i.e. femoropopliteal level) with an occlusion of the peroneal artery, arterial outflow should be “2-vessel outflow”. Moreover, to define arterial outflow in the foot, the patency of both the dorsal and plantar pedal arch should be specified (“yes/no”).

It should be provided whether or not the lesion involves the origin/ostium of a specific artery.

We propose to define the following lesion lengths for use in all segments that apply to stenoses and occlusions alike:

•Focal lesions: ≤1cm

•Short lesions: >1 and<5cm

•Intermediate lesions: ≥5cm and<15cm

•Long lesions: ≥15cm

In case of vessel occlusion within a stenosed segment, both the length of the stenosed segment and the length of the occluded segment should be reported.

Hemodynamic significance of a lesion can be assessed utilizing the following measurement techniques (listed in a hierarchical order):

2.)Intravascular ultrasound (IVUS) measurements indicating≥50% diameter stenosis or ≥75% area stenosis.

3.)Intra-arterial digital subtraction angiography indicating≥50% diameter stenosis by visual estimation or by quantitative vessel analysis software assessing at least two different angiographic projections.

5.)Duplex ultrasound indicating ≥50% diameter stenosis as defined by a peak systolic velocity index (defined as the ratio of intra-stenotic peak systolic velocity to pre-stenotic peak systolic velocity)>2.4.¹⁸

A semi quantitative distinction between no, moderate, and heavy calcification at the site of the lesion should be provided according to findings on the fluoroscopic image obtained prior to the intervention.

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Endpoint Definitions: Clinical Outcomes and Complications 

Endpoint definitions encompass immediate procedural success, complications, and clinical outcome during follow-up (Table 2a, Table 2b, Table 2c, Table 2d). All failures occurring within 30 days of the procedure (i.e. absence of procedural success) are considered “acute procedural failures”, and are attributed to the procedure. To evaluate clinical outcomes we propose a minimum follow-up period of 12 months, which is considered short-term follow-up. Mid-term follow-up refers to follow-up periods of greater than 1 year to 3 years and long-term follow-up to be greater than 3 years of post-procedural follow-up. Special care was taken to grant applicability of clinical outcome definitions (chapters 3.2 and 3.3) also to trials assessing the efficacy of open surgical revascularization.

Table 2a. Immediate outcome

Table 2b. Clinical outcome in patients treated for claudication

•Distribution of Rutherford stages during follow-up as compared to baseline. •Changes in claudication onset time (COT) and absolute claudication time (ACT). •Change in quality of life according to EuroQOL. •Change in walking ability according to walking impairment questionnaire. •Primary sustained clinical improvement (sustained upward shift of≥1 category on Rutherford classification without the need for repeated target lesion revascularization (TLR) in surviving patients). •Secondary sustained clinical improvement (sustained upward shift of≥1 category on Rutherford classification including the need for repeated TLR in surviving patients. •Primary sustained resolution of symptoms from PAD (sustained absence of claudication without the need for repeated TLR in surviving patients). •Secondary sustained resolution of symptoms from PAD (sustained absence of claudication including the need for repeated TLR in surviving patients). •Clinical deterioration (downgrade of≥1 category on the Rutherford classification after endovascular treatment). •Immediate hemodynamic improvement: increase in ABI of≥0.10 or to an ABI≥0.9. •Sustained hemodynamic improvement: persistent improvement of ABI-values with ≥ 0.10 as compared to baseline values or to ABI ≥ 0.9 throughout follow-up without need for repeated TLR in surviving patients. •30-day (procedure-related and all-cause) mortality and mortality during follow-up. •Need for minor (below the ankle) and major (above the ankle) unplanned amputation. Major amputation specified as below-the-knee and above-the-knee amputations. Planned versus unplanned amputations.

Table 2c. Clinical outcome in patients treated for critical limb ischemia

•Distribution of Rutherford stages during follow-up as compared to baseline. •Change in quality of life according to EuroQOL. •Primary sustained clinical improvement (upward shift on the Rutherford classification to a level of claudication without the need for repeated TLR in surviving patients without the need for unplanned amputation). •Secondary sustained clinical improvement (upward shift on the Rutherford classification to a level of claudication, including the need for repeated TLR in surviving patients without the need for unplanned amputation). •Clinical deterioration (downgrade of≥1 category on the Rutherford classification after endovascular treatment). •Immediate hemodynamic improvement: increase in ABI of≥0.10 or to an ABI≥0.9. •Sustained hemodynamic improvement: persistent improvement of ABI-values with ≥ 0.10 as compared to baseline values or to ABI ≥ 0.9 throughout follow-up without need for repeated TLR in surviving patients. •30-day (procedure-related and all-cause) mortality and mortality during follow-up. •Need for minor (below the ankle) and major (above the ankle) unplanned amputation. Major amputation specified as below-the-knee and above-the-knee amputations. Planned versus unplanned amputations.

Table 2d. Complications

Procedural success 

Technical or device success is defined as achievement of a final residual diameter stenosis of <30% on the procedural completion angiogram, using the assigned device only, whereas lesion success is defined as achievement of <30% residual stenosis using any percutaneous method.

Procedural success is technical or device success without the occurrence of major adverse events during the hospital stay.

Clinical outcomes for treatment of IC 

Change in disease severity should be described according to the categories proposed by Rutherford (Appendix).³

Change in walking capacity should be assessed to measure the objective functional response to therapeutic interventions according to the above-mentioned standardized treadmill protocols:², ¹⁰, ¹⁶ Changes in claudication onset time (COT, defined as the time after initiation of exercise when the patient first experienced symptoms of claudication) and absolute claudication time (ACT, defined as the time after initiation of exercise until he/she can not walk further due to severe claudication pain) must be reported in minutes and seconds.

Sustained clinical improvement has to be regarded a primary clinical endpoint in trials assessing outcomes of patients with IC.² Primary sustained clinical improvement is defined as sustained upward shift of at least one category on the Rutherford classification³ (Appendix) without the need for repeated target lesion revascularization (TLR) in surviving patients (i.e. dead patients will be censored at the time point when they were last examined). Secondary sustained clinical improvement is defined as sustained upward shift of at least one category on the Rutherford classification³ (Appendix) including the need for repeated TLR in surviving patients.

Moreover, primary sustained resolution of symptoms from PAD is defined as sustained absence of IC without the need for repeated TLR in surviving patients. In contrast, secondary sustained resolution of symptoms from PAD describes sustained absence of IC including the need for repeated TLR in surviving patients.

Clinical deterioration should be described as a downgrade of≥1 category on the Rutherford classification (Appendix) as a result of endovascular treatment (improvements that occur after secondary procedures are not included, i.e. this endpoint does not include repeated TLR/TER). Furthermore, distribution of clinical stages according to Rutherford³ (Appendix) during all follow-up visits should be given as compared to baseline.²

No change in functional outcome will be captured as absence of primary or secondary sustained clinical improvement or absence of deterioration. Thus, in the cumulative analysis for primary or secondary sustained clinical improvement patients not experiencing any change in the Rutherford classification (Appendix) will have to be uncensored, whereas they will have to be censored in the analysis for clinical deterioration.

Clinical outcomes for treatment of critical limb ischemia (CLI) 

Change in disease severity should be described according to the categories of the criteria proposed by Rutherford (Appendix).³

Change in disease severity in patients treated for CLI 

Sustained clinical improvement has to be regarded a primary clinical endpoint.² Treadmill testing is not required in patients treated for CLI. Primary sustained clinical improvement is defined as an upward shift on the Rutherford classification (Appendix) to a level of IC without the need for repeated TLR in surviving patients without the need for unplanned amputation. Secondary sustained clinical improvement is defined as an upward shift on the Rutherford classification (Appendix) to a level of IC, including the need for repeated TLR in surviving patients without the need for unplanned amputation.

Clinical deterioration is defined as a downgrade of≥1 category on the Rutherford classification (Appendix) as a result of endovascular treatment (improvements that occur after secondary procedures are not included, i.e. this endpoint does not include repeated TLR/TER). Furthermore, distribution of clinical stages according to Rutherford³ (Appendix) during all follow-up visits should be given as compared to baseline.²

No change in functional outcome will be captured as absence of primary or secondary sustained clinical improvement or absence of deterioration. Thus, in the cumulative analysis for primary or secondary sustained clinical improvement patients not experiencing any change in the Rutherford classification (Appendix) will have to be uncensored, whereas they will have to be censored in the analysis for clinical deterioration.

Hemodynamic outcome 

Immediate hemodynamic improvement after endovascular revascularization is defined as ankle brachial index (ABI) improvement of≥0.10 or to an ABI≥0.9.

Sustained hemodynamic improvement is defined as persistent improvement of ABI-values with ≥ 0.10 as compared to baseline values or to an ABI ≥ 0.9 throughout follow-up without the need for repeated target lesion revascularization (TLR) in surviving patients (i.e. patients that died have to be censored in this analysis).³

Desirable for review of data quality is the declaration of mean and median ABI at all follow-up visits as compared to baseline.

In case ABI cannot be appropriately measured such as in patients with medial arterial calcification (e.g. diabetes mellitus or renal insufficiency), photoplethysmographic or oscillometric determination of toe pressure with the calculation of the toe-brachial index should be used.³, ⁵, ¹⁰

Mortality 

Causes of death associated with the endovascular procedure (procedure related mortality, i.e. mortality within 30 days post-procedure or mortality during a hospitalization>30 days due to the procedure) should be reported separately as well as overall mortality.²

Amputation 

Need for minor (below the ankle) and major (above the ankle) unplanned amputation have to be regarded as major outcome criteria in trials, but should be reported separately for patients with IC and chronic CLI.² Major amputation rates should be reported and specified as below-the-knee and above-the-knee amputations. Furthermore, planned and unplanned amputations should be reported separately.

Complications 

Complications should be reported according to the general clinical research guidelines and the applicable (local) laws. For this purpose, reference is made to the International Society for Standardization (ISO) 14155,¹⁹ the International Conference on Harmonisation-Good Clinical Practice (ICH-GCP) guidelines²⁰ and the Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) chapter §812.3.²¹

The primary mode of action of the investigational product as well as the region where the trial is performed will determine which regulations must be used. Additionally, combined products or non-medical devices such as cell therapy may require using a combination of these guidelines.

Any untoward occurrence in a subject should be differentiated as follows:

In case the investigational product is classified different than a medical device, other general definitions may be applicable (e.g. Suspected Unexpected Serious Adverse Reaction [SUSAR]).

An AE is defined as any untoward medical occurrence in a subject.

This definition, however, does not imply that there is a relationship between the adverse event and the device under investigation.

A SAE is an AE that

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

An adverse device defect is defined as any untoward and unintended response to a medical device. This definition includes any event resulting from insufficiencies or inadequacies in the instructions for use or the deployment of the device as well as any event that is a result of a user error.

A serious adverse device effect is defined as adverse device effect that has resulted in any of the consequences characteristic of a serious adverse event or that might have led to any of these consequences if suitable action had not been taken or intervention had not been made or if circumstances had been less opportune.

Any serious adverse effect on health or safety or any life-threatening problem or any life-threatening problem or death 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 or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety or welfare of subjects is defined as an unanticipated adverse device effect.

The MAE definition is different for each protocol and must be 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 a MAE or not. The CEC may define, prior to the start of the study, the type of events that will be reviewed and adjudicated.

All AEs and SAEs must appear in the final report. Information related to the adjudication of the events may be added. Reporting by the manufacturer/sponsor to the regulatory bodies must be performed according the specified national regulations.

The following Major Adverse Event definition is recommended for studies involving patients with peripheral vascular disease:

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

Next to the MAE, the reported (serious) adverse events should be classified and reported according to the following four complication categories: access site complications, vessel specific complications (treatment site including distal to the site), organ-specific complications, systemic complications (Table 2d).

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Morphologic Outcome 

We suggest replacing the term “patency” with “absence of binary restenosis”, which equals≥50% re-obstruction of the target lesion (Table 3). Moreover, cumulative rates of reocclusions (defined as complete occlusion of the initially treated target lesion).

Table 3. Morphologic outcome

•Cumulative rates of absence of binary restenosis (≥ 50% re-obstruction of the target lesion) and rates of reocclusions as assessed by: ■Intra-arterial angiography in at least two different projections (preferably with quantitative vessel analysis). ■IVUS measurements indicating≥50% diameter stenosis or ≥75% area stenosis can be used to determine restenosis. ■Duplex ultrasound (peak systolic velocity index greater than 2.4 at the target lesion). ■Magnetic resonance and computed tomography angiography (pending positive results from accuracy studies assessing their ability to quantify arterial obstructions as outlined above). •Repeated target lesion revascularization (TLR) rate. •Repeated target extremity revascularization (TER) rate. •Reporting of device-specific problems such as stent fractures. •Independent core laboratory analysis of arterial imaging is warranted.

We suggest that independent core laboratory analysis of angiographic and duplex ultrasound images be mandatory for assessment of new devices.

Intra-arterial angiography remains the current gold standard for depiction of lesions in peripheral arteries.⁵ Precise quantitative angiographic assessment of the target lesion with objective measures such as the percent diameter stenosis relative to the adjacent arterial segments is warranted.

Especially in trials comparatively reporting on different peripheral endovascular revascularization strategies (i.e. using stents or other devices aiming at the prevention of restenosis) angiographic analysis using quantitative vessel analysis software derived from the methods established for coronary artery analysis is desirable.²², ²³, ²⁴, ²⁵ However, we acknowledge that continued expansion of self-expandable stents might hamper comparison of immediate post-procedural results with follow-up imaging.

Moreover, intravascular ultrasound (IVUS) measurements indicating≥50% diameter stenosis or ≥75% area stenosis can be used to determine restenosis.

Due to the less invasive character of the examination along with ethical considerations regarding serial intra-arterial angiography for study purposes, we recognize duplex ultrasonography for detection of binary restenosis. Unfortunately, duplex ultrasonography can be associated with a considerable inter- and intraobserver variability, especially in vessels as heterogeneous as the iliac and below-the-knee arteries,²⁶, ²⁷ and, as opposed to angiography, does not help in precisely quantifying the percentage of stenosis in lower limb arteries.²⁸ Therefore, inter- and intra-observer variability of the performing ultrasound laboratory and core laboratory assessment should be included in the report. For uniform reporting standards, we suggest to define binary restenosis on duplex ultrasonography by a peak systolic velocity ratio greater than 2.4 at the target lesion as initially proposed by Ranke.¹⁸ Moreover, we recommend the use of rulers to document the exact distance of the lesion from anatomical landmarks (such as the patella or the iliac or femoral bifurcation) at baseline and during follow-up visits. Formal instruction by the independent core lab to the sites on the annotation of duplex ultrasound images to insure accurate image location to target lesion must be routine and clearly described.

Magnetic resonance and computed tomography angiography might become valuable tools in morphological follow-up after endovascular interventions. However, dedicated studies assessing their accuracy are currently lacking.

If non-angiographic modalities are used for follow-up, they must be compared to the same modality over time.

Since the terms primary patency, primary assisted patency, and secondary patency are mainly used in surgical trials¹⁰ and their use may be confusing after endovascular therapy, we propose, in accordance with coronary trials, the following terminology to describe need for re-interventions: Rates of repeated target lesion revascularization (TLR) should be reported in surviving patients with preserved limb to express the frequency of the need for repeated procedures (endovascular or surgical) due to a problem arising from the lesion (+1cm proximally and distally to include edge phenomena) initially treated. Repeated target extremity revascularization (TER) should be reported in surviving patients with preserved limb to express the frequency of the need for repeated procedures (endovascular or surgical) due to a problem arising remote from the lesion initially treated. A subtraction of TLR from TER rates yields the rate of revascularizations performed due to progression of atherosclerosis.

Device-specific problems such as stent fractures should be reported according to specific standards.²⁹

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Statistical Analysis 

Number of patients lost to follow-up should not exceed 5% at 12 months and reasons for loss of follow-up should be noted.

Procedural success should be reported both on an intention-to-treat and on per-protocol analysis.

A prospective randomized controlled study design should be preferred to reliably assess the efficacy of endovascular revascularization.

Treatment outcomes should be based on the intent to treat and must include all patients who consent to undergo the procedure.

Except for analysis of technical success, periprocedural complications, and quantitative angiographic outcomes, the above-mentioned endpoints should be calculated using cumulative analyses (i.e. according to the life-table method³⁰) or according to the method proposed by Kaplan-Meier.³¹ Thus, patients who have reached specific clinical endpoints (e.g. repeated TLR) should be uncensored within this cumulative analysis and also be excluded from further follow-up assessments such as ABI comparisons or descriptions of clinical stage beyond the time of uncensoring. Dead patients should be censored on the day between the time point when they were last examined and the actual date of death.

Patients undergoing further revascularizations outside the initially treated target lesion (repeated TER) should not be uncensored since this represents a progression of atherosclerosis rather than a failure of the treatment of the initially treated lesion.

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Conclusions 

With the present consensus document the DEFINE group aimed to establish definitions as a point of reference for future clinical trials. Particular care was taken to define clinical outcomes from a patient's perspective. Importantly, clinical outcome definitions can be equally applied to future trials comparing endovascular and open surgical revascularization for chronic lower limb ischemia. These definitions represent mandatory requirements to obtain comparability of studies dealing with endovascular therapy of peripheral arteries to further elucidate and prove long-term credibility of this method. Adherence to these definitions is recommended for future publications.

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Acknowledgement 

We kindly acknowledge David Buckles, PhD, Chief of Peripheral Vascular Devices Branch and Bram Zuckerman, MD, Director, Division of Cardiovascular Devices, Food and Drug Administration, for their help and reflections during the evolution of specific definitions contained in this manuscript.

Furthermore, we kindly acknowledge Antonie Jäger, CongO Congress Organisation and more GmbH, Munich, Germany, for her help in manuscript preparation, organization of the meetings and overall project management of the DEFINE project.

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Disclosures 

Nicolas Diehm: none.

Peter Pattynama: Consultant and Research Support: Cook Medical, Atrium, Edwards Lifesciences.

Alberto Cremonesi: Consultant and research support: Boston Scientific, Abbott Vascular, Invatec.

Gary Becker: none. L. Nelson Hopkins: Consultant and research support: Cordis (Johnson & Johnson), Boston Scientific, Micrus Inc.; Significant financial interest: Boston Scientific, Micrus Inc., Access Closure, Square One.

Michael Jaff: Consultant: Abbott Vascular, Cordis (Johnson & Johnson), Boston Scientific, Pathway Medical, X-Tent, Paragon IP, Harvard Clinical Research Institute, Bacchus Vascular; Significant financial interest: Access closure, Square One, Vascular Therapies, Icon Interventional, Setagon.

Felix Mahler: none.

Aly Talen: investor of genae associates NV.

John Cardella: none.

Stephen Ramee: Consultant and/or Stockholder of Boston Scientific, Medtronic, Cordis (Johnson & Johnson), Access Closure, Square One, I-Therapeutics, Hansen Medical.

Marc van Sambeek: Abbott: Consultant: Abbott, Medtronic, Cardialysis, Sanofi.

Frank Vermassen: Consultant and/or research support: Abbott Vascular, Medtronic, Cordis (Johnson & Johnson), Sanofi.

Giancarlo Biamino: Consultant: Edwards Lifesciences, Igaki, Cordis (Johnson & Johnson), Invatec, Spectranetics.

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Sources of funding 

Unrestricted grants were provided to the DEFINE to cover costs of travel, meeting rooms, and lodging for academic attendees at the Washington, DC, and New York, NY, meetings by Abbott Vascular, Biotronik GmbH, Boston Scientific, Cook Corporation, Cordis (a Johnson & Johnson company), Datascope Corporation, Edwards Lifesciences, Ev3 GmbH, Invatec srl, Medtronic Europe. Contributing physicians did not receive honoraria for participation in the DEFINE project.

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Author contributions 

We hereby declare that all authors listed on the manuscript actively contributed to the manuscript during multiple phone conferences and two meetings as well as in scientific writing and have seen and approved the final version.

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Appendix. Clinical categories of chronic limb ischemia according to Rutherford ³ 

Grade	Category	Clinical description	Objective criteria
0	0	Asymptomatic - no hemodynamically significant occlusive disease	Normal treadmill or reactive hyperemia test
	1	Mild claudication	Completes treadmill exerciseb; AP after exercise >50mm Hg but at least 20mm Hg lower than resting value
I	2	Moderate claudication	Between categories 1 and 3
	3	Severe claudication	Cannot complete standard treadmill exerciseband AP after exercise <50mm Hg
IIa	4	Ischemic rest pain	Resting AP <40mm Hg, flat or barely pulsatile ankle or metatarsal PVR; TP <30mm Hg
IIIa	5	Minor tissue loss - nonhealing ulcer, focal gangrene with diffuse pedal ischemia	Resting AP <60mm Hg, ankle or metatarsal PVR flat or barely pulsatile; TP <40mm Hg
	6	Major tissue loss - extending above TM level, functional foot no longer salvageable	Same as category 5

AP, Ankle pressure; PVR, pulse volume recording; TP, toe pressure; TM, transmetatarsal.

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References 

1. Anderson PL, Gelijns A, Moskowitz A, Arons R, Gupta L, Weinberg A, et al. Understanding trends in inpatient surgical volume: vascular interventions, 1980–2000. J Vasc Surg. 2004;39:1200–1208
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (219 KB)
   • CrossRef
2. Diehm N, Baumgartner I, Jaff M, Do DD, Minar E, Schmidli J, et al. A call for uniform reporting standards in studies assessing endovascular treatment for chronic ischaemia of lower limb arteries. Eur Heart J. 2007;28:798–805
   • View In Article
   • MEDLINE
   • CrossRef
3. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg. 1997;26:517–538
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (1996 KB)
   • CrossRef
4. Sacks D, Marinelli DL, Martin LG, Spies JB. Reporting standards for clinical evaluation of new peripheral arterial revascularization devices. J Vasc Interv Radiol. 2003;14:S395–S404
   • View In Article
   • Full Text
   • Full-Text PDF (103 KB)
   • CrossRef
5. Hirsch AT, Haskal ZJ, Hertzer NR, Bakal CW, Creager MA, Halperin JL, et al. ACC/AHA 2005 guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): executive summary a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease) endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. J Am Coll Cardiol. 2006;47:1239–1312
   • View In Article
   • Full Text
   • Full-Text PDF (1819 KB)
   • CrossRef
6. Gardner AW, Skinner JS, Cantwell BW, Smith LK. Progressive vs single-stage treadmill tests for evaluation of claudication. Med Sci Sports Exerc. 1991;23:402–408
   • View In Article
   • MEDLINE
7. EuroQol–a new facility for the measurement of health-related quality of life. The EuroQol Group. Health Policy. 1990;16:199–208
   • View In Article
   • MEDLINE
   • CrossRef
8. Regensteiner JG, Steiner JF, Panzer RJ, Hiatt WR. Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vasc Med Biol. 1990;2:142–152
   • View In Article
9. Greenland P, Abrams J, Aurigemma GP, Bond MG, Clark LT, Criqui MH, et al. Prevention Conference V: beyond secondary prevention: identifying the high-risk patient for primary prevention: noninvasive tests of atherosclerotic burden: Writing Group III. Circulation. 2000;101:E16–E22
   • View In Article
10. Dormandy JA, Rutherford RB. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Concensus (TASC). J Vasc Surg. 2000;31:S1–S296
    • View In Article
    • MEDLINE
    • CrossRef
11. The Seventh Report of the Joint National Committee on Prevention, Detection, and Treatment of High Blood Pressure: US Department of Health and Human Sciences; 2004.
    • View In Article
12. Grundy SM, Cleeman JI, Merz CN, Brewer HB, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239
    • View In Article
    • CrossRef
13. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 1997;20:1183–1197
    • View In Article
    • MEDLINE
14. Lee TH, Marcantonio ER, Mangione CM, Thomas EJ, Polanczyk CA, Cook EF, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation. 1999;100:1043–1049
    • View In Article
15. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41
    • View In Article
    • MEDLINE
    • CrossRef
16. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33(Suppl. 1):S1–S75
    • View In Article
    • Full Text
    • Full-Text PDF (1906 KB)
    • CrossRef
17. Schillinger M, Diehm N, Baumgartner I, Minar E. TASC II section F on revascularization: commentary from an interventionist's point of view. J Endovasc Ther. 2007;14:734–742
    • View In Article
    • CrossRef
18. Ranke C, Hendrickx P, Roth U, Brassel F, Creutzig A, Alexander K. Color and conventional image-directed Doppler ultrasonography: accuracy and sources of error in quantitative blood flow measurements. J Clin Ultrasound. 1992;20:187–193
    • View In Article
    • MEDLINE
    • CrossRef
19. International Standard ISO 14155, part 1 & 2-clinical investigations of medical devices for human subjects.
    • View In Article
20. ICH Topic E6, Guideline for Good Clinical Practice.
    • View In Article
21. Code of federal regulations, CRF 21, part 812-investigational device exemptions.
    • View In Article
22. Beregi JP, Martin-Teule C, Trogrlic S, Meunier JC, Crochet D. Quantitative angiography: update for peripheral vascular applications. J Radiol. 1999;80:835–841
    • View In Article
    • MEDLINE
23. Duda SH, Pusich B, Richter G, Landwehr P, Oliva VL, Tielbeek A, et al. Sirolimus-eluting stents for the treatment of obstructive superficial femoral artery disease: six-month results. Circulation. 2002;106:1505–1509
    • View In Article
    • CrossRef
24. Duda SH, Bosiers M, Lammer J, Scheinert D, Zeller T, Tielbeek A, et al. Sirolimus-eluting versus bare nitinol stent for obstructive superficial femoral artery disease: the SIROCCO II trial. J Vasc Interv Radiol. 2005;16:331–338
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (251 KB)
    • CrossRef
25. Reiber J, Koning G, Tuinenburg J, Lansky A, Goedhart B. Quantitative coronary arteriography. In:  Oudkerk M editors. Coronary radiology. Berlin: Springer; 2004;p. 41–58
    • View In Article
26. Koelemay MJ, Legemate DA, van Gurp JA, de Vos H, Balm R, Jacobs MJ. Interobserver variation of colour duplex scanning of the popliteal,tibial and pedal arteries. Eur J Vasc Endovasc Surg. 2001;21:160–164
    • View In Article
    • Abstract
    • Full-Text PDF (79 KB)
    • CrossRef
27. Hingorani A, Ascher E, Markevich N, Kallakuri S, Hou A, Schutzer R, et al. Magnetic resonance angiography versus duplex arteriography in patients undergoing lower extremity revascularization: which is the best replacement for contrast arteriography?. J Vasc Surg. 2004;39:717–722
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (232 KB)
    • CrossRef
28. Schlager O, Francesconi M, Haumer M, Dick P, Sabeti S, Amighi J, et al. Duplex sonography versus angiography for assessment of femoropopliteal arterial disease in a “real-world” setting. J Endovasc Ther. 2007;14:452–459
    • View In Article
    • CrossRef
29. Jaff M, Dake M, Pompa J, Ansel G, Yoder T. Standardized evaluation and reporting of stent fractures in clinical trials of noncoronary devices. Catheter Cardiovasc Interv. 2007;70:460–462
    • View In Article
    • CrossRef
30. Berkson J, Gage RP. Calculation of survival rates for cancer. Mayo Clin Proc. 1950;25:270–286
    • View In Article
31. Kaplan ML, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;457–481
    • View In Article