Vascular Quality Initiative (VQI) - Data Extraction and Longitudinal Trend Analysis (DELTA) Paclitaxel Device Safety Analysis - Phase I Study
Conditions: Peripheral Vascular Disease
Sponsor: Lahey Clinic

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VQI-DELTA Paclitaxel Device Safety Analysis – Phase I Study Protocol 
Version: 1.10   
 
 
 
 
 
 
Updated:   May 5, 2020  
Principle Investigators:   Daniel Bertges MD, Jens Jorgensen MD and Frederic S. Resnic, 
MD MSc 
 
1.0  Background:    
In December 2018, a meta-analysis published by Katsanos and colleagues identified an 
association between the use of paclitaxel drug coated balloons (DCB) or drug eluting 
stents (DES) in the treatment of peripheral arterial disease (PAD) and increased mortality 
at two and five years after treatment, when compared to patients treated with non 
paclitaxel-coated or eluting devices1.  After further investigation of the available data, the 
FDA advised physicians to inform patients of this reported risk and consider  alternatives 
to paclitaxel devices in the treatment of PAD. The FDA has initiated additional review of 
the mortality signal and convened an Advisory Panel.   
Since 2004, the Society of Vascular Surgeons has collected detailed clinical data 
regarding the treatment of PAD through the Vascular Quality Initiative (VQI).   Today, 
VQI collects data from over 550 hospitals in North America, and contains over 575,000 
individual patient records.   The VQI Peripheral Vascular Intervention Registry (PVI)  
module was launched in 2010 and began  capturing device identifier information in the 
fall of 2016 with linkage to the Global Unique Device Identification Database (GUDID).   
The PVI registry has established a linkage to the Social Security Death Index file in order 
to ascertain vital status in a longitudinal manner.   As such, the VQI-PVI registry may 
serve as a unique and representative data source for assessing the long-term safety of 
Paclitaxel DCB and DES.   
The Data Extraction and Longitudinal Trend Analysis (DELTA) surveillance system was 
developed to monitor ongoing clinical datasets in an effort improve the efficiency of 
identifying potential medical device safety concerns.  DELTA has been previously 
validated for prospective monitoring of clinical registries and clinical data sets and is 
available as an open source software tool with associated technical documentation 2-5. 
The VQI-DELTA Paclitaxel Device Safety Analysis seeks to assess the comparative 
safety of paclitaxel coated balloons and stents in the treatment of PAD through analysis 
of the Vascular Quality Initiative (VQI) Peripheral Vascular Intervention (PVI) registry 
module using the DELTA system.   
As a National Evaluation System for health Technology (NEST) demonstration project 
the Registry Assessment of Peripheral Devices (RAPID) is a private public partnership of 
academia, industry and governmental regulatory agencies dedicated to the improving the 
national evaluation of peripheral arterial devices throughout the total product lifecycle. 
RAPID has convened the RAPID Pathways Working Group to address issues related to 
paclitaxel in a framework that will improve future device evaluation. The VQI DELTA 
Paclitaxel Device Safety Analysis will be conducted in communication with the RAPID 
Pathways initiative. 
 

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2.0  Study Objectives:    
1. The objective of the VQI – DELTA Paclitaxel Study is to evaluate the relative 
safety of Paclitaxel used as an antiproliferative agent in the treatment of 
symptomatic PAD.   We will analyze Paclitaxel Drug Coated Balloons (DCB) and 
Paclitaxel Drug Eluting Stents (DES), both together and as unique exposures 
using propensity score matched survival analysis.     
2. If a mortality signal is detected we will then analyze factors associated with 
mortality. 
3.0  Active Surveillance System:  All proposed analyses will be performed using 
DELTA v3.65 which has the capability to prospectively monitor clinical data repositories 
for safety signals, and is designed to support risk-adjusted prospective safety surveillance 
analyses of complex clinical datasets.   
4.0  Data Source and Limitations:   All proposed analyses will be performed using VQI 
PVI dataset to maximize consistency of outcome and clinical covariate definitions6.   
Limitations include incomplete linkage to the SSDI because social security numbers are 
not universally available to the VQI PVI registry. This limitation is partly mitigated by 
the ability to ascertain survival status through VQI center reporting directly to the 
registry. While capture of patient, lesion and treatment variables is generally complete for 
the index procedure some covariates may have missing data. While the VQI mandates 
consecutive procedure capture there is obligate time lag for centers to perform audits 
against their claims data. 
5.0  Scientific Oversight Committee:   At the initiation of the project, a study oversight 
committee will be established including two representatives from VQI (Drs. Eldrup-
Jorgensen and Bertges) and two representatives from the DELTA data analysis center 
(Drs. Resnic and Matheny), two representatives from FDA (Misti Malone, PhD, Danica 
Marinac-Dabic, MD, PhD) and two representatives from the peripheral vascular device 
manufacturer industry (Joshua Smale, BS, Aaron Lottes, PhD, MBA). The study 
oversight committee will be responsible for the approval of the study protocol, will have 
oversight of the overall performance and execution of the study, will propose any 
additional exploratory (post-hoc) analyses, and approve any proposed publications 
resulting from the project.   
6.0  Devices of Interest:  The proposed safety analyses will evaluate two classes of 
paclitaxel coated  interventional devices used to treat PAD  and compare patient 
outcomes with propensity score matched patients of similar risk who receive alternative 
devices within the same calendar quarter of the case implant.  The primary outcome will 
be freedom from death using a propensity matched survival analysis approach.   Three 
principle analyses are planned:   
a) Paclitaxel DCB (including the Bard Lutonix, Medtronic In.Pact and Philips 
Spectranetics Stellarex DCB’s) as compared with propensity matched patients 
treated with plain balloons.  

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b) Paclitaxel delivering DES (including the Cook Zilver PTX and Boston Scientific 
Eluvia DES) as compared with propensity matched cases using bare metal stents 
(BMS).  
c) Patients treated with either Paclitaxel DCB or Paclitaxel DES compared with 
propensity matched controls (with DCB patients matched to patients treated with 
plain balloons, and DES patients matched to patients treated with BMS. Matches 
will be retained from the individual device cohort analyses). 
Note that this analysis is planned at the device class level and is not intended to compare 
early or late mortality between specific devices or brands. 
7.0  Missing Data:  Based on previous data quality audits of VQI Registry , it is 
anticipated that less than 3% of all data to be used in the VQI- DELTA Paclitaxel study 
will be missing from the limited dataset.  If missing data represents less than 3% of the 
total dataset, simple imputation methods will be used, substituting missing data with 
median gender-specific values for continuous variables, and assuming “negative” results 
for dichotomous variables.    If missing data represents >3.0% of any covariate used in 
the propensity score match model (see below), the Study Oversight Committee will 
determine the most appropriate manner to handle missing data, including consideration of 
multivariate imputation methods or case-wise deletion.   
8.0  Patient Inclusion and Exclusion Criteria:  All patients, age 18 or older, who 
underwent endovascular interventional treatment of the femoral or popliteal arteries for 
symptomatic PAD between 1/1/17 and 4/1/2020 will be candidates for inclusion in the 
analyses.   See Figure 1 for case inclusion diagram.   
In an effort to focus this safety evaluation on those patients being treated in accordance 
with accepted ‘best practice’ endovascular intervention strategies and ‘on-label’ use of 
devices, patients will be excluded if they received a balloon expandable stent or a balloon 
expandable stent graft in the treatment of femoral or popliteal disease.  Balloon 
expandable stents will be excluded because current best practice favors placement of self-
expanding nitinol stents which were engineered for the femoral popliteal segment and 
tested in multiple trials for this indication 7-9. 
Patients will also be excluded (as either potential cases or controls) if their index 
procedure was performed for acute limb ischemia as compared with chronic conditions as 
they have different treatment strategies and higher major amputation and mortality rates 
as compared with conventional use of PVI for chronic ischemic conditions10-14.   In 
addition, patients with prior angioplasty or stenting of the SFA-popliteal segment will be 
excluded in order to avoid the possibility of improperly assigning paclitaxel exposure to 
the control group. 
Control patients for each of exposure groups will be selected as follows.  For the DCB, 
control patients will be selected from patients treated with “plain balloon” therapies, and 
will exclude those patients treated with any form of stent (including non-Paclitaxel DES, 
self-expanding or covered stents).    Control patients for the Paclitaxel DES analyses will 

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be selected from those patients receiving bare metal self-expanding stents (BSES) with or 
without concomitant plain balloon angioplasty.  
Second and later procedures 
The primary analysis will consider the first procedure recorded in the VQI PVI registry as 
the qualifying index procedure.  Should patients with a first treatment that is not 
paclitaxel and has a subsequent paclitaxel device treatment, the paclitaxel case will be 
considered the index case for that patient.   
 
9.0  Endpoint Definitions:   The primary safety outcome of interest is survival (freedom 
from death from any cause) at 2 years post intervention in three cohorts of patients:   
a) Patients treated with paclitaxel DCB,  
b) Patients treated with paclitaxel DES and  
c) Patients treated with either paclitaxel DCB or DES analyzed together.     
 
See Figure 1 for case/control identification and association with mortality.  
The secondary efficacy endpoint is the composite endpoint of Intervention Success at 2 
years defined as the freedom from death (from any cause), retreatment of the target limb 
or major amputation at 2 years.   An additional secondary efficacy endpoint will be 
successful ambulation at 1 year post treatment.        
 
 

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Figure 1:  Case Inclusion of exposures and controls.   Panel A: Paclitaxel drug coated 
balloon analysis, Panel B: Paclitaxel drug eluting stent analysis and Panel C: Any 
Paclitaxel Device.    
 
 
 

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10.0  Statistical Methodology:     
10.1   Propensity Score Model Development:   Patients receiving a device of interest 
(either DCB or DES) will be matched with control patients (those receiving any 
traditional balloon or BMS respectively) who had undergone an interventional procedure 
during the same  calendar quarter, in a 1:1 ratio based on propensity score matching using 
a non-parsimonious propensity model as described below.     
A propensity score (i.e. probability of receiving the interventional device of interest) for 
each patient will be calculated using the propensity score model via logit estimation.     
The propensity score model itself will be recalibrated with each new cumulative analysis 
performed.   Ordering of patients will be randomized before each match procedure, 
control patients will not be allowed to match to more than 1 exposure (no replacement) 
and no common-support will be imposed during matching.   
10.2   Variable Selection for Propensity Score Matching:   Covariates will be included in 
the propensity score model if they were available to the treating physician at the time the 
index intervention, are considered to be associated with the outcomes of interest based on 
prior published research, or plausibly related to the selection of the interventional device 
(based on expert opinion).    
Proposed variables to be considered for inclusion in the propensity score match model   
include:        
• Age 
• Male Gender 
• Current smoker 
• BMI 
• History of hypertension 
• History of diabetes 
• History of Coronary artery disease 
• Positive Pre-procedural Cardiac Stress Test 
• History of heart failure 
• History of COPD 
• Renal Insufficiency (defined as creatinine > 2.0mg/dL) 
• Dialysis dependent   
• Poor pre-operative functional status 
• Poor pre-operative ambulation  
• Procedural indication for critical limb ischemia 
o Claudication 
o Critical Limb Ischemia – Rest Pain 
o Critical Limb Ischemia – Tissue Loss 
• Presence of active infection in treated limb 
• Emergent procedural status 

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• Treatment length 
• Treatment for chronic occlusion 
Variables will be excluded if they are found to be co-linear with covariates already 
included in the propensity score model.   To guard against the possibility of the model 
being unable to converge due to quasi-complete (or complete) separation, we will 
calculate linear Variance Inflation Factor (VIF) for each candidate covariate, excluding 
from the model any covariate with VIF>8, and further assessing any covariate with a VIF 
>4.15   For this latter group, we will review the correlation to identify those covariates that 
were highly correlated (with correlation coefficient > 0.80) and eliminate one of the two 
highly correlated covariates.    
In addition to guarding against co-linearity, the number of variables will be limited to 
prevent potential instability in the propensity score model through the inclusion of “too 
many” covariates.   We will therefore estimate the number of maximum candidate 
covariates to include by calculating the total number of composite outcomes during the 
first 12 months of accumulating data, and dividing this total by 416. 
10.3    Propensity Score Matching and Survival Analysis:   Matched controls will be 
selected as the nearest-neighbor in a 1:1 ratio from all patients who underwent 
endovascular treatment of PAD during the calendar quarter as the interventional 
treatment of interest (either DCB or DES), using a fixed caliper width of 0.2 SD of the 
logit of propensity score4, 17, 18 using a greedy matching algorithm.   Separate propensity 
score (and matches) will be developed for the DCB and DES analyses.  
The adequacy of the propensity score match model will be assessed by analyzing the 
distribution of risk factors between cohorts.  A propensity score match will be considered 
adequate for all post-match percent standardized differences less than a 0.10 threshold. 
 10.4   DELTA Alerts:   To determine whether any (potentially) observed difference in the 
survival is meaningful we will prospectively establish both a requirement for 
demonstration of statistical significance in the estimated survival function as well as the 
requirement that the magnitude of difference between the performance of the propensity 
score matched controls. Any deviation will be considered meaningful enough to possibly 
warrant further review.    
DELTA alerts will be triggered if the Kaplan-Meier survival probability curve for the 
device of interest (“case”) demonstrates a “clinically meaningful” increased risk of 
mortality, as defined by an increased mortality at 2 years ≥ 50% than the survival rate 
of the alternative (“control”) population, with a final survival analysis Log Rank test 
significant at the p=0.05 level19.     
 

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10.5  Sample Size Expectation and Estimated Statistical Power:  Based on case counts 
(without further exploration of the VQI dataset), annual mortality following femoral-
popliteal endovascular intervention was observed to be 12.1%.   We anticipate a total 
sample of 5,700 paclitaxel DES and 25,200 paclitaxel DCB treated patients would be 
captured by 4/1/2020, with 1,865 PTX-DES and 8,250 PTX-DCB patients having been 
followed for a minimum of 2 years.   Further conservatively assuming 90% match with 
non-paclitaxel treated patients, the statistical power to detect a 50% increase in mortality 
at 5 years, given α=0.05, exceeds 99% for each of the three primary analyses.   
10.6   Pre-specified subgroups::    Pre-specified subgroups will be explored through 
independent propensity score match analyses for any evidence of uniquely increased risk 
of mortality.  These subgroups will include:  age <70yr versus ≥70yrs, female gender, 
patients on dialysis, and patients with cardiac history (including CAD, CHF or a positive 
stress test).    Similarly, the three primary analyses will be further explored through 
analysis of the subgroup of patients treated for critical limb ischemia will be analyzed 
separately from those patients treated for intermittent claudication. 
Additionally, the association between discharge statin medications and treatment with 
Paclitaxel devices will be explored, as well as the potential relationship between 
treatment with optimal medical therapy (discharge medications including statin, aspirin 
+/- P2Y12 inhibitor agent) and mortality.     
10.7   Falsification Hypothesis Analysis:  A pre-specified falsification-hypothesis 
analysis will performed to assess the extent of residual confounding after propensity 
score matching.  For each of the exposures of interest, we will evaluate matched patient 
cohorts for the documentation of resuming smoking on follow up evaluation.   Continued 
active smoking is anticipated to be independent of the selection of the specific 
interventional device, and is therefore an appropriate Falsification Hypothesis candidate 
outcome.  If the falsification hypothesis demonstrates no evidence for residual 
confounding through finding similar rates of smoking in follow up, we will conclude that 
the propensity score match was robust in minimizing residual confounding.   
 
 
 

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11.0   Study Analysis and Final Report:    It is anticipated that the final report will 
serve as the basis for at least one manuscript that will be prepared within 6 months of the 
completion of the analysis and submitted for publication in peer reviewed journal.    
Members of the committee will be invited to participate in the writing and review of each 
of the proposed manuscripts.   Additional, post-hoc and exploratory analyses may be 
deemed suitable for inclusion in additional manuscripts, on the approval of the study 
steering committee.   
 
12.0    Human Subjects Institutional Review:   All study related materials will be 
submitted for IRB review and approval per the institutional requirements of VQI and 
Lahey Clinic.    
 
 
 

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13.0   References 
 
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2. 
Resnic FS, Majithia A, Marinac-Dabic D, et al. Registry-Based Prospective, 
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Kumar A, Matheny ME, Ho KK, et al. The data extraction and longitudinal trend 
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Endovasc Ther. Feb 2009;16 Suppl 1:I147-152. 
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