Suggested objective performance goals and clinical trial design for evaluating catheter-based treatment of critical limb ischemia

Article Outline

• Abstract
• Methods
  • Review of literature and database compilation
  • Definition of critical limb ischemia (CLI) and study population
  • Safety and efficacy measures
    • Definition of events and composite endpoints
    • Safety
    • Efficacy
  • Risk stratification variables
    • Patient-level risk factors
    • Anatomic level of disease
    • Conduit quality/availablility
  • Statistical methods and criteria for determination of suggested OPG
• Results
  • Data quality and heterogeneity between trials
  • Safety outcome and suggested OPGs
  • Efficacy measures and suggested OPGs
  • Risk stratified outcomes and suggested OPGs for defined subgroups
  • Reintervention frequency
• Discussion
  • Vein bypass surgery as the relevant standard
  • Important limitations
  • Efficacy measures in CLI and non-inferiority
  • Comparison to available endovascular data
  • Regulatory environment for CLI and appropriate role for OPGs
• Author contributions
• Appendix (online only). Suggested critical elements of clinical trial design in CLI
  • A. Inclusion/Exclusion Criteria
  • B. Risk factor profile
  • C. Suggested assessments
  • D. Suggested definition of hemodynamic failure
  • E. Endpoints and reporting
  • F. Wound healing
• References
• Copyright

Objective

To develop a set of suggested objective performance goals (OPG) for evaluating new catheter-based treatments in critical limb ischemia (CLI), based on evidence from historical controls.

Methods

Randomized, controlled trials of surgical, endovascular, and pharmacologic/biologic treatments for CLI were reviewed according to specified criteria regarding study population and data quality. Line-item data were obtained for selected studies from the sponsor/funding agency. A set of specific outcome measures was defined in accordance with the treatment goals for the CLI population. Risk factors were examined for their influence on key endpoints, and models of stratification based on specific clinical and anatomic variables developed. Sample size estimates were made for single-arm trial designs based on comparison to the suggested OPG.

Results

Bypass with autogenous vein was considered the established standard, and data compiled from three individual randomized, controlled trials (N = 838) was analyzed. The primary efficacy endpoint was defined as perioperative (30-day) death or any major adverse limb event (amputation or major reintervention) occurring within one year. Results of open surgery controls demonstrated freedom from the primary endpoint in 76.9% (95% confidence interval [CI] 74.0%-79.9%) of patients at one year, with amputation-free survival (AFS) of 76.5% (95% CI 73.7%-79.5). An additional 3% non-inferiority margin was suggested in generating OPG for catheter-based therapies. Defined clinical (age > 80 years and tissue loss) and anatomic (infra-popliteal anatomy or lack of good quality saphenous vein) risk subgroups provided significantly different point estimates and OPG threshold values.

Conclusions

For new catheter-based therapies in CLI, OPGs offer a feasible approach for pre-market evaluation using non-randomized trial designs. Such studies should incorporate risk stratification in design and reporting as the CLI population is heterogeneous with respect to baseline variables and expected outcomes. Guidelines for CLI trial design to address consistency in study cohorts, methods of assessment, and endpoint definitions are provided.

Critical limb ischemia (CLI) caused by infrainguinal atherosclerosis is a substantial source of death and disability. One year mortality ranges from 10% to 40%, and without revascularization up to 40% will suffer limb loss within six months. Rates of major amputation in Western countries range from 120 to 500 per million per year.¹ The global epidemic of diabetes, coupled with smoking, diet, and lifestyle trends, insures that the burden of CLI will continue to grow. Unfortunately, no pharmacologic or biologic therapy has achieved broad success in reversing these arterial obstructions, and in the absence of successful revascularization, both limb loss and early mortality rates are substantial. Limb dysfunction, pain, ulceration, and advanced comorbidities render this an extremely vulnerable population in considering the safety and effectiveness of new treatments.

The primacy of surgical bypass for relieving leg ischemia has recently been challenged by catheter-based revascularization techniques. Endovascular techniques have the potential to achieve limb salvage with less procedural morbidity and mortality. However, multiple challenges arise when attempting to critically evaluate the safety and efficacy of catheter-based devices for treatment of CLI:

Randomized, controlled trials (RCTs) provide the best scientific evidence for medical decision making. They also constitute the highest standard by which regulatory bodies such as the U.S. Food and Drug Administration (FDA) evaluate the entry of new drugs, devices, or other therapeutics into the marketplace. However, such trials pose significant ethical, economic, and scientific challenges for the stakeholders – which include industry, physicians, and the public at large. Furthermore, RCTs can take considerable time to complete, and rapid paced changes in technology may reduce the meaningfulness of their findings. Finally, some new products constitute minor modifications of others already available, or may be considered to pose minimal risk to human health. In recognition of these and other issues, multiple pathways exist for the regulatory approval of therapeutics by FDA, including the 510(k) pathway for Class II devices. For Class III devices, Pre-Market Approval (PMA) requires a safety and effectiveness evaluation be performed (21 CFR 860.7). The FDA Modernization Act of 1997 provided a “least burdensome” mandate for the FDA in its evaluation of medical devices. Accordingly, FDA has determined that the use of well documented historical controls may constitute an alternative to RCTs in specific circumstances.² In the cardiovascular arena, heart valve prostheses are a prominent example of a mature technology with large population experience.³ In such cases, the analysis of validated datasets may be used to generate Objective Performance Criteria (OPC) against which new products may be compared in single-arm trials. In less mature technologies, where historical controls are limited in size, scope, and quality, Objective Performance Goals (OPGs) may be suggested and developed over time into OPC. Recently, OPGs have been suggested in the area of femoropopliteal nitinol stents, for example.⁴, ⁵ The accompanying perspective by Geraghty et al⁶ summarizes the regulatory framework and potential relevance of an OPG standard for device development in CLI.

Due to the challenges noted related to the state of existing evidence, OPGs for catheter-based CLI intervention have previously not been available. We propose the use of risk-adjusted surgical controls to generate OPG/OPC for endovascular devices seeking pre-market approval for the treatment of CLI. Recent availability of validated, multicenter trial datasets of open bypass surgery makes this a feasible exercise. Our aim is to suggest a set of standardized measures for the evaluation of proposed CLI devices via single-armed prospective data collection, thus facilitating a timely and cost-efficient premarket assessment of such devices. It should be emphasized that well conducted RCTs remain the standard for evidence-based medical practice, and OPGs are not to be confused with practice guidelines. However an absolute requirement for RCT-level evidence in the CLI population may unduly hinder innovation in an area where significant unmet clinical needs exist. Suggestions for the design and conduct of such trials are included in this manuscript. Adoption of a common trial design for premarket CLI device evaluation will allow physicians to effectively partner with industry in bringing safe and effective treatments to bear on this debilitating disease.

Back to Article Outline

Methods 

Review of literature and database compilation 

Randomized controlled trials of surgical, endovascular, biologic, and pharmacologic treatment of CLI from 1990 to 2007 were reviewed. Autologous vein was considered the preferred conduit for surgical revascularization. Control arms from gene therapy and medical therapy trials were sought to examine the natural history of non-revascularized CLI. Independently adjudicated data with clinical follow-up to a minimum of one year was sought. We identified five multicenter RCTs that met our criteria: Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III),⁷ Circulase I and II,⁸, ⁹ Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL),¹⁰, ¹¹ and The Study to Assess the Safety of Intramuscular Injection if Hepatocyte Growth Factor Plasmid to Improve Limb Perfusion in Patients with Critical Limb Ischemia (HGF-STAT) trials.¹², ¹³ Following the establishment of data sharing agreements between trial investigators/sponsors and the Society for Vascular Surgery, de-identified line item data were compiled in a central database. After consideration of the quality and quantity of available data from the natural history cohorts, which was limited and highly selected, it was determined that this group could not be employed as a meaningful comparator in any of the OPG. We therefore focused our analysis on the expected outcomes for open bypass surgery with autogenous vein. Data sources for the OPG control group are summarized in Table I.

Table I. Dataset sources for the open surgery control group (N = 838)

BASIL, Bypass versus Angioplasty in Severe Ischemia of the Leg; ESRD, end-stage renal disease; PREVENT III, Project of Ex-Vivo vein graft Engineering via Transfection III.

Definition of critical limb ischemia (CLI) and study population 

CLI is defined as ischemic rest pain or tissue loss, consistent with Fontaine Stages III-IV and Rutherford Classes 4-6. Documentation of severely compromised hemodynamics (ankle <50 mm Hg, toe <30 mm Hg, TcPO2 <30 mm Hg) verified inclusion of patients with rest pain. For patients with tissue loss, documentation of severely compromised hemodynamics, absence of pedal pulses, or both was sought.

We restricted the analysis to infrainguinal disease, and to open surgical bypass performed with autogenous vein, considered as the standard of care for CLI. Patients who received prosthetic grafts or test drugs, in addition to those with end-stage renal disease (CKD 5), were excluded from analysis. In all trials, a per-protocol approach was used in aggregating data; simple randomization to a treatment group was not sufficient to gain access to the study population.

Safety and efficacy measures 

We defined a set of outcome variables (Table II) as the basis for our safety and efficacy targets. Death was used in several of the composite measures as outlined below. Amputation was defined by major index limb loss at or proximal to the transtibial level. Major adverse cardiovascular event (MACE) included myocardial infarction and stroke in addition to death from any cause. Reintervention was defined as any repeat vascular procedure in the index limb. We subdivided reinterventions into major and minor categories to reflect the magnitude of the procedure and its presumed impact on the patient. Major reinterventions included the creation of a new surgical bypass graft, the use of thrombectomy or thrombolysis (ie, procedures done in the setting of lost primary-assisted patency), or a major surgical graft revision such as a jump graft or an interposition graft. Minor reinterventions included endovascular procedures (PTA, atherectomy, stenting) without thrombectomy/thrombolysis, and minor surgical revisions (patch angioplasty). Based on this subdivision, we defined a major adverse limb event as the composite of either amputation or major reintervention. We combined this limb-specific endpoint with perioperative (30 day) mortality, to generate the primary efficacy endpoint of perioperative death or any major adverse limb event. The endpoint reintervention or amputation captured the first vascular event in the limb while censoring death.

Table II. Endpoint definitions

MI, Myocardial infarction.

While reintervention and amputation are clinical events indicative of revascularization failure, the decision to perform reintervention is driven by the approach to surveillance and by objective findings of hemodynamic failure. These events are thus only indirectly linked to the sustained effectiveness of the original procedure. Differences in criteria for reintervention can greatly influence clinical endpoints while masking important differences in therapeutic benefit. Conversely, long term hemodynamic success may not be required in all patients to achieve meaningful clinical benefit in CLI. In either case, it is considered that some measure of sustained hemodynamic improvement is intrinsically important in the evaluation of limb revascularization procedures. For open surgery, vein graft surveillance is well established, and its incorporation into standard care and RCT designs such as PREVENT III directly influences both the timing and occurrence of reinterventions, many of which are prophylactic and designed to maintain long term secondary graft patency. Unfortunately, there are no accepted norms for surveillance or reintervention for catheter-based treatments. In the Appendix (online only), we suggest an approach for measuring hemodynamic success in CLI trials of endovascular devices. For the purposes of generating an OPG incorporating sustained hemodynamic benefit, we defined stenosis for the open surgery controls based on ultrasound graft surveillance criteria, which were available from PREVENT III.¹⁴ This resulted in a composite endpoint that incorporated the first occurrence of reintervention, amputation, or stenosis.

We considered 30 days as the standard temporal window for evaluation of post-procedural adverse events. Key safety measures included MACE, major adverse limb event, and amputation.

We considered one year as an appropriate minimal exposure time for assessing therapeutic efficacy in CLI. The key efficacy endpoints should reflect the treatment goal of survival with a functional limb. However, the need for reinterventions and the magnitude of these reinterventions have a clear impact on patient quality of life, and these were considered by the incorporation of reintervention into several endpoints, and by count of total number of reinterventions over the year. Of these measures, we considered perioperative death or any major adverse limb event to be primary and amputation-free survival (AFS) as the key secondary endpoint, which together best captured the clinical efficacy of the initial procedure for treatment of CLI. Hemodynamic success is also a critical and objective measure of therapeutic gain for any revascularization procedure, and is best reflected in the surgical control data by reintervention, amputation, or stenosis. Limb salvage and survival should also be reported independently. Performance goals for all six efficacy measures (perioperative death or any major adverse limb event, AFS, reintervention/amputation/stenosis, reintervention/amputation, amputation, mortality) were developed.

Risk stratification variables 

The CLI population encompasses a broad spectrum of disease severity, anatomic determinants, and comorbidities that influence clinical decision making, and therefore pre-trial risk stratification should be a consideration in study designs and outcome comparisons. We considered stratification of cohorts based on key variables that would be available at trial entry, and suitable (from an ethical, clinical, and practical perspective) for defining either stratification, exclusion, or focused design of a clinical trial. Stratification of key predictive variables should be incorporated into trial design and each subgroup powered adequately. It was assumed that a two-tiered risk cohort approach would be most practical for design and execution of studies. Modeling of outcomes was performed based on the primary and key secondary efficacy endpoints at one year. Potential predictive categorical variables were assessed with Kaplan-Meier plots and log-rank tests to determine if the risk classification resulted in statistically meaningful divergence of outcomes. Continuous predictive variables were originally assessed with Cox proportional hazards regression then subsequently reduced to binary variables based on clinically significant thresholds where appropriate or (in the case of age) via a series of analyses performed to find a breakpoint of maximum effect. For this decision, data was repeatedly resampled and subsets reassessed for maximum discrimination between primary and key secondary efficacy endpoints.

Demographic, comorbidity, and disease severity variables from the individual trial databases were examined and variables mapped by common definitions or groupings. Variables selected for analysis were age, gender, race, diabetes, hypertension, coronary artery disease, hypercholesterolemia, chronic renal disease (CKD class), smoking (ever/never), and CLI criterion (rest pain vs tissue loss). Comparison of the individual study populations across these key variables is summarized in Table III. Sensitivity analysis of age data was performed to define an optimal threshold for a two-tiered model. This resulted in the selection of 80 years of age as a meaningful breakpoint. Results demonstrated that the two most potent patient-level predictors at one year were age >80 and presence of tissue loss (TL) at study entry (Table IV). The combination of these two variables was assessed in a number of ways, in a univariate fashion as shown in Fig 1, as a four-level categorical variable, and in a multivariate proportional hazards model (not shown). This resulted in the designation of patients with both age >80 and TL as a “Clinical High Risk” subgroup (N = 136).

Table III. Covariate distribution (%) among contributing trial sources

	PREVENT III	CIRCULASE	BASIL	P value
Clinical
Age ≥ 80	17.9	17.7	25.7	.0889
Male	64.8	78.8	65.5	.0365
AA race#	17.9	9.4	0	<.0001
Diabetes	62.3	50.6	39.2	<.0001
Smoking	75.5	87.1	82.4	.0195
Hypercholesterolemia	46.0	62.4	62.1	.0005
Hypertension	81.0	75.3	58.1	<.0001
TL†	74.1	69.4	75.0	.6145
Age ≥ 80 + TL	15.4	12.9	21.6	.1244
Anatomic
Infrapopliteal	66.6	54.1	37.8	<.0001
Conduit
Poor quality vein⁎	26.9	n/a	n/a	n/a

Table IV. Univariate analysis of risk factors

Risk factor	Mortality			MALE+POD			AFS
	+	−	P	+	−	P	+	−	P
Clinical
Age ≥ 80	71.8	89.0	<.0001	70.0	78.5	.0324	62.9	79.7	<.0001
Male	85.3	86.4	.7886	76.7	72.4	.8327	74.9	79.6	.1658
AA race	87.8	85.3	.6276	65.5	74.3	.1641	74.0	76.9	.3810
Diabetes	85.7	85.6	.9386	75.2	79.1	.0475	74.7	78.8	.1596
Smoking	85.4	81.9	.7214	76.9	77.0	.7057	76.1	78.1	.5314
Hypercholesterolemia	88.3	84.2	.0560	76.6	77.8	.6020	79.6	75.1	.1245
HTN	86.7	82.5	.1277	76.5	78.3	.4119	77.2	74.4	.3493
TL	84.1	90.3	.0318	76.0	79.5	.1189	72.8	87.0	<.0001
Age ≥ 80 + TL	70.3	88.7	<.0001	69.1	78.3	.0344	60.5	79.6	<.0001
Anatomic
Infra-popliteal	85.9	85.3	.7818	74.0	81.3	.0041	74.4	79.8	.0718
Conduit
Poor quality vein	86.3	87.7	.5902	69.2	79.0	.0031	76.4	79.3	.2335

AA, African-American; AFS, amputation-free survival; HTN, hypertension; MALE, major adverse limb event; POD, perioperative death; TL, tissue loss.

Percents are Kaplan-Meier survival estimates at one year (freedom from event).

Comparisons are between those with (+) versus without (−) the given risk factor.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 1. 

  Primary (Panel A: Peri-operative death or any Major Adverse Limb Event [MALE+POD]) and Key Secondary (Panel B: Amputation Free Survival [AFS]) endpoints from the surgical control dataset, dichotomized by clinical risk (high risk defined as being both age 80 or older and having tissue loss). N = 136 for high risk and 702 for low risk.

The results of endovascular interventions have been closely linked to anatomic burden of disease using various grading schemes such as the TASC classification. By contrast, outcomes of lower extremity bypass with autogenous vein have not demonstrated a clear relationship to arterial anatomy, although various studies have suggested that graft length and outflow may have influence. Data available from PREVENT and BASIL specified the location of anastomotic sites; anatomic classification based on preoperative angiographic data was not available. Bypass grafts were categorized based on the level of the distal anastomosis into one of two groups; infrapopliteal (anastomosis to a tibial or pedal vessel) or above (anastomosis to popliteal or superficial femoral artery at any level). Stratified outcomes based on the anatomic level are shown in Fig 2. Infrapopliteal anatomy was designated as an “Anatomic High Risk” subgroup (N = 505).

• 
  • View Large Image
  • Download to PowerPoint

• Fig 2. 

  Primary (Panel A: Peri-operative death or any Major Adverse Limb Event [MALE+POD]) and Key Secondary (Panel B: Amputation Free Survival [AFS]) endpoints from the surgical control dataset, dichotomized by anatomic risk (infra-popliteal vs otherwise). N = 505 for infra-popliteal target and 333 for more proximal vessel.

The most potent factor influencing the long term outcomes of autogenous vein bypass is conduit (vein) quality. Specifically, the ability to complete a graft procedure using a single segment of great saphenous vein (SSGSV) results in superior expected outcomes in comparison to grafts comprised of ectopic veins either as single-segment or spliced constructs.¹⁵ Therefore, the potential advantages of an endovascular approach for an individual patient may be greatly influenced by the availability of adequate GSV. While it is understood that this determination may not be completely made until the time of surgery, we rationalized that conduit availability may be categorized based on clinical evaluation and ultrasound vein mapping studies in a significant proportion of patients. We therefore segregated the surgical bypass data based on graft composition between those composed of a single GSV segment of diameter ≥ 3 mm versus other venous conduits (Fig 3). The latter group was designated as a “Conduit High Risk” subgroup (N = 163).

• 
  • View Large Image
  • Download to PowerPoint

• Fig 3. 

  Primary (Panel A: Peri-operative death or any Major Adverse Limb Event [MALE+POD]) and Key Secondary (Panel B: Amputation Free Survival [AFS]) endpoints from the surgical control dataset, dichotomized by conduit risk (high risk defined by use of non-single segment great saphenous vein [SSGSV] or vein diameter < 3mm). N = 163 for high risk grafts and 442 for low risk grafts.

Statistical methods and criteria for determination of suggested OPG 

Differences in frequencies of categorical variables between contributing datasets were assessed with Chi-square tests. Risk stratified subgroups were determined via assessment of potential covariates with univariate Kaplan-Meier plots and log-rank tests.

After review of the pooled dataset, the Working Group used a consensus approach to develop the suggested OPGs. Given that catheter-based treatments offer a less invasive approach in comparison to open surgery, we felt that a non-inferiority comparison was most relevant for the OPG. For the key safety outcomes (MACE, major adverse limb event, and amputation within 30 days), the upper bound of the 95% confidence interval (UCL) for the control group defined the maximum allowable event rate (OPG) for a less invasive treatment to be considered not inferior. No additional margin was incorporated for the safety OPG, as open surgery is considered more invasive with inherently greater procedural morbidity. Therefore, the upper bound of confidence (UCL) for safety outcomes for the test treatment must be equal to or less than the safety OPG (Table Va).

Table Va. Summary of safety outcomes for overall CLI cohort

Outcome	30 day events (%; 95% CI)	Maximum allowable events (trial N = 392)	Safety OPG
MACE	6.2%(4.7-8.1)	20(5.1%,3.1-7.8%)	8%
• Death	2.7%
• MI	3.1%
• CVA	1.0%
MALE	6.1%(4.6-7.9)	18(4.6%,2.7-7.2)	8%
Amputation	1.9%(1.1-3.1)	5(1.3%,0.4-3.0)	3%

CVA, Cerebrovascular accident; MACE, major adverse cardiovascular event; MI, myocardial infarction.

Maximal events calculated based on trial design using sample size of 392 as calculated from Table Vb. The upper bound of the 95% Confidence Interval must be ≤ the OPG.

Trial design based on these OPG should be primarily driven by the key CLI efficacy endpoints. Non-inferiority for the test therapy was defined as having an observed event rate within 3% (added margin) of the lower confidence limit (LCL) for the control group. The OPGs were set to include this additional margin, so that the LCL for observed events in the test group should meet or exceed each OPG as reported. The rationale for an additional margin is based on the presumed trade-off for a less invasive treatment. The 3% level was selected as an acceptable compromise between reduced clinical efficacy at one year, likely further decreases in long-term durability, and reasonable sample sizes for trial design.

We maintained the same 3% margin in setting the OPG for the infrapopliteal anatomy subgroup, which had a robust control dataset (N = 505). However, both the clinical high-risk and conduit high-risk categories had significantly smaller study populations reflected by wider confidence intervals. In addition, conduit quality was felt to be a unique risk factor affecting bypass graft performance only. Given these considerations, no additional buffer is suggested for the OPG in the clinical high-risk and conduit high-risk subgroups.

Suggested sample sizes were based on the primary efficacy endpoint of perioperative death or any major adverse limb event. These sizes were calculated via a one sample survival method assuming an α of 0.05 and 80% power, an exponential distribution, and an equivalent one-year event rate to the OPG sample. A 5% loss to follow-up was assumed, and an additional adjustment was made to account for mortality falling outside our endpoint definition (all deaths following the first 30 days).

Back to Article Outline

Results 

Data quality and heterogeneity between trials 

Line item data was incorporated into a combined open surgery dataset when all variables of interest could be ascertained. In some instances, minor covariate availability varied between trials; for example, race was not available for all observations in the BASIL trial while conduit quality and stenosis could only be assessed in PREVENT-III. The frequencies of clinical visits also differed from study to study leading to potential variation in determination of loss to follow-up. For a full comparison of covariate characteristics between component trials, please see Table III.

Safety outcome and suggested OPGs 

Safety outcomes for the open surgery control group are summarized in Table Va. Overall 30-day MACE was 6.2% (95% CI 4.7-8.1), major adverse limb events occurred in 6.1% (95% CI 4.6%-7.9%), and major amputation was 1.9% (95% CI 1.1%-3.1%). The OPG are therefore set at 8%, 8%, and 3% respectively. Based on a presumed sample size of 392 patients for an all-comers trial (see below), the maximum number of observable safety events is shown in the table. We suggest that all three of these safety endpoints should be met individually to achieve the OPG for a new CLI treatment.

Efficacy measures and suggested OPGs 

Summary of the one-year outcomes is presented in Table Vb, and Kaplan-Meier curves are illustrated in Fig 4 (online only), Fig 5 (online only), Fig 6 (online only), Fig 7 (online only). For the primary efficacy endpoint of perioperative death or any major adverse limb event, freedom from event in the control surgery group was 76.9% (95% CI 74.0%-79.9%) at one year. With the 3% non-inferiority margin subtracted from the LCL, the OPG for the primary endpoint is set at 71%. If the observed event rate in the proposed trial population was identical to that observed in the surgical controls, a sample size of 392 patients would be required to meet the OPG as defined.

Table Vb. Summary of efficacy outcomes (one year) for overall CLI cohort and suggested OPG for each endpoint

Outcome	Point (95% CI)	Efficacy OPG
MALE + POD	76.9%(74.0-79.9)	71%
AFS	76.5%(73.7-79.5)	71%
RAS	46.5%(42.3-51.2)	39%
RAO	61.3%(58.0-64.9)	55%
Limb salvage	88.9%(86.7-91.1)	84%
Survival	85.7%(83.3-88.1)	80%

AFS, Amputation-free survival; CI, confidence interval; CLI, critical limb ischemia; MALE, major adverse limb event; OPG, objective performance goals; POD, perioperative death; RAO, any reintervention or above ankle amputation of the index limb; RAS, any reintervention, above ankle amputation of the index limb, or stenosis.

Rates reported as proportion free from adverse event.

AFS for the combined surgical control population was 76.5% (95% confidence interval 73.7%-79.5%) at one year. Freedom from amputation or any reintervention was 61.3% (95% CI 58.0%-64.9%). Freedom from amputation, reintervention or stenosis was 46.5% (95% CI 42.3%-51.2%) at one year. Limb salvage was 88.9% (95% CI 86.7%-91.1%) and survival was 85.7% (95% CI 83.3%-88.1%). The respective OPG rates are listed in Table Vb. It is suggested that all six of these OPG be met by a candidate device/therapy tested via a single-arm trial design.

Risk stratified outcomes and suggested OPGs for defined subgroups 

Based on the clinical, anatomic, and conduit high-risk categories defined above, two level stratified trials or exclusive high-risk cohort designs may be considered. Univariate Kaplan-Meier analysis demonstrated significantly inferior outcomes in the clinical high-risk group for the primary and key secondary efficacy endpoints (Figs 1a and 1b), while anatomic and conduit high-risk subgroups performed significantly worse in the primary endpoint (Figs 2a and 3a). Safety and efficacy outcomes for each of these risk groupings are summarized in Table VIa, Table VIb, Table VIIa, Table VIIb, Table VIIIa, Table VIIIb. The format is identical to Table Va, Table Vb. The maximal number of safety events was calculated based on the sample size required to meet the primary endpoint OPG for the defined subgroup. All-comer CLI trials should report their outcomes data stratified by the clinical and anatomic risk groupings suggested above, to allow for meaningful comparisons to existing datasets.

Table VIa. Summary of safety outcomes for clinical high risk (age ≥ 80 and tissue loss) subgroup

Outcome	30 day events (%; 95% CI)	Maximum allowable events (Trial N = 264)	Safety OPG
MACE	11.8%(6.9-18.4)	36(13.6%,9.7-18.4)	18%
• Death	6.6%
• MI	5.2%
• CVA	2.2%
MALE	5.1%(2.1-10.3)	17(6.4%,3.8-10.1)	10%
Amputation	2.9%(0.8-7.4)	11(4.2%,2.1-7.3)	7%

CLI, Critical limb ischemia; CVA, cerebrovascular accident; MACE, major adverse cardiovascular event; MI, myocardial infarction; OPG, objective performance goals.

Table VIb. Summary of efficacy outcomes (one year) for clinical high risk (age ≥ 80 and tissue loss) subgroup and suggested OPG

Outcome	Point (95% CI)	Efficacy OPG
MALE+POD	69.1%(61.3-78.0)	61%
AFS	60.5%(52.7-69.4)	53%
RAS	40.4%(29.3-55.8)	29%
RAO	62.8%(54.3-72.6)	54%
Limb salvage	86.5%(80.2-93.2)	80%
Survival	70.3%(63.0-78.5)	63%

AFS, Amputation-free survival; CI, confidence interval; MALE, major adverse limb event; OPG, objective performance goals; POD, perioperative death; RAO, any reintervention or above ankle amputation of the index limb; RAS, any reintervention, above ankle amputation of the index limb, or stenosis.

Rates reported as proportion free from adverse event.

Table VIIa. Summary of safety outcomes for anatomic high risk (infra-popliteal) subgroup

Outcome	30 day events (%; 95% CI)	Maximum allowable events (Trial N = 317)	Safety OPG
MACE	7.3%(5.2-10.0)	21(6.6%,4.1-9.9)	10%
• Death	2.8%
• MI	4.2%
• CVA	1.2%
MALE	6.1%(4.2-8.6)	17(5.4%,3.2-8.4)	9%
Amputation	2.2%(1.1-3.9)	5(1.5%,0.5-3.6%)	4%

CVA, Cerebrovascular accident; MACE, major adverse cardiovascular event; MI, myocardial infarction; OPG, objective performance goals.

Table VIIb. Summary of efficacy outcomes (one year) for anatomic high risk (infra-popliteal) subgroup and suggested OPG

Outcome	Point (95% CI)	Efficacy OPG
MALE+POD	74.0%(70.2-78.1)	67%
AFS	74.4%(70.6-78.3)	68%
RAS	44.0%(38.8-49.8)	36%
RAO	58.3%(54.0-63.0)	51%
Limb salvage	86.6%(83.6-89.8)	81%
Survival	85.9%(82.9-89.0)	80%

AFS, Amputation-free survival; CI, confidence interval; MALE, major adverse limb event; OPG, objective performance goals; POD, perioperative death; RAO, any reintervention or above ankle amputation of the index limb; RAS, any reintervention, above ankle amputation of the index limb, or stenosis.

Rates reported as proportion free from adverse event.

Table VIIIa. Summary of safety outcomes for conduit high risk (non-SSGSV or diameter < 3 mm) subgroup

Outcome	30 day events (%; 95% CI)	Maximum allowable events (Trial N = 333)	Safety OPG
MACE	6.1%(3.0-11.0)	25(7.5%,4.9-10.9)	11%
• Death	1.8%
• MI	4.3%
• CVA	1.2%
MALE	9.2%(5.2-14.7)	36(10.8%,7.7-14.7)	15%
Amputation	3.1%(1.0-7.0)	14(4.2%,2.3-7.0)	7%

CVA, Cerebrovascular accident; MACE, major adverse cardiovascular event; MI, myocardial infarction; OPG, objective performance goals.

Table VIIIb. Summary of efficacy outcomes (one year) for conduit high risk (non-SSGSV or diameter < 3 mm) subgroup and suggested OPG

Outcome	Point (95% CI)	Efficacy OPG
MALE+POD	69.2%(62.3-76.9)	62%
AFS	76.4%(70.1-83.2)	70%
RAS	30.0%(23.1-39.1)	23%
RAO	46.3%(38.9-55.1)	39%
Limb salvage	87.5%(82.3-92.9)	82%
Survival	86.3%(81.2-91.8)	81%

AFS, Amputation-free survival; CI, confidence interval; MALE, major adverse limb event; OPG, objective performance goals; POD, perioperative death; RAO, any reintervention or above ankle amputation of the index limb; RAS, any reintervention, above ankle amputation of the index limb, or stenosis; SSGSV, single segment of great saphenous vein.

Rates reported as proportion free from adverse event.

Reintervention frequency 

Reintervention rate is reported as mean number of repeat vascular procedures over time in Table IX. These values are adjusted for the time a particular index limb remained at risk. This data is provided as a framework for comparison but is not suggested as an OPG standard at this time.

Table IX. Mean reinterventions per limb-year

Back to Article Outline

Discussion 

New and less-invasive therapies are needed to meet the growing world-wide burden of CLI in a highly vulnerable population with advanced cardiovascular disease. Surgical bypass with autogenous vein remains the gold standard of revascularization for patients who are suitable candidates. The patient and limb-level outcomes for CLI are highly dependent on baseline risk factor distribution, which renders meaningful comparisons of non-randomized data prone to error due to mismatched populations. Risk stratification is paramount for data reporting and for appropriate design of clinical trials in CLI.

Vein bypass surgery as the relevant standard 

What is the optimal control group for comparing the outcomes of a new catheter-based therapy in CLI? For patients considered suitable for attempted open bypass, the primacy of vein grafting seems well established in the literature, though this concept has recently been challenged. The BASIL trial¹¹ randomized patients to a bypass-first versus angioplasty-first strategy, and demonstrated no meaningful clinical difference within the first year, although improved outcomes for surgery-first were evident at two years and beyond.¹⁰ However, it is important to remember that the design of this trial meant patients could only be randomized if they were considered equally suitable (‘grey area of clinical equipoise') for both bypass surgery and balloon angioplasty. In addition, prosthetic grafts comprised more than 25% of the bypasses in the surgery-first arm, and only a small number of the interventions performed were at the infrapopliteal level. Balloon angioplasty (PTA) must still be considered a relatively unproven therapy for CLI, and currently there is inadequate data (both quantity and quality) to base an OPG for CLI on PTA outcomes. Patients deemed unsuitable for surgical revascularization may be ideal candidates for endovascular approaches; however, data available from pharmacologic and gene therapy trials are limited, and are highly skewed by the extensive selection criteria employed. Conversely, the multicenter datasets available for open bypass surgery in CLI provided a rich source of validated outcomes for generating OPG. These data provide the most suitable current framework for non-randomized comparisons. An RCT approach would be required to directly compare new device technology with PTA alone, or with best medical therapy in non-operative candidates.

Important limitations 

There were few available RCT in the CLI population that could serve as potential sources for this analysis. These trials had limited data in regard to some variables that may have significant impact on outcomes, most especially degree of tissue loss and anatomic extent of disease. In addition to the limitations imposed by patient selection, the use of an open surgery control group did not allow for benchmarking of important adverse events that may be unique to catheter-based therapies. In the same way that wound dehiscence is a uniquely surgical complication, access-related complications (eg, pseudoaneurysm, arteriovenous fistula) for catheter-based approaches cannot be compared with bypass controls, but must be reported in device trials. Most concerning among these is the potential risk of plaque embolization with loss of run-off vessels or additional tissue injury, a complication reported with significant frequency for endovascular procedures such as atherectomy,¹⁶, ¹⁷ and one that may severely impact patient outcomes. The surgical control data did not provide usable information on clinical deterioration (ie, worsening of Rutherford grade). We believe that clinical trials of catheter-based approaches in CLI should report peri-procedural rates of embolization and clinical deterioration, and suggest a framework for defining such endpoints in the Appendix (online only).

We defined a risk stratification scheme based on clinical, anatomic, and conduit availability criteria that were supported by statistical analysis and were felt to be practical for clinical trial execution. We provided specific OPG for defined high-risk cohorts, and others (eg, end-stage renal disease) could be considered with more data. The potential advantages of catheter-based therapies would seem most attractive in a high risk setting. Although not provided in this manuscript, OPG for the complementary low-risk groups (ie, for trials excluding these defined high-risk patients) could be generated from the existing data. It is noteworthy that diabetes was not associated with differential mortality or AFS in the surgical bypass controls, and had a marginal impact on the primary efficacy endpoint.

It should be stressed that these data were compiled from surgical RCTs with broadly inclusive entry criteria, most importantly in regard to tissue loss. The percentage of tissue loss patients was 69%-75% across the three trials and Rutherford 6 category patients were included in all. As tissue loss is one of the more potent variables influencing outcomes in the CLI population, single-arm studies based on these OPG must enroll a similar population to be comparable to these data. Specifically, studies in which Rutherford 6 patients are either excluded or not represented in enrollment can not be compared with the outcomes from these surgical controls. With further data collection from ongoing or future trials, it may be possible to provide additional risk-stratified OPG based on the prevalence and severity of tissue loss in a given CLI cohort.

Efficacy measures in CLI and non-inferiority 

No single efficacy endpoint captures the full impact of revascularization in CLI, and we have pointed out the hazards of non-randomized comparisons for endpoints such as AFS or limb salvage, which may be highly skewed by patient selection. Efficacy of revascularization must be assessed at both limb and patient levels, and is incompletely measured by clinical events such as amputation or reintervention. All survival-based outcomes incorporate only the first clinical event, and therefore do not assess the cumulative burden of multiple procedures or symptom recurrences on the patient. The timing of such events is heavily influenced by clinical judgment of the treating physician. Reporting of the frequency and magnitude of all subsequent interventions is considered critical in the evaluation of new treatments that are fraught by limited durability. We have recognized the difference between minor and major reinterventions in definition of the primary efficacy endpoint. Finally, there are challenges evident in attempting to compare hemodynamic success between open surgery and endovascular therapies, primarily related to established surveillance methodologies on the one hand and a lack thereof in the other. Future trials should incorporate measures of sustained hemodynamic benefit, since this is an objective endpoint directly linked to the efficacy of revascularization. A majority, though not all, of CLI patients meeting the defined entry criteria will experience recrudescence of ischemic symptoms in the limb upon treatment failure, though the timing and severity of presentation may be highly variable. We have suggested a definition for hemodynamic success in CLI (Appendix, online only) and have used the reintervention/amputation/stenosis endpoint from the open surgery data to define an OPG. We recognize the measures are slightly different in derivation, but are sufficiently comparable in our view to justify this approach at this time. Duplex ultrasound is a highly sensitive and validated measure for vein graft disease, and the resulting rate of reintervention and stenosis in the surgical trials are reflected by the low OPG target of 39%. Further refinement of a hemodynamic performance goal for catheter-based therapies in CLI may be attainable with data from future trials utilizing the assessment and reporting standards suggested herein. Other important clinical outcomes in CLI such as wound healing, relief of pain, and level of function suffer from lack of standardization of measures and unavailable or incomplete data.

The definition of non-inferiority for a less invasive treatment strategy is to some degree subjective, and the recommendations provided herein reflect the consensus of the Working Group. In assessing safety measures, we rationalized that outcomes for open surgery should be the upper limit of acceptability for major peri-procedural events. Comparison to a standard PTA group might be more relevant for assessing safety of catheter-based devices; unfortunately, adequate data for the CLI population do not exist. For efficacy, we attempted to strike a balance between reduced invasiveness and durability versus masking potential futility of the test therapy in the absence of randomized controls. Sample size requirements were modeled across a range of non-inferiority margins (0%-5%) for the key efficacy endpoints. We selected an additional 3% buffer in setting the efficacy OPGs, which amounted to a 5%-23% relative increase in allowable event rates in comparison to the open controls. Reducing or eliminating the non-inferiority margin from the all-comers or anatomic high risk cohorts would result in a dramatic increase in the required sample sizes for a single-arm trial, likely rendering the OPG impractical for use.

Comparison to available endovascular data 

Comparison of these suggested OPG to published reports of endovascular treatment of CLI is challenging due to small patient numbers, differences in patient selection, use of multiple therapeutic modalities, variable or inconsistent endpoints, lack of confidence intervals for data, and variable study duration. The LACI (Laser Angioplasty for Critical Limb Ischemia) trial¹⁸ enrolled 145 patients with 155 critically ischemic limbs, 69% of whom presented with tissue loss. Technical success rates were low (85%), and adjunctive stent placement was utilized in 45%. At six months, they reported an amputation-free survival (AFS) point estimate of 82%. Direct comparison to the one-year suggested AFS OPG of 71% is not possible. Bosiers et al presented a series of 51 critically ischemic limbs in 47 patients treated with angioplasty and nitinol (XPert) stents for infrapopliteal disease.¹⁹ The protocol allowed only one or two stents to be deployed, resulting in a mean lesion length of 32.4 mm, and also permitted intervention on a diseased tibial artery in the presence of a second patent tibial artery. The one-year AFS for this cohort was 79%, suggesting that the lower confidence level might fall within the suggested AFS OPG of 68% for high-risk anatomy. However, clinicians should remain cautious of extrapolating these results to the treatment of diffuse tibial disease. Giles²⁰ reported a retrospective series of 163 patients (176 limbs) who underwent infrapopliteal angioplasty for CLI. At one year, the incidence of restenosis, major amputation, or reintervention for the treated limbs was 39% (no confidence interval [CI] reported), comparable to the suggested OPG of 36% for infrapopliteal anatomy. Lastly, we compared outcomes of the BASIL Trial¹⁰ angioplasty arm with the proposed OPGs. For the primary efficacy endpoint, perioperative death or any major adverse limb event in the BASIL angioplasty arm was 68.6% (95% CI, 62.6%-75.1%), failing to meet the OPG of 71%. It is noteworthy, however, that the BASIL results would meet the primary endpoint OPG of 62% for a high-risk conduit subgroup. In summary, comparison of the proposed OPGs to current literature is statistically challenging. However, the latter two examples show that recent angioplasty results may approach or exceed the proposed OPG for selected populations, confirming that the proposed standards are challenging but not insurmountable. Furthermore, new devices for CLI should be expected to outperform standard angioplasty if they are to become a useful and cost-effective clinical tool.

Regulatory environment for CLI and appropriate role for OPGs 

Off-label use of devices in the treatment of peripheral atherosclerosis is currently extensive, and is a by-product of the existing regulatory framework. In many cases, device application is driven by available sizes, sheath, and guide-wire considerations, as opposed to demonstrated safety and efficacy for the clinical condition being treated. A complicating feature is that a given catheter-based device may not be applied, or effective, as a stand-alone therapy. However, we believe that new devices clearly targeting the CLI population should be required to demonstrate specific efficacy in that disease. This should be considered to include any device intended to treat occlusive lesions in the infrapopliteal (tibial or pedal) vessels, for which CLI is the only appropriate clinical indication. Devices seeking approval for use in the superficial femoral artery (SFA) should be limited to appropriate sizes for that vessel, and their extension to smaller, more distal vessels be regulated within the CLI framework suggested. Similarly, safety and efficacy considerations for the coronary circulation are entirely different from those in the periphery.

It is important to reiterate the contrast between these suggested OPG and the development of evidence-based guidelines for clinical practice. OPG are designed to provide a framework for determining appropriate entry of a candidate therapy into the market, meeting the least-burdensome criteria by which FDA regulates medical devices. The optimal role for such therapies in patient care must be based on subsequent clinical investigation. The best evidence to support clinical practice comes from well-executed and adequately powered RCTs, which are sorely lacking in the CLI arena. Such RCTs should employ two years as the minimal observation time for clinical outcomes, and should incorporate the guidelines for cohort definition, risk stratification, endpoint assessments, and outcomes measures suggested herein.

As additional data become available for endovascular treatments in CLI, these OPG are expected to require periodic reassessment and updating. Prospectively collected, validated data employing a uniform approach to cohort definition, surveillance, and endpoint definitions in CLI are sorely needed. The suggestions set forth in this manuscript and the Appendix (online only) provide such a framework.

This work was supported by funding from the Society for Vascular Surgery (SVS). The final report was reviewed and approved by the Document Oversight Committee of the SVS. We thank Anesiva, Inc. (formerly Corgentech), the UK National Health Service (NHS) Research and Development Health Technology Assessment (HTA) programme, Mitsubishi Pharma Corporation, and AnGes Inc. for providing line-item data from their clinical trials for use in this project.^⁎

Back to Article Outline

Author contributions 

Back to Article Outline

Appendix (online only) Suggested critical elements of clinical trial design in CLI 

A. Inclusion/Exclusion Criteria 

CLI is defined as ischemic rest pain or tissue loss, consistent with Fontaine Stages III-IV and Rutherford Classes 4-6. Documentation of severely compromised hemodynamics (ankle <50 mm Hg, toe <30 mm Hg, TcPO2 <30 mm Hg) should be used to verify inclusion of patients with rest pain. For minor tissue loss (Rutherford 5), ankle and toe pressures should be less than 70 mm Hg and 50 mm Hg, respectively. For patients with more extensive tissue loss, either documentation of severely compromised hemodynamics or confirmed absence of pedal pulses should be required.

Patients with acute limb-threatening ischemia, trauma, non-atherosclerotic disease (eg, arteritis), embolic disease, or documented hypercoagulable states should be excluded. Patients with end-stage renal disease (CKD 5) and CLI have markedly inferior survival and limb-related outcomes—therefore they should either be excluded from an all-comers trial or subject to stratification in the design. There is insufficient data upon which to base an OPG for the end-stage renal population.

B. Risk factor profile 

Baseline demographic, comorbidity, and anatomic variables have profound influence on patient mortality, complications, and successful revascularization. All CLI studies should collect and report data on the following key factors:

RCTs should demonstrate adequate balance between arms for these key variables. Non-randomized studies should consider a priori stratification or report data for the following specific subgroups:

Vein quality is a primary determinant of the outcome of surgical revascularization. Therefore, patients lacking adequate saphenous vein are a bona fide subgroup for a test therapy, as demonstrated by the data provided in this manuscript. Definition of such a cohort for exclusive or stratified trial design should incorporate duplex ultrasound vein mapping of both lower extremities. Criteria to establish the conduit high-risk cohort include inadequate length of saphenous vein of sufficient quality (≥3 mm diameter, normal compressibility, absence of morphologic changes suggestive of sclerosis) to construct the planned revascularization. Patients lacking ipsilateral saphenous vein in whom the contralateral extremity is also afflicted by severe peripheral artery disease (Rutherford categories 3-6, ABI <0.5) may be considered for this category if clinical judgment precludes use of the contralateral intact saphenous vein.

C. Suggested assessments 

Follow-up surveillance should be included in any clinical trial evaluating peripheral revascularization. Clinical follow-up routinely includes documentation of pulses, assessment of wounds and healing, evidence of change in symptoms. Noninvasive hemodynamic assessment of the treated limb is essential. Methods of noninvasive assessment include:

The following is suggested as a minimum schedule of vascular assessments in a CLI intervention trial:

Functional and quality of life (QoL) outcomes such as ambulatory status, independent living status, and pain should also be assessed at baseline and during follow-up. There is no gold standard instrument for QoL measurement in the CLI population; the Short Form-36 (SF-36), EuroQol, and VascuQol have been used for this purpose.

D. Suggested definition of hemodynamic failure 

We suggest a definition of hemodynamic failure as an endpoint in future CLI trials, reported in a time-to-event fashion as the first occurrence of any of the following events:

E. Endpoints and reporting 

Peri-procedural complications including death, MACE, amputation, and reinterventions should be reported. Standard surgical complications include bleeding, wound-related morbidity, and reoperations. For catheter-based treatments, access site complications, contrast-induced complications, and evidence of embolization should be reported as key safety outcomes. Embolization events should be classified as either major (loss of a major named branch of the femoral, popliteal, tibial, or pedal vessels; or change in clinical status), or minor (loss of unnamed branches or clinical evidence of diffuse microemboli [ie, “trash foot”]). While improvement in ischemic signs/symptoms may be variable following successful revascularization, clear evidence of deterioration (ie, decline in Rutherford grade from baseline) should be reported.

Follow-up in CLI trials should be for a minimum of one-year, and two years would be preferred based on the results of recent studies. Efficacy measures should include standard endpoints such as death, major amputation, and graft patency. They should also include the following measures:

Endpoints reported should include perioperative death plus any major adverse limb event, AFS, reintervention/amputation, hemodynamic failure, sustained clinical success (freedom from clinical failure). See manuscript text for definitions.

F. Wound healing 

Patients with CLI and non-healing wounds incur pain, disability, and extensive treatments that may be dramatically relieved by effective revascularization. Wound healing is an important measure of clinical success, but is fraught with difficulties as a clinical trial endpoint. Wound care guidelines should be established by protocol to provide uniform care for all subjects in a trial where healing is an endpoint. Ulcers should be photographed at baseline, at three months, six months, and 12 months post-treatment, and prior to revascularization or major amputation. The size of ischemic ulcers at baseline should be reviewed by independent core laboratory and the complete healing of the target ulcers post-treatment should also be confirmed by an independent observer (physician). The duration of complete healing as confirmed by the outside observer should be at least two weeks.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 4 (online only) 

  K-M plot for the primary efficacy endpoint: freedom from perioperative death or any Major Adverse Limb Event (MALE+POD), open surgery controls, full dataset N = 838.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 5 (online only) 

  K-M plot for the key secondary endpoint, amputation-free survival (AFS), open surgery controls, full dataset N = 838.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 6 (online only) 

  K-M plot for the secondary endpoint of freedom from reintervention or amputation (RAO), open surgery controls, full dataset N = 838.

• 
  • View Large Image
  • Download to PowerPoint

• Fig 7 (online only) 

  K-M plot for the secondary endpoint of freedom from reintervention, amputation or stenosis (RAS), open surgery controls, N = 605.

Back to Article Outline

References 

1. Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FG TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg. 2007;45(Suppl S):S5–S67
   • View In Article
   • Full Text
   • Full-Text PDF (1677 KB)
   • CrossRef
2. Chen E, Sapirstein W, Ahn C, Swain J, Zuckerman B. FDA perspective on clinical trial design for cardiovascular devices. Ann Thorac Surg. 2006;82:773–775
   • View In Article
   • CrossRef
3. Grunkemeier GL, Jin R, Starr A. Prosthetic heart valves: Objective Performance Criteria versus randomized clinical trial. Ann Thorac Surg. 2006;82:776–780
   • View In Article
   • CrossRef
4. Goode J, Sapirstein W, Zuckerman B. FDA perspective on clinical trial design for femoropopliteal stent correction of peripheral vascular insufficiency cardiovascular devices. Catheter Cardiovasc Interv. 2007;69:920–921
   • View In Article
   • MEDLINE
   • CrossRef
5. Rocha-Singh KJ, Jaff MR, Crabtree TR, Bloch DA, Ansel G VIVA Physicians, Inc.. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv. 2007;69:910–919
   • View In Article
   • MEDLINE
   • CrossRef
6. Geraghty PJ, Matsumura JS, Conte MS. Premarket assessment of devices for treatment of critical limb ischemia: the role of Objective Performance Criteria and Goals. J Vasc Surg. 2009;50:1459–1461
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (81 KB)
   • CrossRef
7. Conte MS, Bandyk DF, Clowes AW, Moneta GL, Seely L, Lorenz TJ, et al. Results of PREVENT III: a multicenter, randomized trial of edifoligide for the prevention of vein graft failure in lower extremity bypass surgery. J Vasc Surg. 2006;43:742–751
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (205 KB)
   • CrossRef
8. Brass EP, Anthony R, Dormandy J, Hiatt WR, Jiao J, Nakanishi A, et al. Circulase Investigators Parenteral therapy with lipo-ecraprost, a lipid-based formulation of a PGE1 analog, does not alter six-month outcomes in patients with critical leg ischemia. J Vasc Surg. 2006;43:752–759
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (264 KB)
   • CrossRef
9. Nehler MR, Brass EP, Anthony R, Dormandy J, Jiao J, McNamara TO, et al. Adjunctive parenteral therapy with lipo-ecraprost, a prostaglandin E1 analog, in patients with critical limb ischemia undergoing distal revascularization does not improve 6-month outcomes. J Vasc Surg. 2007;45:953–960discussion 960-1
   • View In Article
   • Abstract
   • Full Text
   • Full-Text PDF (190 KB)
   • CrossRef
10. Adam DJ, Beard JD, Cleveland T, Bell J, Bradbury AW, Forbes JF, et al. BASIL trial participants Bypass versus angioplasty in severe ischaemia of the leg (BASIL): multicentre, randomised controlled trial. Lancet. 2005;366:1925–1934
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (125 KB)
    • CrossRef
11. Bradbury A, Wilmink T, Lee AJ, Bell J, Prescott R, Gillespie I, et al. Bypass versus angioplasty to treat severe limb ischemia: factors that affect treatment preferences of UK surgeons and interventional radiologists. J Vasc Surg. 2004;39:1026–1032
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (99 KB)
    • CrossRef
12. Powell RJ, Dormandy J, Simons M, Morishita R, Annex BH. Therapeutic angiogenesis for critical limb ischemia: design of the hepatocyte growth factor therapeutic angiogenesis clinical trial. Vasc Med. 2004;9:193–198
    • View In Article
    • MEDLINE
    • CrossRef
13. Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, et al. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008;118:58–65
    • View In Article
    • CrossRef
14. Conte MS, Lorenz TJ, Bandyk DF, Clowes AW, Moneta GL, Seely BL. Design and rationale of the PREVENT III clinical trial: edifoligide for the prevention of infrainguinal vein graft failure. Vasc Endovascular Surg. 2005;39:15–23
    • View In Article
    • MEDLINE
    • CrossRef
15. Schanzer A, Hevelone N, Owens CD, Belkin M, Bandyk DF, Clowes AW, et al. Technical factors affecting autogenous vein graft failure: observations from a large multicenter trial. J Vasc Surg. 2007;46:1180–1190discussion 1190
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (438 KB)
    • CrossRef
16. Lam RC, Shah S, Faries PL, McKinsey JF, Kent KC, Morrissey NJ. Incidence and clinical significance of distal embolization during percutaneous interventions involving the superficial femoral artery. J Vasc Surg. 2007;46:1155–1159
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (218 KB)
    • CrossRef
17. Shammas NW, Dippel EJ, Coiner D, Shammas GA, Jerin M, Kumar A. Preventing lower extremity distal embolization using embolic filter protection: results of the PROTECT registry. J Endovasc Ther. 2008;15:270–276
    • View In Article
    • CrossRef
18. Laird JR, Zeller T, Gray BH, Scheinert D, Vranic M, Reiser C, et al. Limb salvage following laser-assisted angioplasty for critical limb ischemia: results of the LACI multicenter trial. J Endovasc Ther. 2006;13:1–11
    • View In Article
    • MEDLINE
    • CrossRef
19. Bosiers M, Deloose K, Verbist J, Peeters P. Nitinol stenting for treatment of “below-the-knee” critical limb ischemia: 1-year angiographic outcome after Xpert stent implantation. J Cardiovasc Surg (Torino). 2007;48:455–461
    • View In Article
20. Giles KA, Pomposelli FB, Hamdan AD, Blattman SB, Panossian H, Schermerhorn ML. Infrapopliteal angioplasty for critical limb ischemia: relation of TransAtlantic InterSociety Consensus class to outcome in 176 limbs. J Vasc Surg. 2008;48:128–136
    • View In Article
    • Abstract
    • Full Text
    • Full-Text PDF (254 KB)
    • CrossRef
21. 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
22. 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

• ⁎ Independent peer-review and oversight has been provided by members of the SVS Document Oversight Committee (K. Wayne Johnston (chair), Enrico Ascher, Jack L. Cronenwett, R. Clement Darling, Vivian Gahtan, Peter Gloviczki, Thomas F. Lindsay, Gregorio A. Sicard)